%0 Journal Article %~ PubMed %A Wang, Guan %A Mikami, Eri %A Chiu, Li-Ling %A de Perini, Alessandra %A Deason, Michael %A Fuku, Noriyuki %A Miyachi, Motohiko %A Kaneoka, Koji %A Murakami, Haruka %A Tanaka, Masashi %A Hsieh, Ling-Ling %A Hsieh, Sandy S %A Caporossi, Daniela %A Pigozzi, Fabio %A Hilley, Alan %A Lee, Rob %A Galloway, Stuart D R %A Gulbin, Jason %A Rogozkin, Viktor A %A Ahmetov, Ildus I %A Yang, Nan %A North, Kathryn N %A Ploutarhos, Saraslanidis %A Montgomery, Hugh E %A Bailey, Mark E S %A Pitsiladis, Yannis P %T Association analysis of ACE and ACTN3 in Elite Caucasian and East Asian Swimmers. %B Medicine and Science in Sports and Exercise %D 2013 %C United States %I Lippincott Williams & Wilkins %V 45 %N 5 %P 892-900 %@ 0195-9131 %X %Z FOR Codes: 111403 60410 %0 Journal Article %~ PubMed %A Payne, Jonathan M %A Barton, Belinda %A Shores, E Arthur %A North, Kathryn N %T Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials. %B Journal of Neurology %D 2013 %C Germany %I Springer Medizin %V 260 %N 1 %P 214-220 %@ 1432-1459 %X Studies investigating behavior in mice with a heterozygous null mutation of the NF1 gene (Nf1 (+/-)) have provided critical insights into the molecular and cellular mechanisms underlying cognitive impairments associated with neurofibromatosis type 1 (NF1). Hyperactivation of the Ras-MAPK signaling cascade, which results in increased GABA-mediated inhibition and significantly reduced long-term potentiation, has been proposed as a core mechanism underlying Nf1 (+/-) mice deficits in visuospatial learning and attention. This assertion has been reinforced by preclinical trials that reveal that these impairments can be rescued both at a cognitive and cellular level. We attempted to demonstrate a phenotypic parallel between Nf1 (+/-) mice and children with NF1 using a well-validated measure of visuospatial learning. Children with NF1 (n??=??71) and healthy controls (n??=??29) were assessed on a computerized paired associate learning task. Interrelationships between visuospatial learning and other cognitive abilities that may influence performance, such as intelligence, attention and visuospatial function, were explored. Children with NF1 displayed significant impairments in visuospatial learning, with reduced initial retention and poorer learning across repeated trials. Importantly, we demonstrated that visuospatial learning was inferior in NF1 even after accounting for group differences in intelligence, sustained attention and visuospatial abilities. We have thus identified impaired visuospatial learning as a core phenotypic feature in children with NF1. These findings imply that hippocampal-based learning networks are dysfunctional in children with NF1 and provide validation for a primary outcome measure for clinical trials aiming to correct aberrant Ras signaling. %Z FOR Codes: 170101 111403 60410 %0 Journal Article %~ PubMed %A Fitzsimons, David A %A Jones, David L %A Barton, Belinda %A North, Kathryn N %T A procedure for the computerised analysis of cleft palate speech transcription. %B Clinical Linguistics & Phonetics %D 2012 %C United Kingdom %I Informa Healthcare %V 26 %N 1 %P 18-38 %@ 1464-5076 %X The phonetic symbols used by speech-language pathologists to transcribe speech contain underlying hexadecimal values used by computers to correctly display and process transcription data. This study aimed to develop a procedure to utilise these values as the basis for subsequent computerized analysis of cleft palate speech. A computer keyboard file and a modified font file were developed using symbols from the International Phonetic Alphabet and extensions to the International Phonetic Alphabet to improve the computerized storage of phonetic symbols used in cleft palate speech transcription. Computerized coding procedures were written to retrieve hexadecimal values of transcribed symbols and match these to their phonetic attributes as defined in the International Phonetic Alphabet and extensions to the International Phonetic Alphabet. Computerized procedures were subsequently developed to analyse transcription data based on these matched hexadecimal values and their associated phonetic attributes, with respect to cleft palate speech. This method will be a useful addition to existing computerized speech analysis tools. %Z FOR Codes: 1114 1109 80107 80107 %0 Journal Article %~ PubMed %A Oates, Emily C %A Reddel, Stephen %A Rodriguez, Michael L %A Gandolfo, Luke C %A Bahlo, Melanie %A Hawke, Simon H %A Lamand??, Shireen R %A Clarke, Nigel F %A North, Kathryn N %T Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells. %B Brain %D 2012 %C United States %I Oxford University Press %V 135 %N Pt 6 %P 1714-1723 %@ 1460-2156 %X Autosomal dominant congenital spinal muscular atrophy is characterized by predominantly lower limb weakness and wasting, and congenital or early-onset contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown. It has been hypothesized that differences in the timing and site of anterior horn cell loss in the central nervous system account for the variations in clinical phenotype between different forms of spinal muscular atrophy, but there has been a lack of neuropathological data to support this concept in dominant congenital spinal muscular atrophy. We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a reduction in anterior horn cell number in the lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the ventral nerve roots at these levels, in the absence of additional peripheral nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young age of the child at the time of autopsy, there was no pathological evidence of ongoing loss or degeneration of anterior horn cells suggesting that anterior horn cell loss in dominant congenital spinal muscular atrophy occurs in early life, and is largely complete by the end of infancy. These findings confirm that dominant congenital spinal muscular atrophy is a true form of spinal muscular atrophy caused by a loss of anterior horn cells localized to lumbar and cervical regions early in development. %Z FOR Codes: 111403 110904 60410 %0 Journal Article %~ PubMed %A Biancalana, Valérie %A Beggs, Alan H %A Das, Soma %A Jungbluth, Heinz %A Kress, Wolfram %A Nishino, Ichizo %A North, Kathryn %A Romero, Norma B %A Laporte, Jocelyn %T Clinical utility gene card for: Centronuclear and myotubular myopathies. %B European Journal of Human Genetics %D 2012 %C United Kingdom %I Nature Publishing Group %V 20 %N 10 %P 0 %@ 1476-5438 %X %Z FOR Codes: 111403 60410 110904 %0 Journal Article %~ PubMed %A Wang, Ching H %A Dowling, James J %A North, Kathryn %A Schroth, Mary K %A Sejersen, Thomas %A Shapiro, Frederic %A Bellini, Jonathan %A Weiss, Hali %A Guillet, Marc %A Amburgey, Kimberly %A Apkon, Susan %A Bertini, Enrico %A Bonnemann, Carsten %A Clarke, Nigel %A Connolly, Anne M %A Estournet-Mathiaud, Brigitte %A Fitzgerald, Dominic %A Florence, Julaine M %A Gee, Richard %A Gurgel-Giannetti, Juliana %A Glanzman, Allan M %A Hofmeister, Brittany %A Jungbluth, Heinz %A Koumbourlis, Anastassios C %A Laing, Nigel G %A Main, Marion %A Morrison, Leslie A %A Munns, Craig %A Rose, Kristy %A Schuler, Pamela M %A Sewry, Caroline %A Storhaug, Kari %A Vainzof, Mariz %A Yuan, Nanci %T Consensus statement on standard of care for congenital myopathies. %B Journal of Child Neurology %D 2012 %C United States %I Sage Publications, Inc. %V 27 %N 3 %P 363-382 %@ 1708-8283 %X Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee''s recommendations for symptom assessments and therapeutic interventions. It is the committee''s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome. %Z FOR Codes: 1114 %0 Book Section %A Waddell, Leigh %A Evesson, Frances J %A North, Kathryn %A Cooper, Sandra %A Clarke, Nigel %T Diagnosis of the Muscular Dystrophies %B Muscular Dystrophy %D 2012 %C Croatia %I InTech %V %N %P 261-288 %@ 9789535106036 %E Hegde, Madhuri %E Ankala, Arunkanth %X %Z FOR Codes: 110603 %0 Journal Article %~ PubMed %A Payne, Jonathan M %A Arnold, Shelley S %A Pride, Natalie A %A North, Kathryn N %T Does attention-deficit-hyperactivity disorder exacerbate executive dysfunction in children with neurofibromatosis type 1? %B Developmental Medicine and Child Neurology %D 2012 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 54 %N 10 %P 898-904 %@ 0012-1622 %X Aim??? Although approximately 40% of children with neurofibromatosis type 1 (NF1) meet diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD), the impact of ADHD on the executive functioning of children with NF1 is not understood. We investigated whether spatial working memory and response inhibition are impaired in children with NF1 without a diagnosis of ADHD and whether executive deficits are exacerbated in children with a comorbid diagnosis. Method??? Forty-nine children aged 7 to 15???years with NF1 only (31 males, 18 females; mean age 11y, SD 2y 4mo) or 35 with NF1 and ADHD (18 males, 17 females; mean age 10y 8mo, SD 2y 4mo) and 30 typically developing comparison children (16 males, 14 females; mean age 10y, SD 2y 8mo) were compared on measures of spatial working memory and response inhibition. Group differences in IQ and visuospatial ability were controlled for as required. Results??? Compared with typically developing children, children with NF1 with or without comorbid ADHD demonstrated significant impairment of both spatial working memory (both p<0.004) and inhibitory control (both p<0.010). There were, however, no differences between the two NF1 groups in spatial working memory (p=0.91) or response inhibition (p=0.78). Interpretation??? Executive dysfunction occurs with the same severity in children with NF1, whether or not they have a comorbid diagnosis of ADHD, suggesting that executive impairments are not unique contributors to ADHD symptomatology in NF1. The findings are discussed within the context of recent evidence in Nf1 optic glioma (OPG) mice, in which a mechanistic connection between NF1 gene expression, executive system failure, and dopaminergic pathway integrity has been established. %Z FOR Codes: 111403 60410 170101 %0 Journal Article %~ PubMed %A Lek, Angela %A Evesson, Frances J %A Sutton, R Bryan %A North, Kathryn N %A Cooper, Sandra T %T Ferlins; regulators of vesicle fusion for auditory neurotransmission, receptor trafficking and membrane repair. %B Traffic %D 2012 %C United States %I Wiley-Blackwell Publishing, Inc. %V 13 %N 2 %P 185-194 %@ 1600-0854 %X Ferlins are a family of multiple C2 domain proteins with emerging roles in vesicle fusion and membrane trafficking. Ferlin mutations are associated with muscular dystrophy (dysferlin) and deafness (otoferlin) in humans, and infertility in C.elegans (Fer-1) and Drosophila (misfire), demonstrating their importance for normal cellular functioning. Ferlins show ancient origins in eukaryotic evolution and are detected in all eukaryotic kingdoms, including unicellular eukaryotes and apicomplexian protists, suggesting origins in a common ancestor predating eukaryotic evolutionary branching. The characteristic feature of the ferlin family is their multiple tandem cytosolic C2 domains (5-7 C2 domains), the most of any protein family, and an extremely rare feature amongst eukaryotic proteins. Ferlins also bear a unique nested DysF domain, and small conserved 60-70 residue ferlin-specific sequences (Fer domains). Ferlins segregate into two subtypes based on the presence (Type I ferlin) or absence (Type II ferlin) of the DysF and FerA domains. Ferlins have diverse tissue-specific and developmental expression patterns, with ferlin animal models united by pathologies arising from defects in vesicle fusion. Consistent with their proposed role in vesicle trafficking, ferlin interaction-partners include cytoskeletal motors, other vesicle-associated trafficking proteins, and transmembrane receptors or channels. Herein we summarize the research history of the ferlins, an intriguing family of structurally conserved proteins with a preserved ancestral function as regulators of vesicle fusion and receptor trafficking. %Z FOR Codes: 111403 110904 60410 %0 Journal Article %~ PubMed %A Menezes, M P %A Waddell, L B %A Evesson, F J %A Cooper, S %A Webster, R %A Jones, K %A Mowat, D %A Kiernan, M C %A Johnston, H M %A Corbett, A %A Harbord, M %A North, K N %A Clarke, N F %T Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy. %B Neurology %D 2012 %C United States %I Lippincott Williams & Wilkins %V 78 %N 16 %P 1258-1263 %@ 1526-632X %X To identify the most useful clinical and histologic markers that facilitate early diagnosis in LMNA-related muscular dystrophy and to assess the usefulness of Western blotting (WB) for lamin A/C. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Menezes, Manoj P %A North, Kathryn N %T Inherited neuromuscular disorders: Pathway to diagnosis. %B Journal of Paediatrics and Child Health %D 2012 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 48 %N 6 %P 458-465 %@ 1034-4810 %X Muscle weakness in childhood can be caused by a lesion at any point extending from the motor cortex, brainstem and spinal cord to the anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A comprehensive history and physical examination is essential to aid classification of the neuromuscular disorder and direct gene testing. The more common disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy and facioscapulohumeral dystrophy may be diagnosed on direct gene testing based on the history and clinical examination. The congenital myopathies are classified based on structural abnormalities on muscle biopsy, while protein abnormalities on immunohistochemistry and immunoblotting aid classification of the muscular dystrophies. In this review, we provide an approach to diagnosis of a child with weakness, with a focus on the inherited neuromuscular disorders, and the features on history, examination and investigation that help to distinguish between them. %Z FOR Codes: 111403 110904 110905 %0 Journal Article %~ PubMed %A Clarke, Nigel F %A Waddell, Leigh B %A Sie, Lilian T L %A van Bon, Bregje W M %A McLean, Catriona %A Clark, Damian %A Kornberg, Andrew %A Lammens, Martin %A North, Kathryn N %T Mutations in TPM2 and congenital fibre type disproportion. %B Neuromuscular Disorders %D 2012 %C United Kingdom %I Elsevier Ltd %V 22 %N 11 %P 955-958 %@ 1873-2364 %X The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small ''caps'' were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis. %Z FOR Codes: 111403 60410 110904 %0 Journal Article %~ PubMed %A Kalamarides, Michel %A Acosta, Maria T %A Babovic-Vuksanovic, Dusica %A Carpen, Olli %A Cichowski, Karen %A Evans, D Gareth %A Giancotti, Filippo %A Hanemann, C Oliver %A Ingram, David %A Lloyd, Alison C %A Mayes, Debra A %A Messiaen, Ludwine %A Morrison, Helen %A North, Kathryn %A Packer, Roger %A Pan, Duojia %A Stemmer-Rachamimov, Anat %A Upadhyaya, Meena %A Viskochil, David %A Wallace, Margret R %A Hunter-Schaedle, Kim %A Ratner, Nancy %T Neurofibromatosis 2011: a report of the Children's Tumor Foundation annual meeting. %B Acta Neuropathologica %D 2012 %C Germany %I Springer %V 123 %N 3 %P 369-380 %@ 1432-0533 %X The 2011 annual meeting of the Children''s Tumor Foundation, the annual gathering of the neurofibromatosis (NF) research and clinical communities, was attended by 330 participants who discussed integration of new signaling pathways into NF research, the appreciation for NF mutations in sporadic cancers, and an expanding pre-clinical and clinical agenda. NF1, NF2, and schwannomatosis collectively affect approximately 100,000 persons in US, and result from mutations in different genes. Benign tumors of NF1 (neurofibroma and optic pathway glioma) and NF2 (schwannoma, ependymoma, and meningioma) and schwannomatosis (schwannoma) can cause significant morbidity, and there are no proven drug treatments for any form of NF. Each disorder is associated with additional manifestations causing morbidity. The research presentations described in this review covered basic science, preclinical testing, and results from clinical trials, and demonstrate the remarkable strides being taken toward understanding of and progress toward treatments for these disorders based on the close interaction among scientists and clinicians. %Z FOR Codes: 111403 60410 %0 Journal Article %~ PubMed %A Johnson, K J %A Fisher, M J %A Listernick, R L %A North, K N %A Schorry, E K %A Viskochil, D %A Weinstein, M %A Rubin, J B %A Gutmann, D H %T Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway gliomas. %B Familial Cancer %D 2012 %C Netherlands %I Springer Netherlands %V 11 %N 4 %P 653-656 %@ 1573-7292 %X %Z FOR Codes: 111403 60410 %0 Journal Article %~ PubMed %A Anderson, Vincent B %A McKenzie, Jennifer A %A Seton, Chris %A Fitzgerald, Dominic A %A Webster, Richard I %A North, Kathryn N %A Joffe, David A %A Young, Helen K %T Sniff nasal inspiratory pressure and sleep disordered breathing in childhood neuromuscular disorders. %B Neuromuscular Disorders %D 2012 %C United Kingdom %I Elsevier Ltd %V 22 %N 6 %P 528-533 %@ 1873-2364 %X The ease of sniff nasal inspiratory pressure testing may extend application of respiratory muscle assessment to younger and cognitively-impaired children. We sought to quantify sniff nasal inspiratory pressure in childhood neuromuscular disorders, and to correlate this measure with conventional pulmonary function tests and overnight polysomnography. Thirty children (mean 9.7??3.8years, range 4.3-16.5years) with diagnosed neuromuscular disorders (Duchenne muscular dystrophy, spinal muscular atrophy, Becker muscular dystrophy, congenital myopathy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, multi-minicore disease) underwent assessment. Thirty-seven percent displayed cognitive impairment. Those with neuromuscular disorders were then compared with 32 volunteer age- and gender-matched controls (mean 10.9??2.9years, range 6.6-17.2years) with normal respiratory function. Twenty-three children with neuromuscular disorders also underwent overnight polysomnography. Children with neuromuscular disorders demonstrated significantly impaired sniff nasal inspiratory pressure, maximal inspiratory pressure, FEV(1) and FVC (p<0.05). A positive correlation was identified between daytime sniff nasal inspiratory pressure and maximal inspiratory pressure (r=0.58), FEV(1) (r=0.55) and FVC (r=0.46), though not with polysomnography variables (respiratory disturbance index, nadir SpO(2), peak CO(2)). Moderate prevalence of nocturnal hypoxia was observed, and 32% of children demonstrated sleep disordered breathing. Sniff nasal inspiratory pressure assessment was well tolerated, representing a promising surrogate measure for assessment of respiratory function in childhood neuromuscular disorders. %Z FOR Codes: 111403 110904 %0 Journal Article %~ PubMed %A Pride, Natalie A %A Payne, Jonathan M %A North, Kathryn N %T The Impact of ADHD on the Cognitive and Academic Functioning of Children With NF1. %B Developmental Neuropsychology %D 2012 %C United States %I Psychology Press %V 37 %N 7 %P 590-600 %@ 1532-6942 %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Acosta, Maria T %A Bearden, Carrie E %A Castellanos, Xavier F %A Cutting, Laurie %A Elgersma, Ype %A Gioia, Gerard %A Gutmann, David H %A Lee, Yong-Seok %A Legius, Eric %A Muenke, Maximillian %A North, Kathryn %A Parada, Luis F %A Ratner, Nancy %A Hunter-Schaedle, Kim %A Silva, Alcino J %T The Learning Disabilities Network (LeaDNet): using neurofibromatosis type 1 (NF1) as a paradigm for translational research. %B American Journal of Medical Genetics. Part A %D 2012 %C United States %I John Wiley & Sons, Inc. %V 158A %N 9 %P 2225-2232 %@ 1552-4833 %X %Z FOR Codes: 111403 60410 %0 Journal Article %~ PubMed %A Ardern-Holmes, Simone L %A North, Kathryn N %T Treatment for plexiform neurofibromas in patients with NF1. %B Lancet Oncology %D 2012 %C United Kingdom %I The Lancet Publishing Group %V 13 %N 12 %P 1175-1176 %@ 1474-5488 %X %Z FOR Codes: 60410 111403 1103 %0 Journal Article %~ PubMed %A Yang, Nan %A Schindeler, Aaron %A McDonald, Michelle M %A Seto, Jane T %A Houweling, Peter J %A Lek, Monkol %A Hogarth, Marshall %A Morse, Alyson R %A Raftery, Joanna M %A Balasuriya, Dominic %A Macarthur, Daniel G %A Berman, Yemima %A Quinlan, Kate Gr %A Eisman, John A %A Nguyen, Tuan V %A Center, Jacqueline R %A Prince, Richard L %A Wilson, Scott G %A Zhu, Kathy %A Little, David G %A North, Kathryn N %T α-Actinin-3 deficiency is associated with reduced bone mass in human and mouse. %B Bone %D 2011 %C United States %I Elsevier Inc. %V 49 %N 4 %P 790-798 %@ 8756-3282 %X Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. ?-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the ?-actinin-3 protein in approximately 20% of Eurasians. Absence of ?-actinin-3 does not cause any disease phenotypes in muscle because of compensation by ?-actinin-2. However, ?-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for ?-actinin-3 in bone. ?-Actinin-3 but not ?-actinin-2 is expressed in osteoblasts. The Actn3(-/-) mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14%) and trabecular number (-61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3(-/-) mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study. %Z FOR Codes: 60405 %0 Journal Article %~ PubMed %A Waddell, Leigh B %A Tran, Jenny %A Zheng, Xi F %A Bönnemann, Carsten G %A Hu, Ying %A Evesson, Frances J %A Lek, Monkol %A Arbuckle, Susan %A Wang, Min-Xia %A Smith, Robert L %A North, Kathryn N %A Clarke, Nigel F %T A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients. %B Neuromuscular disorders : NMD %D 2011 %C United Kingdom %I Elsevier Ltd %V 21 %N 11 %P 776-81 %@ 1873-2364 %X FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n=102) and TCAP (n=100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n=9), MATR3 (n=15) and PTRF (n=7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy. %Z FOR Codes: 110311 110904 111403 %0 Journal Article %~ PubMed %A Wang, Dongwei %A Nykanen, Marko %A Yang, Nan %A Winlaw, David %A North, Kathryn %A Verkman, A S %A Owler, Brian Kenneth %T Altered cellular localisation of aquaporin-1 in experimental hydrocephalus in mice and reduced ventriculomegaly in aquaporin-1 deficiency. %B Molecular and cellular neurosciences %D 2011 %C United States %I Academic Press %V 46 %N 4 %P 318-24 %@ 1095-9327 %X Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF) in the cerebral ventricles that constitutes a significant cause of neurological morbidity and mortality. Surgical treatment involving shunt placement is associated with a high failure rate and complications due to infection, motivating the development of alternative, non-surgical therapies. Here, we investigated the role in hydrocephalus of water channel aquaporin-1 (AQP1), which is expressed at the apical membrane of choroid plexus epithelium and is believed to facilitate CSF production. AQP1 expression and subcellular localization were studied in a kaolin-induced hydrocephalus model in mice and the effect AQP1 deficiency on the severity of hydrocephalus was determined. While total choroidal AQP1 protein was not significantly altered in hydrocephalus, ~50% of AQP1 protein was redistributed from the apical membrane to intracellular vesicles. We found that the ventricular size in AQP1-deficient mice was smaller than in wild-type mice, both at baseline and following hydrocephalus. The reduced plasma membrane AQP1 localization following kaolin-induced hydrocephalus, which involves endocytosis, may be a compensatory mechanism to reduce CSF secretion. The reduced ventricular size in AQP1-deficient mice following kaolin-induced hydrocephalus suggests AQP1 inhibition or down-regulation as a potential adjunctive treatment for hydrocephalus. %Z FOR Codes: 30499 %0 Journal Article %~ PubMed %A Payne, Jonathan M %A Hyman, Shelley L %A Shores, E Arthur %A North, Kathryn N %T Assessment of executive function and attention in children with neurofibromatosis type 1: Relationships between cognitive measures and real-world behavior. %B Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence %D 2011 %C Netherlands %I Psychology Press %V 17 %N 4 %P 313-29 %@ 1744-4136 %X The aim of this study was to examine functional attention and executive deficits present in everyday living in a large sample of children with neurofibromatosis type 1 (NF1). Data are presented from 199 children with NF1 and 55 unaffected sibling controls who were administered the Behavior Rating Inventory of Executive Function (BRIEF) and Conners'' ADHD DSM-IV Scales (CADS). Convergent validity was examined by correlating scale scores from these functional measures with scores from traditional cognitive measures of attention and executive function. Results indicated global functional attention and executive deficits in children with NF1. Relationships between functional impairments and scores on cognitive measures were inconsistent; at best, the magnitude of these relationships was in the moderate range, yet there was also a lack of association between many cognitive tasks and the functional skills they purport to assess. Findings suggest that cognitive and functional measures may tap different constructs and that neuropsychological evaluations should be supplemented with functional assessment tools to provide a more accurate and sensitive encapsulation of a child''s strengths and weaknesses to guide remediation programs. %Z FOR Codes: 111403 110904 60410 %0 Journal Article %~ PubMed %A Huson, Susan M %A Acosta, Maria T %A Belzberg, Allan J %A Bernards, Andre %A Chernoff, Jonathan %A Cichowski, Karen %A Gareth Evans, D %A Ferner, Rosalie E %A Giovannini, Marco %A Korf, Bruce R %A Listernick, Robert %A North, Kathryn N %A Packer, Roger J %A Parada, Luis F %A Peltonen, Juha %A Ramesh, Vijaya %A Reilly, Karlyne M %A Risner, John W %A Schorry, Elizabeth K %A Upadhyaya, Meena %A Viskochil, David H %A Zhu, Yuan %A Hunter-Schaedle, Kim %A Giancotti, Filippo G %T Back to the future: Proceedings from the 2010 NF Conference. %B American journal of medical genetics. Part A %D 2011 %C United States %I John Wiley & Sons, Inc. %V %N 2 %P %@ 1552-4833 %X The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children''s Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010. ?? 2010 Wiley-Liss, Inc. %Z FOR Codes: 60412 %0 Journal Article %~ PubMed %A North, Kathryn N %T Clinical approach to the diagnosis of congenital myopathies. %B Seminars in Pediatric Neurology %D 2011 %C United States %I W.B. Saunders Co. %V 18 %N 4 %P 216-220 %@ 1558-0776 %X In this issue of Seminars in Pediatric Neurology, each chapter will focus on the features and management of individual congenital myopathies. This introductory chapter will provide an overview of the clinical features that alert the clinician to the likely diagnosis of a congenital myopathy, and specific features on history and examination that are characteristic of a specific genetic subtype. Most congenital myopathies share a common pattern of clinical features, which makes it difficult to predict the genetic cause in a patient by clinical assessment alone. Although no single feature is specific for the congenital myopathies, the presence of this common pattern highlights patients in whom a muscle biopsy is likely to provide important diagnostic information. The diagnosis of a specific congenital myopathy should only be made when the defining morphologic feature is the predominant pathologic change, other possible causes have been excluded, and the clinical course is nonprogressive or only slowly progressive. %Z FOR Codes: 111403 110904 %0 Journal Article %~ PubMed %A Seto, Jane T %A Lek, Monkol %A Quinlan, Kate G R %A Houweling, Peter J %A Zheng, Xi F %A Garton, Fleur %A Macarthur, Daniel G %A Raftery, Joanna M %A Garvey, Sean M %A Hauser, Michael A %A Yang, Nan %A Head, Stewart I %A North, Kathryn N %T Deficiency of {alpha}-Actinin-3 is Associated with Increased Susceptibility to Contraction-Induced Damage and Skeletal Muscle Remodeling. %B Human molecular genetics %D 2011 %C United Kingdom %I Oxford University Press %V 20 %N 15 %P 2914-27 %@ 0964-6906 %X Sarcomeric ??-actinins (??-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific ??-actinin-3 in ???20% of the general population. ??-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that ??-actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of ??-actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that ??-actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of ??-actinin-3 and up-regulation of ??-actinin-2 resulted in no significant changes to the total pool of sarcomeric ??-actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between ??-actinin-2 and ??-actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to ??-actinin-2. Thus, the loss of ??-actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in ??-actinin-3-deficient individuals. %Z FOR Codes: 110904 60410 111403 %0 Journal Article %~ PubMed %A Waddell, Leigh B %A Lemckert, Frances A %A Zheng, Xi F %A Tran, Jenny %A Evesson, Frances J %A Hawkes, Joanne M %A Lek, Angela %A Street, Neil E %A Lin, Peihui %A Clarke, Nigel F %A Landstrom, Andrew P %A Ackerman, Michael J %A Weisleder, Noah %A Ma, Jianjie %A North, Kathryn N %A Cooper, Sandra T %T Dysferlin, Annexin A1, and Mitsugumin 53 Are Upregulated in Muscular Dystrophy and Localize to Longitudinal Tubules of the T-System With Stretch. %B Journal of Neuropathology and Experimental Neurology %D 2011 %C United States %I Lippincott Williams & Wilkins %V 70 %N 4 %P 302-313 %@ 0022-3069 %X Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex. %Z FOR Codes: 110904 60105 %0 Journal Article %~ PubMed %A Yiu, Eppie M %A Klausegger, Alfred %A Waddell, Leigh B %A Grasern, Nikolaus %A Lloyd, Lyn %A Tran, Kim %A North, Kathryn N %A Bauer, Johann W %A McKelvie, Penelope %A Chow, C W %A Ryan, Monique M %A Murrell, Dedee F %T Epidermolysis bullosa with late-onset muscular dystrophy and plectin deficiency. %B Muscle & Nerve %D 2011 %C United States %I John Wiley & Sons, Inc. %V 44 %N 1 %P 135-141 %@ 0148-639X %X Epidermolysis bullosa associated with muscular dystrophy is a rare, autosomal recessive form of epidermolysis bullosa simplex caused by mutations in the plectin gene, PLEC1. We describe a phenotypically mild case due to compound heterozygous mutations in PLEC1 (2677_2685del and the novel mutation Q1644X). Clinical features included mild skin blistering since birth, slowly progressive and late-onset upper limb-predominant weakness, facial weakness, ptosis, incomplete ophthalmoplegia, and paroxysmal atrial fibrillation. %Z FOR Codes: 110603 %0 Journal Article %~ PubMed %A Ravenscroft, Gianina %A Sollis, Elliot %A Charles, Adrian K %A North, Kathryn N %A Baynam, Gareth %A Laing, Nigel G %T Fetal akinesia: review of the genetics of the neuromuscular causes. %B Journal of Medical Genetics %D 2011 %C United Kingdom %I BMJ Group %V 48 %N 12 %P 793-801 %@ 0022-2593 %X Fetal akinesia refers to a broad spectrum of disorders in which the unifying feature is a reduction or lack of fetal movement. Fetal akinesias may be caused by defects at any point along the motor system pathway including the central and peripheral nervous system, the neuromuscular junction and the muscle, as well as by restrictive dermopathy or external restriction of the fetus in utero. The fetal akinesias are clinically and genetically heterogeneous, with causative mutations identified to date in a large number of genes encoding disparate parts of the motor system. However, for most patients, the molecular cause remains unidentified. One reason for this is because the tools are only now becoming available to efficiently and affordably identify mutations in a large panel of disease genes. Next-generation sequencing offers the promise, if sufficient cohorts of patients can be assembled, to identify the majority of the remaining genes on a research basis and facilitate efficient clinical molecular diagnosis. The benefits of identifying the causative mutation(s) for each individual patient or family include accurate genetic counselling and the options of prenatal diagnosis or preimplantation genetic diagnosis. In this review, we summarise known single-gene disorders affecting the spinal cord, peripheral nerves, neuromuscular junction or skeletal muscles that result in fetal akinesia. This audit of these known molecular and pathophysiological mechanisms involved in fetal akinesia provides a basis for improved molecular diagnosis and completing disease gene discovery. %Z FOR Codes: 110904 60412 %0 Journal Article %~ PubMed %A Bray, Paula %A Bundy, Anita C %A Ryan, Monique M %A North, Kathryn N %A Burns, Joshua %T Health status of boys with Duchenne muscular dystrophy: A parent's perspective. %B Journal of paediatrics and child health %D 2011 %C United Kingdom, Australia %I Wiley-Blackwell Publishing Ltd. %V 47 %N 8 %P 557-62 %@ 1034-4810 %X To investigate parent-reported health status of boys with Duchenne muscular dystrophy (DMD) compared with a large Australian normative population and a cohort of children with Charcot-Marie-Tooth disease type 1A (CMT1A). %Z FOR Codes: 110904 111403 %0 Journal Article %~ PubMed %A Nguyen, Mai-Anh T %A Joya, Josephine E %A Kee, Anthony J %A Domazetovska, Ana %A Yang, Nan %A Hook, Jeff W %A Lemckert, Frances A %A Kettle, Emma %A Valova, Valentina A %A Robinson, Philip J %A North, Kathryn N %A Gunning, Peter W %A Mitchell, Christina A %A Hardeman, Edna C %T Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy. %B Brain %D 2011 %C United Kingdom %I Oxford University Press %V 134 %N Pt 12 %P 3516-3529 %@ 1460-2156 %X Nemaline myopathy, the most common congenital myopathy, is caused by mutations in genes encoding thin filament and thin filament-associated proteins in skeletal muscles. Severely affected patients fail to survive beyond the first year of life due to severe muscle weakness. There are no specific therapies to combat this muscle weakness. We have generated the first knock-in mouse model for severe nemaline myopathy by replacing a normal allele of the ??-skeletal actin gene with a mutated form (H40Y), which causes severe nemaline myopathy in humans. The Acta1(H40Y) mouse has severe muscle weakness manifested as shortened lifespan, significant forearm and isolated muscle weakness and decreased mobility. Muscle pathologies present in the human patients (e.g. nemaline rods, fibre atrophy and increase in slow fibres) were detected in the Acta1(H40Y) mouse, indicating that it is an excellent model for severe nemaline myopathy. Mating of the Acta1(H40Y) mouse with hypertrophic four and a half LIM domains protein 1 and insulin-like growth factor-1 transgenic mice models increased forearm strength and mobility, and decreased nemaline pathologies. Dietary l-tyrosine supplements also alleviated the mobility deficit and decreased the chronic repair and nemaline rod pathologies. These results suggest that l-tyrosine may be an effective treatment for muscle weakness and immobility in nemaline myopathy. %Z FOR Codes: 110904 111699 %0 Journal Article %~ PubMed %A Au, Carol G %A Butler, Tanya L %A Sherwood, Megan C %A Egan, Jonathan R %A North, Kathryn N %A Winlaw, David S %T Increased connective tissue growth factor associated with cardiac fibrosis in the mdx mouse model of dystrophic cardiomyopathy. %B International journal of experimental pathology %D 2011 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 92 %N 1 %P 57-65 %@ 1365-2613 %X Cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder. A major feature of the hearts of DMD patients and the mdx mouse model of the disease is cardiac fibrosis. Connective tissue growth factor (CTGF) is involved in the fibrotic process in many organs. This study utilized the mdx mouse model to assess the role of CTGF and other extracellular matrix components during the development of fibrosis in the dystrophic heart. Left ventricular function of mdx and control mice at 6, 29 and 43 weeks was measured by echocardiography. Young (6 weeks old) mdx hearts had normal function and histology. At 29 weeks of age, mdx mice developed cardiac fibrosis and increased collagen expression. The onset of fibrosis was associated with increased CTGF transcript and protein expression. Increased intensity of CTGF immunostaining was localized to fibrotic areas in mdx hearts. The upregulation of CTGF was also concurrent with increased expression of tissue inhibitor of matrix metalloproteinases (TIMP-1). These changes persisted in 43 week old mdx hearts and were combined with impaired cardiac function and increased gene expression of transforming growth factor (TGF)-??1 and matrix metalloproteinases (MMP-2, MMP-9). In summary, an association was observed between cardiac fibrosis and increased CTGF expression in the mdx mouse heart. CTGF may be a key mediator of early and persistent fibrosis in dystrophic cardiomyopathy. %Z FOR Codes: 110201 %0 Journal Article %~ PubMed %A Pistilli, Emidio E %A Bogdanovich, Sasha %A Garton, Fleur %A Yang, Nan %A Gulbin, Jason P %A Conner, Jennifer D %A Anderson, Barbara G %A Quinn, LeBris S %A North, Kathryn %A Ahima, Rexford S %A Khurana, Tejvir S %T Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. %B Journal of Clinical Investigation %D 2011 %C United States %I American Society for Clinical Investigation %V 121 %N 8 %P 3120-3132 %@ 1558-8238 %X IL-15 receptor ? (IL-15R?) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15R? is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15R? have unique phenotypes. IL-15 and IL-15R? have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15R? induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15R?-knockout (IL-15R?-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15R? has a role in defining the phenotype of fast skeletal muscles in vivo. %Z FOR Codes: 111403 110904 %0 Journal Article %~ PubMed %A Lorenzo, Jennifer %A Barton, Belinda %A Acosta, Maria T %A North, Kathryn %T Mental, Motor, and Language Development of Toddlers with Neurofibromatosis Type 1. %B The Journal of pediatrics %D 2011 %C United States %I Mosby, Inc %V 158 %N 4 %P 660-5 %@ 0022-3476 %X To examine the mental, motor, and language development of toddlers with neurofibromatosis type 1 (NF1). %Z FOR Codes: 1701 1114 %0 Journal Article %~ PubMed %A Koutsopoulos, Olga S %A Koch, Catherine %A Tosch, Valerie %A Böhm, Johann %A North, Kathryn N %A Laporte, Jocelyn %T Mild functional differences of dynamin 2 mutations associated to centronuclear myopathy and Charcot-Marie Tooth peripheral neuropathy. %B PLoS One %D 2011 %C United States %I Public Library of Science %V 6 %N 11 %P e27498 %@ 1932-6203 %X The large GTPase dynamin 2 is a key player in membrane and cytoskeletal dynamics mutated in centronuclear myopathy (CNM) and Charcot-Marie Tooth (CMT) neuropathy, two discrete dominant neuromuscular disorders affecting skeletal muscle and peripheral nerves respectively. The molecular basis for the tissue-specific phenotypes observed and the physiopathological mechanisms linked to dynamin 2 mutations are not well established. In this study, we have analyzed the impact of CNM and CMT implicated dynamin 2 mutants using ectopic expression of four CNM and two CMT mutations, and patient fibroblasts harboring two dynamin 2 CNM mutations in established cellular processes of dynamin 2 action. Wild type and CMT mutants were seen in association with microtubules whereas CNM mutants lacked microtubules association and did not disrupt interphase microtubules dynamics. Most dynamin 2 mutants partially decreased clathrin-mediated endocytosis when ectopically expressed in cultured cells; however, experiments in patient fibroblasts suggested that endocytosis is overall not defective. Furthermore, CNM mutants were seen in association with enlarged clathrin stained structures whereas the CMT mutant constructs were associated with clathrin structures that appeared clustered, similar to the structures observed in Dnm1 and Dnm2 double knock-out cells. Other roles of dynamin 2 including its interaction with BIN1 (amphiphysin 2), and its function in Golgi maintenance and centrosome cohesion were not significantly altered. Taken together, these mild functional defects are suggestive of differences between CMT and CNM disease-causing dynamin 2 mutants and suggest that a slight impairment in clathrin-mediated pathways may accumulate over time to foster the respective human diseases. %Z FOR Codes: 111403 110904 %0 Journal Article %~ PubMed %A Lo, Harriet P %A Bertini, Enrico %A Mirabella, Massimiliano %A Domazetovska, Ana %A Dale, Russell C %A Petrini, Stefania %A D'Amico, Adele %A Valente, Enza Maria %A Barresi, Rita %A Roberts, Mark %A Tozzi, Giulia %A Tasca, Giorgio %A Cooper, Sandra T %A Straub, Volker %A North, Kathryn N %T Mosaic caveolin-3 expression in acquired rippling muscle disease without evidence of myasthenia gravis or acetylcholine receptor autoantibodies. %B Neuromuscular disorders : NMD %D 2011 %C United Kingdom %I Elsevier Ltd %V 21 %N 3 %P 194-203 %@ 1873-2364 %X Inherited rippling muscle disease is an autosomal dominant disorder usually associated with caveolin-3 mutations. Rare cases of acquired rippling muscle disease with abnormal caveolin-3 localisation have been reported, without primary caveolin-3 mutations and in association with myasthenia gravis and acetylcholine receptor autoantibodies, or thymoma. We present three new patients with electrically-silent muscle rippling and abnormal caveolin-3 localisation, but without acetylcholine receptor autoantibodies, or clinical or electrophysiological evidence of myasthenia gravis. An autoimmune basis for rippling muscle disease is supported by spontaneous recovery and normalisation of caveolin-3 staining in one patient and alleviation of symptoms in response to plasmapheresis and immunosuppression in another. These patients expand the autoimmune rippling muscle disease phenotype, and suggest that autoantibodies to additional unidentified muscle proteins result in autoimmune rippling muscle disease. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Sangster, Jennifer %A Shores, E Arthur %A Watt, Sharon %A North, Kathryn N %T The Cognitive Profile of Preschool-Aged Children with Neurofibromatosis Type 1. %B Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence %D 2011 %C United Kingdom %I Psychology Press %V 17 %N 1 %P 1-16 %@ 1744-4136 %X Few studies have examined the cognitive profile of young children with NF1. In this study, 26 children with NF1 (M(age) = 5 years 3 months) were compared with 21 peer comparisons (M(age) = 4 years 8 months) and available normative data on neuropsychological measures. Children with NF1 demonstrated the characteristic downward shift in IQ, poor visuospatial constructional skills, and inattention. Working memory deficits were common in parental ratings. These findings suggest that at least some of the cognitive deficits associated with NF1 can be identified in the preschool-age group, highlighting the need for early assessment and intervention. %Z FOR Codes: 170102 %0 Journal Article %~ PubMed %A Seto, Jane T %A Chan, Stephen %A Turner, Nigel %A Macarthur, Daniel G %A Raftery, Joanna M %A Berman, Yemima D %A Quinlan, Kate G R %A Cooney, Gregory J %A Head, Stewart %A Yang, Nan %A North, Kathryn N %T The effect of α-actinin-3 deficiency on muscle aging. %B Experimental gerontology %D 2011 %C United States %I Elsevier Inc. %V 46 %N 4 %P 292-302 %@ 1873-6815 %X Deficiency of the fast-twitch muscle protein ??-actinin-3 due to homozygosity for a nonsense polymorphism (R577X) in the ACTN3 gene is common in humans. ??-Actinin-3 deficiency (XX) is associated with reduced muscle strength/power and enhanced endurance performance in elite athletes and in the general population. The association between R577X and loss in muscle mass and function (sarcopenia) has previously been investigated in a number of studies in elderly humans. The majority of studies report loss of ACTN3 genotype association with muscle traits in the elderly, however, there is some indication that the XX genotype may be associated with faster muscle function decline. To further explore these potential age-related effects and the underlying mechanisms, we examined the effect of ??-actinin-3 deficiency in aging male and female Actn3 knockout (KO) mice (2, 6, 12, and 18 months). Our findings support previous reports of a diminished influence of ACTN3 genotype on muscle performance in the elderly: genotype differences in intrinsic exercise performance, fast muscle force generation and male muscle mass were lost in aged mice, but were maintained for other muscle function traits such as grip strength. The loss of genotype difference in exercise performance occurred despite the maintenance of some "slower" muscle characteristics in KO muscles, such as increased oxidative metabolism and greater force recovery after fatigue. Interestingly, muscle mass decline in aged 18 month old male KO mice was greater compared to wild-type controls (WT) (-12.2% in KO; -6.5% in WT). These results provide further support that ??-actinin-3 deficient individuals may experience faster decline in muscle function with increasing age. %Z FOR Codes: 60410 110904 110308 %0 Journal Article %~ PubMed %A Ardern-Holmes, Simone L %A North, Kathryn N %T Therapeutics for Childhood Neurofibromatosis Type 1 and Type 2. %B Current treatment options in neurology %D 2011 %C United States %I Current Medicine Group LLC %V 13 %N 6 %P 529-43 %@ 1534-3138 %X OPINION STATEMENT: Neurofibromatosis type 1 (NF1) and type 2 (NF2) are genetically and medically distinct neurocutaneous disorders that are both associated with tumors affecting the central and peripheral nervous systems. NF1 has a frequency of 1 in 3,000, compared with 1 in 30,000 for NF2. Careful surveillance is important for both conditions, to allow early identification and treatment of complications. The most common and important problems in NF1 are cognitive impairment, optic pathway gliomas, plexiform neurofibromas, and orthopaedic issues. Early intervention and tailored educational programs are indicated for learning difficulties. Attention deficit hyperactivity disorder may be amenable to treatment with stimulant medication. A clinical trial is under way to evaluate lovastatin in the treatment of cognitive problems in children with NF1. Chemotherapy with vincristine and carboplatin is the current standard of care for symptomatic optic pathway gliomas, but new agents with improved efficacy are needed. Plexiform neurofibromas may be treated with surgery, but often recur. To date, no medical therapy has proven effective in limiting plexiform neurofibroma growth, but several candidate medications are under consideration in clinical trials. Malignant peripheral nerve sheath tumors may arise in preexisting plexiform neurofibromas, so changes in tumor growth or an increase in pain or focal neurologic deficit should prompt further investigation and early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy. Specialist surgical intervention may be needed for scoliosis and tibial pseudoarthrosis. In NF2, surgical treatment remains a cornerstone of management for symptomatic progressive vestibular schwannomas, meningiomas, and spinal tumors. Vascular endothelial growth factor inhibitors show promise for the treatment of vestibular schwannomas, with the aim of delaying surgery, and other targeted molecular therapies are becoming available as investigational options. Hearing aids and brainstem and cochlear implants have a role in optimizing functional hearing in some patients. Specialist ophthalmology input should be arranged to monitor for ophthalmologic complications. A coordinated effort is needed to enroll NF1 and NF2 patients in international multicenter clinical trials of promising new pharmacologic agents. Genetic testing is useful for prenatal diagnosis and may be important in understanding individual responses to novel medical therapies in the future. Effective transition to adult services is important, considering the likelihood of further complications in the adult years. %Z FOR Codes: 111403 110904 60410 %0 Journal Article %~ PubMed %A Waddell, Leigh B %A Monnier, Nicole %A Cooper, Sandra T %A North, Kathryn N %A Clarke, Nigel F %T Using complementary DNA from MyoD-transduced fibroblasts to sequence large muscle genes. %B Muscle & Nerve %D 2011 %C United States %I John Wiley & Sons, Inc. %V 44 %N 2 %P 280-282 %@ 0148-639X %X Large muscle genes are often sequenced using complementary DNA (cDNA) made from muscle messenger RNA (mRNA) to reduce the cost and workload associated with sequencing from genomic DNA. Two potential barriers are the availability of a frozen muscle biopsy, and difficulties in detecting nonsense mutations due to nonsense-mediated mRNA decay (NMD). We present patient examples showing that use of MyoD-transduced fibroblasts as a source of muscle-specific mRNA overcomes these potential difficulties in sequencing large muscle-related genes. Muscle Nerve, 2011. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Berman, Yemima %A North, Kathryn N %T A Gene for Speed: The Emerging Role of {alpha}-Actinin-3 in Muscle Metabolism. %B Physiology %D 2010 %C United States %I American Physiological Society %V 25 %N 4 %P 250-259 %@ 1548-9221 %X A common polymorphism (R577X) in the ACTN3 gene results in complete deficiency of alpha-actinin-3 protein in approximately 16% of humans worldwide. The presence of alpha-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population. Despite this, there is evidence that the null genotype XX has been acted on by recent positive selection, likely due to its emerging role in the regulation of muscle metabolism. alpha-Actinin-3 deficiency reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization. %Z FOR Codes: 110904 60409 110602 %0 Journal Article %~ PubMed %A Scott, Robert A %A Irving, Rachael %A Irwin, Laura %A Morrison, Errol %A Charlton, Vilma %A Austin, Krista %A Tladi, Dawn %A Deason, Michael %A Headley, Samuel A %A Kolkhorst, Fred W %A Yang, Nan %A North, Kathryn %A Pitsiladis, Yannis P %T ACTN3 and ACE genotypes in elite Jamaican and US sprinters. %B Medicine and Science in Sports and Exercise %D 2010 %C United States %I Lippincott Williams & Wilkins %V 42 %N 1 %P 107-112 %@ 0195-9131 %X The angiotensin-converting enzyme (ACE) and the alpha-actinin-3 (ACTN3) genes are two of the most studied "performance genes" and both have been associated with sprint/power phenotypes and elite performance. PURPOSE: To investigate the association between the ACE and the ACTN3 genotypes and sprint athlete status in elite Jamaican and US African American sprinters. METHODS: The ACTN3 R577X and the ACE I/D and A22982G (rs4363) genotype distributions of elite Jamaican (J-A; N = 116) and US sprinters (US-A; N = 114) were compared with controls from the Jamaican (J-C; N = 311) and US African American (US-C; N = 191) populations. Frequency differences between groups were assessed by exact test. RESULTS: For ACTN3, the XX genotype was found to be at very low frequency in both athlete and control cohorts (J-C = 2%, J-A = 3%, US-C = 4%, US-A = 2%). Athletes did not differ from controls in ACTN3 genotype distribution (J, P = 0.87; US, P = 0.58). Similarly, neither US nor Jamaican athletes differed from controls in genotype at ACE I/D (J, P = 0.44; US, P = 0.37). Jamaican athletes did not differ from controls for A22982G genotype (P = 0.28), although US sprinters did (P = 0.029), displaying an excess of heterozygotes relative to controls but no excess of GG homozygotes (US-C = 22%, US-A = 18%). CONCLUSIONS: Given that ACTN3 XX genotype is negatively associated with elite sprint athlete status, the underlying low frequency in these populations eliminates the possibility of replicating this association in Jamaican and US African American sprinters. The finding of no excess in ACE DD or GG genotypes in elite sprint athletes relative to controls suggests that ACE genotype is not a determinant of elite sprint athlete status. %Z FOR Codes: 110604 110604 %0 Journal Article %~ PubMed %A Quinlan, Kate G R %A Seto, Jane T %A Turner, Nigel %A Vandebrouck, Aurelie %A Floetenmeyer, Matthias %A Macarthur, Daniel G %A Raftery, Joanna M %A Lek, Monkol %A Yang, Nan %A Parton, Robert G %A Cooney, Gregory J %A North, Kathryn N %T Alpha-actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle. %B Human molecular genetics %D 2010 %C United Kingdom %I Oxford University Press %V 19 %N 7 %P 1335-1346 %@ 0964-6906 %X Approximately one billion people worldwide are homozygous for a stop codon polymorphism in the ACTN3 gene (R577X) which results in complete deficiency of the fast fibre muscle protein alpha-actinin-3. ACTN3 genotype is associated with human athletic performance and alpha-actinin-3 deficient mice [Actn3 knockout (KO) mice] have a shift in the properties of fast muscle fibres towards slower fibre properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. alpha-Actinins have been shown to interact with a number of muscle proteins including the key metabolic regulator glycogen phosphorylase (GPh). In this study, we demonstrated a link between alpha-actinin-3 and glycogen metabolism which may underlie the metabolic changes seen in the KO mouse. Actn3 KO mice have higher muscle glycogen content and a 50% reduction in the activity of GPh. The reduction in enzyme activity is accompanied by altered post-translational modification of GPh, suggesting that alpha-actinin-3 regulates GPh activity by altering its level of phosphorylation. We propose that the changes in glycogen metabolism underlie the downstream metabolic consequences of alpha-actinin-3 deficiency. Finally, as GPh has been shown to regulate calcium handling, we examined calcium handling in KO mouse primary mouse myoblasts and find changes that may explain the slower contractile properties previously observed in these mice. We propose that the alteration in GPh activity in the absence of alpha-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance. %Z FOR Codes: 604 %0 Journal Article %~ PubMed %A Lek, Monkol %A North, Kathryn N %T Are biological sensors modulated by their structural scaffolds? The role of the structural muscle proteins alpha-actinin-2 and alpha-actinin-3 as modulators of biological sensors. %B FEBS letters %D 2010 %C Netherlands %I Elsevier BV %V 584 %N 14 %P 2974-80 %@ 0014-5793 %X Biological sensors and their ability to detect and respond to change in the cellular environment can be modulated by protein scaffolds acting within their interaction network. The skeletal muscle alpha-actinins have been considered as primarily structural scaffold proteins. However, deficiency of alpha-actinin-3 due to a common null polymorphism results in predominantly metabolic changes in skeletal muscle function. In this review, we explore the range of phenotypes associated with alpha-actinin-3 deficiency, and draw supporting evidence from known interaction partners for its role as a scaffold which acts to modulate biological sensors that result in changes in muscle metabolism and structure. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Payne, Jonathan M %A Moharir, Mahendranath D %A Webster, Richard %A North, Kathryn N %T Brain structure and function in neurofibromatosis type 1: current concepts and future directions. %B Journal of Neurology, Neurosurgery and Psychiatry %D 2010 %C United Kingdom %I BMJ Group %V 81 %N 3 %P 304-309 %@ 1468-330X %X Neurofibromatosis type 1 (NF1) is a common neurogenetic condition associated with cognitive dysfunction and learning disability. Over the past decade, important and consistent findings have emerged that provide insight into the neurobiological correlates of NF1. In this review, we examine the structural and functional neuroimaging literature in individuals with NF1 and discuss findings that have emerged. Collectively, the studies reviewed here highlight structural and functional brain abnormalities as a feature of NF1 and that these abnormalities contribute to the cognitive impairments that are commonly seen. The most compelling structural finding has been an increase in total brain volume with additional areas of interest including the corpus callosum, cerebral asymmetries and differences in grey and white matter. Although the application of functional neuroimaging techniques in NF1 is in its infancy, early evidence suggests alterations in brain organisation for language and visuospatial function as well as thalamic hypometabolism. Suggestions for future research are discussed, including the importance of addressing specific hypotheses in well-defined subsamples of children with NF1 using appropriate control groups. Identifying the underlying neuropathology of NF1 will be of increased importance as targeted interventions begin to emerge. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Tooley, Leona D %A Zamurs, Laura K %A Beecher, Nicola %A Baker, Naomi L %A Peat, Rachel A %A Adams, Naomi E %A Bateman, John F %A North, Kathryn N %A Baldock, Clair %A Lamande, Shireen R %T Collagen VI microfibril formation is abolished by an {alpha}2(VI) von Willebrand factor A-domain mutation in a patient with Ullrich congenital muscular dystrophy. %B The Journal of biological chemistry %D 2010 %C United States %I American Society for Biochemistry and Molecular Bi %V 285 %N 43 %P 33567-76 %@ 1083-351X %X Collagen VI is an extracellular protein that most often contains the three genetically distinct polypeptide chains, ??1(VI), ??2(VI), and ??3(VI), although three recently identified chains, ??4(VI), ??5(VI), and ??6(VI), may replace ??3(VI) in some situations. Each chain has a triple helix flanked by N- and C-terminal globular domains that share homology with the von Willebrand factor type A (VWA) domains. During biosynthesis, the three chains come together to form triple helical monomers, which then assemble into dimers and tetramers. Tetramers are secreted from the cell and align end-to-end to form microfibrils. The precise molecular mechanisms responsible for assembly are unclear. Mutations in the three collagen VI genes can disrupt collagen VI biosynthesis and matrix organization and are the cause of the inherited disorders Bethlem myopathy and Ullrich congenital muscular dystrophy. We have identified a Ullrich congenital muscular dystrophy patient with compound heterozygous mutations in ??2(VI). The first mutation causes skipping of exon 24, and the mRNA is degraded by nonsense-mediated decay. The second mutation is a two-amino acid deletion in the C1 VWA domain. Recombinant C1 domains containing the deletion are insoluble and retained intracellularly, indicating that the mutation has detrimental effects on domain folding and structure. Despite this, mutant ??2(VI) chains retain the ability to associate into monomers, dimers, and tetramers. However, we show that secreted mutant tetramers containing structurally abnormal C1 VWA domains are unable to associate further into microfibrils, directly demonstrating the critical importance of a correctly folded ??2(VI) C1 domain in microfibril formation. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pride, Natalie %A Payne, Jonathan M %A Webster, Richard %A Shores, E Arthur %A Rae, Caroline %A North, Kathryn N %T Corpus Callosum Morphology and Its Relationship to Cognitive Function in Neurofibromatosis Type 1. %B Journal of child neurology %D 2010 %C United States %I Sage Publications, Inc. %V 25 %N 7 %P 834-41 %@ 1708-8283 %X Neurofibromatosis type 1 (NF1) is associated with cognitive dysfunction and structural brain abnormalities such as an enlarged corpus callosum. This study aimed to determine the relationship between corpus callosum morphology and cognitive function in children with neurofibromatosis type 1 using quantitative neuroanatomic imaging techniques. Children with neurofibromatosis type 1 (n = 46) demonstrated a significantly larger total corpus callosum and corpus callosum index compared with control participants (n = 30). A larger corpus callosum index in children with neurofibromatosis type 1 was associated with significantly lower IQ, reduced abstract concept formation, reduced verbal memory, and diminished academic ability, specifically reading and math. Our results suggest an enlarged corpus callosum in children with neurofibromatosis type 1 is associated with cognitive impairment and may provide an early structural marker for the children at risk of cognitive difficulties. Cognitive deficits associated with structural brain abnormalities in neurofibromatosis type 1 are unlikely to be reversible and so may not respond to proposed pharmacological therapies for neurofibromatosis type 1-related cognitive impairments. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Sambuughin, Nyamkhishig %A Yau, Kyle S %A Olivé, Montse %A Duff, Rachael M %A Bayarsaikhan, Munkhuu %A Lu, Shajia %A Gonzalez-Mera, Laura %A Sivadorai, Padma %A Nowak, Kristen J %A Ravenscroft, Gianina %A Mastaglia, Frank L %A North, Kathryn N %A Ilkovski, Biljana %A Kremer, Hannie %A Lammens, Martin %A van Engelen, Baziel G M %A Fabian, Vicki %A Lamont, Phillipa %A Davis, Mark R %A Laing, Nigel G %A Goldfarb, Lev G %T Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. %B American Journal of Human Genetics %D 2010 %C United States %I Cell Press %V 87 %N 6 %P 842-847 %@ 0002-9297 %X We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule''s beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies. %Z FOR Codes: 60402 %0 Journal Article %~ PubMed %A Waddell, Leigh B %A Kreissl, Michaela %A Kornberg, Andrew %A Kennedy, Paul %A McLean, Catriona %A Labarre-Vila, Annick %A Monnier, Nicole %A North, Kathryn N %A Clarke, Nigel F %T Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3. %B Neuromuscular disorders : NMD %D 2010 %C United Kingdom %I Elsevier Ltd %V 20 %N 7 %P 464-6 %@ 1873-2364 %X We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Susman, Rachel D %A Quijano-Roy, Susana %A Yang, Nan %A Webster, Richard %A Clarke, Nigel F %A Dowling, Jim %A Kennerson, Marina %A Nicholson, Garth %A Biancalana, Valerie %A Ilkovski, Biljana %A Flanigan, Kevin M %A Arbuckle, Susan %A Malladi, Chandra %A Robinson, Phillip %A Vucic, Steven %A Mayer, Michčle %A Romero, Norma B %A Urtizberea, Jon Andoni %A García-Bragado, Federico %A Guicheney, Pascale %A Bitoun, Marc %A Carlier, Robert-Yves %A North, Kathryn N %T Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy. %B Neuromuscular Disorders %D 2010 %C United Kingdom %I Elsevier Ltd. %V 20 %N 4 %P 229-237 %@ 1873-2364 %X Mutations in dynamin-2 (DNM2) cause autosomal dominant centronuclear myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies; one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy. %Z FOR Codes: 110904 60410 %0 Journal Article %~ PubMed %A Rose, Kristy J %A Burns, Joshua %A North, Kathryn N %T Factors Associated With Foot and Ankle Strength in Healthy Preschool-Age Children and Age-Matched Cases of Charcot-Marie-Tooth Disease Type 1A. %B Journal of child neurology %D 2010 %C United States %I Sage Publications, Inc. %V 25 %N 4 %P 463-8 %@ 1708-8283 %X Charcot-Marie-Tooth disease affects foot and ankle strength from the earliest stages of the disease; however, little is known about factors influencing normal strength development or the pathogenesis of foot weakness and deformity in Charcot-Marie-Tooth disease. The authors investigated factors associated with foot and ankle strength in healthy preschool-age children and compared to age-matched cases of Charcot-Marie-Tooth disease type 1A. In healthy children, ankle dorsiflexion range of motion was one of the strongest independent correlates of foot and ankle strength. Compared with healthy children, those with Charcot-Marie-Tooth disease type 1A had significantly less dorsiflexion strength and range as well as imbalance in inversion-to-eversion and plantarflexion-to-dorsiflexion strength ratios. Given the association between ankle dorsiflexion strength and range in the healthy children, and the abnormality of these parameters in Charcot-Marie-Tooth disease, investigation of the cause-effect relationship is warranted to identify more targeted therapy and further understand the pathogenesis of foot deformity in Charcot-Marie-Tooth disease. %Z FOR Codes: 110905 %0 Journal Article %~ PubMed %A Bray, Paula %A Bundy, Anita C %A Ryan, Monique M %A North, Kathryn N %T Feasibility of a computerized method to measure quality of "everyday" life in children with neuromuscular disorders. %B Physical & Occupational Therapy in Pediatrics %D 2010 %C United States %I Informa Healthcare %V 30 %N 1 %P 43-53 %@ 1541-3144 %X Measurement of quality of life is becoming increasingly important in health care. Self-reported quality of life is the preferred method of gathering this information, but children are often excluded from this process, their input being replaced by parent-proxy report. This feasibility study tested assessment of "daily" quality-of-life by a self-reported computerized method in boys with neuromuscular disorders. To establish feasibility, the method was required to be engaging, consistent, and convenient. Ten boys, aged 9-16 years, were given a personal digital assistant (PDA) and prompted randomly, eight times/day for 1 week, to answer 19 questions about their daily experiences (including happiness, mood, self-esteem, location, and activity). Subjects completed sampling with an acceptable response rate (79%). Split-week reliability analysis for participant variability (r = 0.45-0.88) indicated acceptable consistency. Participants reported that the method was easy and convenient, and analysis of standardized mean scores supported internal validity. The computerized method to assess "daily" quality of life, from the child''s perspective, was feasible and may be useful to understand the impact of disease progression and interventions on day-to-day function. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Bray, Paula %A Bundy, Anita C %A Ryan, Monique M %A North, Kathryn N %A Everett, Anna %T Health-related Quality of Life in Boys With Duchenne Muscular Dystrophy: Agreement Between Parents and Their Sons. %B Journal of child neurology %D 2010 %C United States %I Sage Publications, Inc. %V 25 %N 0 %P 1188-94 %@ 1708-8283 %X This study investigated agreement between boys and their parents when reporting on health-related quality of life and the effects of steroid use, age, and physical functioning on self-reported health-related quality of life in boys with Duchenne muscular dystrophy. The Pediatric Quality of Life Inventory??? and brief functional measures were administered to 35 parent-son dyads. We found that agreement between parents and their sons was moderate (intraclass correlation coefficient [ICC](2,1) = 0.66; 95% confidence interval [CI], 0.40-0.80) to poor (ICC(2,1) = 0.64; 95% CI, 0.43-0.64). The boys'' self-reports revealed a relationship between disease progression and physical functioning (r = -.75; P = .01); however, disease stage was not related to psychosocial functioning (r = -.27; NS). Parents and boys affected by Duchenne muscular dystrophy have a moderate to poor agreement on health-related quality of life measures, with parents reporting lower overall health-related quality of life when compared with their sons. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Vandebrouck, Aurélie %A Domazetovska, Ana %A Mokbel, Nancy %A Cooper, Sandra T %A Ilkovski, Biljana %A North, Kathryn N %T In Vitro Analysis of Rod Composition and Actin Dynamics in Inherited Myopathies. %B Journal of neuropathology and experimental neurology %D 2010 %C United States %I Lippincott Williams & Wilkins %V 69 %N 5 %P 429-41 %@ 0022-3069 %X Rods are the pathological hallmark of nemaline myopathy, but they can also occur as a secondary phenomenon in other disorders, including mitochondrial myopathies such as complex I deficiency. The mechanisms of rod formation are not well understood, particularly when rods occur in diverse disorders with very different structural and metabolic defects. We compared the characteristics of rods associated with abnormalities in structural components of skeletal muscle thin filament (3 mutations in the skeletal actin gene ACTA1) with those of rods induced by the metabolic cell stress of adenosine triphosphate depletion. C2C12 and NIH/3T3 cell culture models and immunocytochemistry were used to study rod composition and conformation. Fluorescent recovery after photobleaching was used to measure actin dynamics inside the rods. We demonstrate that not all rods are the same. Rods formed under different conditions contain a unique fingerprint of actin-binding proteins (cofilin and alpha-actinin) and display differences in actin dynamics that are specific to the mutation, to the cellular location of the rods (intranuclear vs cytoplasmic), and/or to the underlying pathological process (i.e. mutant actin or adenosine triphosphate depletion). Thus, rods likely represent a common morphological end point of a variety of different pathological processes, either structural or metabolic. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Rose, Kristy J %A Burns, Joshua %A Wheeler, Danielle M %A North, Kathryn N %T Interventions for increasing ankle range of motion in patients with neuromuscular disease. %B Cochrane Database of Systematic Reviews %D 2010 %C United Kingdom %I John Wiley & Sons Ltd. %V 17 %N 2 %P CD006973 %@ 1469-493X %X BACKGROUND: Reduced ankle dorsiflexion range of motion, or ankle equinus, is a common and disabling problem for patients with neuromuscular disease. Clinicians devote considerable time and resources implementing interventions to correct this problem although few of these interventions have been subject to rigorous empirical investigation. OBJECTIVES: To assess the effect of interventions to reduce or resolve ankle equinus in people with neuromuscular disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (August 2009), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009), MEDLINE (1966 to August 2009), EMBASE (1980 to August 2009), CINAHL 1982 to August 2009), AMED (1985 to August 2009) and The Physiotherapy Evidence Database (PEDro) (1929 to August 2009). We searched the reference lists of identified articles and also contacted known experts in the field to identify additional or unpublished data. SELECTION CRITERIA: Randomised controlled trials evaluating interventions for increasing ankle dorsiflexion range of motion in neuromuscular disease. Outcomes included ankle dorsiflexion range of motion, functional improvement, foot alignment, foot and ankle muscle strength, health-related quality of life, satisfaction with the intervention and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Four studies involving 149 participants met inclusion criteria for this review. Two studies assessed the effect of night splinting in a total of 26 children and adults with Charcot-Marie-Tooth disease type 1A. There were no statistically or clinically significant differences between wearing a night splint and not wearing a night splint. One study assessed the efficacy of prednisone treatment in 103 boys with Duchenne muscular dystrophy. While a daily dose of prednisone at 0.75 mg/kg/day resulted in significant improvements in some strength and function parameters compared with placebo, there was no significant difference in ankle range of motion between groups. Increasing the prednisone dose to 1.5 mg/kg/day had no significant effect on ankle range of motion. One study evaluated early surgery in 20 young boys with Duchenne muscular dystrophy. Surgery resulted in increased ankle dorsiflexion range at 12 months but functional outcomes favoured the control group. By 24 months, many boys in the surgical group experienced a relapse of achilles tendon contractures. AUTHORS'' CONCLUSIONS: There is no evidence of significant benefit from any intervention for increasing ankle range of motion in Charcot-Marie-Tooth disease type 1A or Duchenne muscular dystrophy. Further research is required. %Z FOR Codes: 110999 110321 %0 Journal Article %~ PubMed %A Lek, Angela %A Lek, Monkol %A North, Kathryn N %A Cooper, Sandra T %T Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins. %B BMC Evolutionary Biology %D 2010 %C United Kingdom %I BioMed Central Ltd. %V 10 %N %P 231 %@ 1471-2148 %X ABSTRACT: BACKGROUND: The ferlin gene family possesses a rare and identifying feature consisting of multiple tandem C2 domains and a C-terminal transmembrane domain. Much currently remains unknown about the fundamental function of this gene family, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease. The availability of genome sequences from a wide range of species makes it possible to explore the evolution of the ferlin family, providing contextual insight into characteristic features that define the ferlin gene family in its present form in humans. RESULTS: Ferlin genes were detected from all species of representative phyla, with two ferlin subgroups partitioned within the ferlin phylogenetic tree based on the presence or absence of a DysF domain. Invertebrates generally possessed two ferlin genes (one with DysF and one without), with six ferlin genes in most vertebrates (three DysF, three non-DysF). Expansion of the ferlin gene family is evident between the divergence of lamprey (jawless vertebrates) and shark (cartilaginous fish). Common to almost all ferlins is an N-terminal C2-FerI-C2 sandwich, a FerB motif, and two C-terminal C2 domains (C2E and C2F) adjacent to the transmembrane domain. Preservation of these structural elements throughout eukaryotic evolution suggests a fundamental role of these motifs for ferlin function. In contrast, DysF, C2DE, and FerA are optional, giving rise to subtle differences in domain topologies of ferlin genes. Despite conservation of multiple C2 domains in all ferlins, the C-terminal C2 domains (C2E and C2F) displayed higher sequence conservation and greater conservation of putative calcium binding residues across paralogs and orthologs. Interestingly, the two most studied non-mammalian ferlins (Fer-1 and Misfire) in model organisms C. elegans and D. melanogaster, present as outgroups in the phylogenetic analysis, with results suggesting reproduction-related divergence and specialization of species-specific functions within their genus. CONCLUSIONS: Our phylogenetic studies provide evolutionary insight into the ferlin gene family. We highlight the existence of ferlin-like proteins throughout eukaryotic evolution, from unicellular phytoplankton and apicomplexan parasites, through to humans. We characterise the preservation of ferlin structural motifs, not only of C2 domains, but also the more poorly characterised ferlin-specific motifs representing the DysF, FerA and FerB domains. Our data suggest an ancient role of ferlin proteins, with lessons from vertebrate biology and human disease suggesting a role relating to vesicle fusion and plasma membrane specialization. %Z FOR Codes: 110904 60409 %0 Journal Article %~ PubMed %A Lek, Monkol %A Macarthur, Daniel G %A Yang, Nan %A North, Kathryn N %T Phylogenetic analysis of gene structure and alternative splicing in {alpha}-actinins. %B Molecular biology and evolution %D 2010 %C United States %I Oxford University Press %V 27 %N 4 %P 773-80 %@ 1537-1719 %X The alpha-actinins are an important family of actin-binding proteins with the ability to cross-link actin filaments when in dimer form. Members of the alpha-actinin family share a domain topology composed of highly conserved actin-binding and EF-hand domains separated by a rod domain composed of spectrin-like repeats. Functional diversity within this family has arisen through exon duplication and the formation of alternate splice isoforms as well as gene duplications during the evolution of vertebrates. In addition to the known functional domains, alpha-actinins also contain a consensus PDZ-binding site. The completed genome sequence of over 32 invertebrate species has allowed the analysis of gene structure and exon-gene duplication over a diverse range of phyla. Our analysis shows that relative to early branching metazoans, there has been considerable intron loss especially in arthropods with few cases of intron gains. The C-terminal PDZ-binding site is conserved in nearly all invertebrates but is missing in some nematodes and platyhelminths. Alternative splicing in the actin-binding domain is conserved in chordates, arthropods, and some nematodes and platyhelminths. In contrast, alternative splicing of the EF-hand domain is only observed in chordates. Finally, given the prevalence of exon duplications seen in the actin-binding domain, this may act as a significant mechanism in the modification of actin-binding properties. %Z FOR Codes: 111601 %0 Journal Article %~ PubMed %A Chan, Stephen %A Seto, Jane T %A Houweling, Peter J %A Yang, Nan %A North, Kathryn N %A Head, Stewart I %T Properties of extensor digitorum longus muscle and skinned fibers from adult and aged male and female Actn3 knockout mice. %B Muscle & nerve %D 2010 %C United States %I John Wiley & Sons, Inc. %V 43 %N %P 37-48 %@ 0148-639X %X Absence of ??-actinin-3, encoded by the ACTN3 "speed gene," is associated with poorer sprinting performance in athletes and a slowing of relaxation in fast-twitch muscles of Actn3 knockout (KO) mice. Our first aim was to investigate, at the individual-fiber level, possible mechanisms for this slowed relaxation. Our second aim was to characterize the contractile properties of whole extensor digitorum longus (EDL) muscles from KO mice by age and gender. We examined caffeine-induced Ca(2+) release in mechanically skinned EDL fibers from KO mice, and measured isolated whole EDL contractile properties. The sarcoplasmic reticulum of KO muscle fibers loaded Ca(2+) more slowly than that of wild-types (WTs). Whole KO EDL muscles had longer twitch and tetanus relaxation times than WTs, and reduced mass and cross-sectional area. These effects occurred in both male and female mice, but they diminished with age. These changes in KO muscles and fibers help to explain the effects of ??-actinin-3 deficiency observed in athletes. %Z FOR Codes: 60410 111499 %0 Journal Article %~ PubMed %A Clarke, Nigel F %A Waddell, Leigh B %A Cooper, Sandra T %A Perry, Margaret %A Smith, Robert L L %A Kornberg, Andrew J %A Muntoni, Francesco %A Lillis, Suzanne %A Straub, Volker %A Bushby, Kate %A Guglieri, Michela %A King, Mary D %A Farrell, Michael A %A Marty, Isabelle %A Lunardi, Joel %A Monnier, Nicole %A North, Kathryn N %T Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. %B Human mutation %D 2010 %C United States %I John Wiley & Sons, Inc. %V 31 %N 7 %P E1544-50 %@ 1059-7794 %X The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Evesson, Frances J %A Peat, Rachel A %A Lek, Angela %A Brilot, Fabienne %A Lo, Harriet P %A Dale, Russell C %A Parton, Robert G %A North, Kathryn N %A Cooper, Sandra T %T Reduced plasma membrane expression of dysferlin mutants is due to accelerated endocytosis via a syntaxin-4 associated pathway. %B The Journal of biological chemistry %D 2010 %C United States %I American Society for Biochemistry and Molecular Bi %V 285 %N 37 %P 28529-39 %@ 1083-351X %X Ferlins are an ancient family of C2 domain-containing proteins, with emerging roles in vesicular trafficking and human disease. Dysferlin mutations cause inherited muscular dystrophy, and dysferlin also shows abnormal plasma membrane expression in other forms of muscular dystrophy. We establish dysferlin as a short-lived (protein half-life approximately 4-6 h) and transitory transmembrane protein (plasma membrane half-life approximately 3 h), with a propensity for rapid endocytosis when mutated, and an association with a syntaxin-4 endocytic route. Dysferlin plasma membrane expression and endocytic rate is regulated by the C2B-FerI-C2C motif, with a critical role identified for C2C. Disruption of C2C dramatically reduces plasma membrane dysferlin (by 2.5-fold), due largely to accelerated endocytosis (by 2.5-fold). These properties of reduced efficiency of plasma membrane expression due to accelerated endocytosis are also a feature of patient missense mutant L344P (within FerI, adjacent to C2C). Importantly, dysferlin mutants that demonstrate accelerated endocytosis also display increased protein lability via endosomal proteolysis, implicating endosomal-mediated proteolytic degradation as a novel basis for dysferlin-deficiency in patients with single missense mutations. Vesicular labeling studies establish that dysferlin mutants rapidly transit from EEA1-positive early endosomes through to dextran-positive lysosomes, co-labeled by syntaxin-4 at multiple stages of endosomal transit. In summary, our studies define a transient biology for dysferlin, relevant to emerging patient therapeutics targeting dysferlin replacement. We introduce accelerated endosomal-directed degradation as a basis for lability of dysferlin missense mutants in dysferlinopathy, and show that dysferlin and syntaxin-4 similarly transit a common endosomal pathway in skeletal muscle cells. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Rose, Kristy J %A Raymond, Jacqueline %A Refshauge, Kathryn %A North, Kathryn N %A Burns, Joshua %T Serial night casting increases ankle dorsiflexion range in children and young adults with Charcot-Marie-Tooth disease: a randomised trial. %B Journal of Physiotherapy %D 2010 %C Australia %I Australian Physiotherapy Association %V 56 %N 2 %P 113-119 %@ 1836-9553 %X Question: Does 4 weeks of serial night casting followed by 4 weeks of stretching of the gastrocnemius and soleus improve ankle dorsiflexion range and other outcomes compared with no intervention in children and young adults with Charcot-Marie-Tooth disease? Design: Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Participants: 30 children and young adults with Charcot-Marie-Tooth disease and restricted ankle dorsiflexion range. Intervention: The experimental group received 4 weeks of serial night casting followed by 4 weeks of weightbearing stretches. The control group received no intervention. Outcome measures: Primary outcome was ankle dorsiflexion range; secondary outcomes included foot deformity, mobility, balance, falls, and self-reported activity limitations. Outcomes were measured at baseline, 4, and 8 weeks. Results: By 4 weeks, serial night casting had increased ankle dorsiflexion range by a mean of 4 deg (95% CI 2 to 6) more in the experimental group than the control group. After a further 4 weeks of weightbearing stretches, the experimental group still had a mean of 3 deg (95% CI 0 to 5) more ankle dorsiflexion range than the control group. Other than reduced time to walk 10 metres at self-selected pace favouring night casting at 4 weeks, outcomes did not differ between groups at any time point. Two minor adverse events were reported in the experimental group. Conclusion: 4 weeks of serial night casting increased ankle dorsiflexion range compared with no intervention, but at 8 weeks there was no significant difference between groups. Trial registration: ACTRN12605000011684. %Z FOR Codes: 110905 110317 110321 %0 Journal Article %~ PubMed %A Lek, Monkol %A Quinlan, Kate G R %A North, Kathryn N %T The evolution of skeletal muscle performance: gene duplication and divergence of human sarcomeric alpha-actinins. %B BioEssays %D 2010 %C United Kingdom %I John Wiley & Sons Ltd. %V 32 %N 1 %P 17-25 %@ 1521-1878 %X In humans, there are two skeletal muscle alpha-actinins, encoded by ACTN2 and ACTN3, and the ACTN3 genotype is associated with human athletic performance. Remarkably, approximately 1 billion people worldwide are deficient in alpha-actinin-3 due to the common ACTN3 R577X polymorphism. The alpha-actinins are an ancient family of actin-binding proteins with structural, signalling and metabolic functions. The skeletal muscle alpha-actinins diverged approximately 250-300 million years ago, and ACTN3 has since developed restricted expression in fast muscle fibres. Despite ACTN2 and ACTN3 retaining considerable sequence similarity, it is likely that following duplication there was a divergence in function explaining why alpha-actinin-2 cannot completely compensate for the absence of alpha-actinin-3. This paper focuses on the role of skeletal muscle alpha-actinins, and how possible changes in functions between these duplicates fit in the context of gene duplication paradigms. %Z FOR Codes: 110699 %0 Journal Article %~ PubMed %A Moharir, Mahendranath %A London, Kevin %A Howman-Giles, Robert %A North, Kathryn %T Utility of positron emission tomography for tumour surveillance in children with neurofibromatosis type 1. %B European Journal of Nuclear Medicine and Molecular Imaging %D 2010 %C Germany %I Springer %V 37 %N 7 %P 1309-1317 %@ 1619-7089 %X There is little consensus regarding optimal surveillance of optic pathway glioma (OPG) and plexiform neurofibroma (PNF) in childhood neurofibromatosis type 1 (NF1). (18)F-2-Fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography and computed tomography (PET/CT) is employed in the surveillance of adult PNFs; but its utility has neither been specifically studied in children with PNFs nor in children with OPG. %Z FOR Codes: 111403 111399 %0 Journal Article %~ PubMed %A Garton, Fleur %A Seto, Jane T %A North, Kathryn N %A Yang, Nan %T Validation of an automated computational method for skeletal muscle fibre morphometry analysis. %B Neuromuscular disorders : NMD %D 2010 %C United Kingdom %I Elsevier Ltd %V 20 %N 8 %P 540-7 %@ 1873-2364 %X Accurate and fast measurement of muscle fibre size and evaluation of fibre type proportions in large cross-sectional areas remains challenging as existing methods require extensive manual measurements. In this study, we assessed the fibre morphometry of approximately 1000 fibres in mouse and human control and diseased muscle cross-sections. We compared fibre size, percentage fibre proportion and percentage fibre surface area results obtained by an automated method using MetaMorph with those obtained manually using Image Pro. Data collection using MetaMorph software was faster and produced similar results to those obtained using Image Pro. The ability to quickly and accurately measure large numbers of fibres with MetaMorph allows the researcher to make a more precise assessment of fibre type and fibre size changes in human muscle biopsies and animal models of muscle disease. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Kissil, Joseph L %A Blakeley, Jaishri O %A Ferner, Rosalie E %A Huson, Susan M %A Kalamarides, Michel %A Mautner, Victor-Felix %A McCormick, Frank %A Morrison, Helen %A Packer, Roger %A Ramesh, Vijaya %A Ratner, Nancy %A Rauen, Katherine A %A Stevenson, David A %A Hunter-Schaedle, Kim %A North, Kathryn %T What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. %B American Journal of Medical Genetics. Part A %D 2010 %C United States %I John Wiley & Sons, Inc. %V 152A %N 2 %P 269-283 %@ 1552-4833 %X The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been convened by the Children''s Tumor Foundation for over 20 years. The 2009 NF Conference was held in Portland, Oregon from June 13 to June 16, 2009 and co-chaired by Kathryn North from the University of Sydney and The Children''s Hospital at Westmead, Sydney, Australia; and Joseph Kissil from the Wistar Institute, Philadelphia. The Conference included 80 platform presentations in 9 sessions over 4 days; over 100 abstracts presented as posters; and three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromatosis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical researchers. Correspondingly the NF Conference scope has expanded to include translational research, clinical trials and clinical management issues while retaining a core of basic research. These themes are reflected in the highlights from the 2009 NF Conference presented here. %Z FOR Codes: 60410 %0 Book Section %A North, Kathryn %T Adolescent medicine: towards evidence based practice in a young specialty %B Challenges in Adolescent Health: An Australian Perspective %D 2009 %C United States %I Nova Science Publishers %V %N %P ix-xi %@ 9781607416166 %E Bennett, David %E Towns, Susan %E Elliott, Elizabeth %E Nerrick, Joav %X %Z FOR Codes: 111704 %0 Journal Article %~ PubMed %A Clarke, Nigel F %A Domazetovska, Ana %A Waddell, Leigh %A Kornberg, Andrew %A McLean, Catriona %A North, Kathryn N %T Cap disease due to mutation of the beta-tropomyosin gene (TPM2). %B Neuromuscular Disorders %D 2009 %C United Kingdom %I Elsevier Ltd %V 19 %N 5 %P 348-351 %@ 1873-2364 %X Cap disease or cap myopathy is a form of congenital myopathy in which peripheral, well-demarcated ''caps'' of disorganised thin filaments are seen in muscle fibres. Mutation of the TPM2 gene, that encodes beta-tropomyosin, is the first reported genetic cause. In this paper, we describe a further case of cap disease due to a mutation in TPM2, confirming the importance of this genetic association. This is the first report of cardiac dysfunction due to a mutation in TPM2. Our patient has an identical TPM2 mutation to the first genetically diagnosed cap disease patient, a denovo heterozygous three base pair deletion that removes glutamic acid 139 from the centre of beta-tropomyosin (p.E139del). 2D-gel electrophoresis studies show that the shortened mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Butler, Tanya L %A Egan, Jonathan R %A Graf, Fabian G %A Au, Carol G %A McMahon, Aisling C %A North, Kathryn N %A Winlaw, David S %T Dysfunction induced by ischemia versus edema: does edema matter? %B The Journal of Thoracic and Cardiovascular Surgery %D 2009 %C United States %I Mosby, Inc. %V 138 %N 1 %P 141-147 %@ 1097-685X %X OBJECTIVES: Recovery from pediatric cardiac surgery is affected by ischemia-reperfusion injury, cardiac edema, and in some cases a low cardiac output syndrome. Although association has been made between the development of edema and dysfunction, modeling is confounded by intercurrent injurious stimuli that also cause cardiac edema and dysfunction. We tested whether a true causal relationship exists between edema and cardiac dysfunction. METHODS: We induced either ischemia or edema alone in isolated cardiomyocytes and whole Langendorff-perfused hearts. Function was measured as shortening dynamics and developed pressure, respectively. RESULTS: Ischemic injury impaired function in both cardiomyocytes and whole hearts. Isolated cells showed significant reduction in peak shortening and departure and relaxation velocities. Whole hearts displayed severely reduced developed pressures. Hyposmotic solution forced cardiomyocytes to swell to 7% greater than their normal size. No significant effect on shortening was seen. Similarly, Langendorff-perfused hearts were induced to take on 3% more water than control-perfused hearts and 9% more water than nonperfused hearts. This additional water was associated with mild dysfunction. CONCLUSIONS: We demonstrate the capacity of the heart to tolerate edema greater than that seen in clinical settings without residual effect. Ischemia results in ongoing contractile dysfunction of both isolated cardiomyocytes and whole hearts. We conclude that dysfunction resulting from edema in ex vivo cardiac models is mild and suggest review of the importance given to edema-mediated dysfunction after cardiac surgery. %Z FOR Codes: 606 1102 %0 Journal Article %~ PubMed %A Bastiani, Michele %A Liu, Libin %A Hill, Michelle M %A Jedrychowski, Mark P %A Nixon, Susan J %A Lo, Harriet P %A Abankwa, Daniel %A Luetterforst, Robert %A Fernandez-Rojo, Manuel %A Breen, Michael R %A Gygi, Steven P %A Vinten, Jorgen %A Walser, Piers J %A North, Kathryn N %A Hancock, John F %A Pilch, Paul F %A Parton, Robert G %T MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes. %B The Journal of Cell Biology %D 2009 %C United States %I Rockefeller University Press %V 185 %N 7 %P 1259-1273 %@ 1540-8140 %X Polymerase I and transcript release factor (PTRF)/Cavin is a cytoplasmic protein whose expression is obligatory for caveola formation. Using biochemistry and fluorescence resonance energy transfer-based approaches, we now show that a family of related proteins, PTRF/Cavin-1, serum deprivation response (SDR)/Cavin-2, SDR-related gene product that binds to C kinase (SRBC)/Cavin-3, and muscle-restricted coiled-coil protein (MURC)/Cavin-4, forms a multiprotein complex that associates with caveolae. This complex can constitutively assemble in the cytosol and associate with caveolin at plasma membrane caveolae. Cavin-1, but not other cavins, can induce caveola formation in a heterologous system and is required for the recruitment of the cavin complex to caveolae. The tissue-restricted expression of cavins suggests that caveolae may perform tissue-specific functions regulated by the composition of the cavin complex. Cavin-4 is expressed predominantly in muscle, and its distribution is perturbed in human muscle disease associated with Caveolin-3 dysfunction, identifying Cavin-4 as a novel muscle disease candidate caveolar protein. %Z FOR Codes: 60199 %0 Book Section %A North, Kathryn %A Shield, Lloyd %T Muscle Disorders %B Diseases of the Nervous System in Children %D 2009 %C United States %I Wiley-Blackwell Publishing, Inc. %V %N %P 0 %@ 9781898683599 %E Aicardi, Jean %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Liu, Renjing %A Ginn, Samantha L %A Lek, Monkol %A North, Kathryn N %A Alexander, Ian E %A Little, David G %A Schindeler, Aaron %T Myoblast sensitivity and fibroblast insensitivity to osteogenic conversion by BMP-2 correlates with the expression of Bmpr-1a. %B BMC musculoskeletal disorders %D 2009 %C United Kingdom %I BioMed Central Ltd. %V 10 %N 0 %P 51 %@ 1471-2474 %X BACKGROUND: Osteoblasts are considered to primarily arise from osseous progenitors within the periosteum or bone marrow. We have speculated that cells from local soft tissues may also take on an osteogenic phenotype. Myoblasts are known to adopt a bone gene program upon treatment with the osteogenic bone morphogenetic proteins (BMP-2,-4,-6,-7,-9), but their osteogenic capacity relative to other progenitor types is unclear. We further hypothesized that the sensitivity of cells to BMP-2 would correlate with BMP receptor expression. METHODS: We directly compared the BMP-2 sensitivity of myoblastic murine cell lines and primary cells with osteoprogenitors from osseous tissues and fibroblasts. Fibroblasts forced to undergo myogenic conversion by transduction with a MyoD-expressing lentiviral vector (LV-MyoD) were also examined. Outcome measures included alkaline phosphatase expression, matrix mineralization, and expression of osteogenic genes (alkaline phosphatase, osteocalcin and bone morphogenetic protein receptor-1A) as measured by quantitative PCR. RESULTS: BMP-2 induced a rapid and robust osteogenic response in myoblasts and osteoprogenitors, but not in fibroblasts. Myoblasts and osteoprogenitors grown in osteogenic media rapidly upregulated Bmpr-1a expression. Chronic BMP-2 treatment resulted in peak Bmpr-1a expression at day 6 before declining, suggestive of a negative feedback mechanism. In contrast, fibroblasts expressed low levels of Bmpr-1a that was only weakly up-regulated by BMP-2 treatment. Bioinformatics analysis confirmed the presence of myogenic responsive elements in the proximal promoter region of human and murine BMPR-1A/Bmpr-1a. Forced myogenic gene expression in fibroblasts was associated with a significant increase in Bmpr-1a expression and a synergistic increase in the osteogenic response to BMP-2. CONCLUSION: These data demonstrate the osteogenic sensitivity of muscle progenitors and provide a mechanistic insight into the variable response of different cell lineages to BMP-2. %Z FOR Codes: 110314 %0 Journal Article %~ PubMed %A Egan, Jonathan R %A Butler, Tanya L %A Cole, Andrew D %A Abraham, Smartin %A Murala, John S %A Baines, David %A Street, Neil %A Thompson, Lance %A Biecker, Oliver %A Dittmer, John %A Cooper, Sandra %A Au, Carol G %A North, Kathryn N %A Winlaw, David S %T Myocardial membrane injury in pediatric cardiac surgery: An animal model. %B The Journal of Thoracic and Cardiovascular Surgery %D 2009 %C United States %I Mosby, Inc. %V 137 %N 5 %P 1154-1162 %@ 1097-685X %X OBJECTIVE: Reduced myocardial performance invariably follows pediatric cardiac surgery and is manifested by a low cardiac output state in its severest form. The role of myocardial membrane proteins in this setting is unknown. Dystrophin and dysferlin are involved in membrane integrity, whereas aquaporins selectively transport water. These proteins were examined in a model of pediatric cardiac surgery, together with a trial of poloxamer 188, which may reduce membrane injury. METHODS: Eight lambs were randomized to saline with or without poloxamer 188. Lambs underwent 2 hours of cardiopulmonary bypass and aortic crossclamping. After a further 9 hours of monitoring, the hearts were assessed for water content, capillary leak, and protein expression. RESULTS: Dystrophin expression was unaffected by ischemia/reperfusion, but dysferlin expression was reduced. Aquaporin 1 protein increased after ischemia/reperfusion. Poloxamer 188 administration was associated with supranormal levels of dystrophin, preservation of dysferlin expression, and normalization of aquaporin 1 expression. Poloxamer 188 was associated with less capillary leak, maintained colloid osmotic pressure, and less hemodilution. Poloxamer 188 was associated with an improved hemodynamic profile (higher blood pressure, higher venous saturation, and lower lactate), although the heart rate tended to be higher. CONCLUSIONS: Changes in protein expression within the myocardial membrane were found in a clinically relevant model of pediatric cardiac surgery. Indicators of reduced performance, such as lower blood pressure and lower oxygen delivery, were lessened in association with the administration of the membrane protecting poloxamer 188. Poloxamer 188 was also associated with potentially beneficial changes in membrane protein expression, reduced capillary leakage, and less hemodilution. %Z FOR Codes: 606 1102 %0 Journal Article %~ PubMed %A Rose, Kristy J %A Burns, Joshua %A North, Kathryn N %T Relationship between foot strength and motor function in preschool-age children. %B Neuromuscular disorders : NMD %D 2009 %C United Kingdom %I Elsevier %V 19 %N 0 %P 104-7 %@ 0960-8966 %X Foot weakness occurs in many paediatric neuromuscular disorders, which overtime can cause considerable functional motor difficulties. Measuring foot strength with hand-held dynamometry is reliable in preschool-age children, but its validity in this age group is unknown. If foot strength measures are collected as endpoints in clinical trials, they should represent functionally meaningful outcomes. We evaluated the foot strength-motor function relationship in 60 healthy children aged 2-4 years. Foot strength measures included inversion, eversion, dorsiflexion and plantarflexion using hand-held dynamometry. Motor function parameters included time to run 10-m, standing long jump distance and vertical jump height. Measures of foot strength showed significant correlations with all measures of motor function (r=0.40-0.57, p<0.001). Hand-held dynamometry may be used as a valid and functionally meaningful measure of foot strength in very young children. %Z FOR Codes: 1106 %0 Journal Article %A Houweling, Peter J %A North, Kathryn %T Sarcomeric α-actinins and their role in human muscle disease %B Future Neurology %D 2009 %C United Kingdom %I Future Medicine Ltd. %V 4 %N 6 %P 731-743 %@ 1479-6708 %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Yang, Nan %A Garton, Fleur %A North, Kathryn %T alpha-actinin-3 and performance. %B Medicine and Sport Science %D 2009 %C Switzerland %I S. Karger AG %V 54 %N %P 88-101 %@ 0254-5020 %X The human sarcomeric alpha-actinins (ACTN2 and ACTN3) are major structural components of the Z line in skeletal muscle; they play a role in the maintenance of sarcomeric integrity and also interact with a wide variety of structural, signaling and metabolic proteins. ACTN2 is expressed in all muscle fibers, and expression of ACTN3 is restricted to the type 2 (fast glycolytic) fibers that are responsible for forceful contraction at high velocity. There is a common stop codon polymorphism R577X in the ACTN3 gene. Homozygosity for the R577X null-allele results in the absence of alpha-actinin-3 in fast muscle fibers with frequencies that vary from < 1% in Africans to approximately 18% in Caucasians. A number of association studies have demonstrated that the ACTN3 R577X genotype influences athletic performance in Caucasians; the frequency of the XX genotype is significantly lower than controls in sprint athletes, and it appears that alpha-actinin-3 deficiency is detrimental to sprint performance. In the general population, the ACTN3 genotype contributes to the normal variations in muscle strength and sprinting speed. In an Actn3 knockout mouse model, alpha-actinin-3 deficiency is associated with a shift in the characteristics of fast, glycolytic 2B muscle fibers towards a slow phenotype, with decreased muscle mass and fiber diameter, slower contractile properties, increased fatigue resistance, and an increase in oxidative enzyme activity. The shift towards a more efficient oxidative metabolism may underlie the selective advantage of the X-allele during evolution. In turn, the shift towards a ''slow'' muscle phenotype in fast muscle fibers likely explains why loss of alpha-actinin-3 is detrimental to sprint performance. %Z FOR Codes: 111601 %0 Journal Article %~ PubMed %A Chan, Stephen %A Seto, Jane T %A Macarthur, Daniel G %A Yang, Nan %A North, Kathryn %A Head, Stewart %T A gene for speed: contractile properties of isolated whole EDL muscle from an {alpha}-actinin-3 knockout mouse. %B American journal of physiology. Cell physiology %D 2008 %C USA %I American Physiological Society %V 295 %N 4 %P C897-904 %@ 0363-6143 %X The actin-binding protein alpha-actinin-3 is one of the two isoforms of alpha-actinin that are found in the Z-discs of skeletal muscle. alpha-Actinin-3 is exclusively expressed in fast glycolytic muscle fibers. Homozygosity for a common polymorphism in the ACTN3 gene results in complete deficiency of alpha-actinin-3 in about 1 billion individuals worldwide. Recent genetic studies suggest that the absence of alpha-actinin-3 is detrimental to sprint and power performance in elite athletes and in the general population. In contrast, alpha-actinin-3 deficiency appears to be beneficial for endurance athletes. To determine the effect of alpha-actinin-3 deficiency on the contractile properties of skeletal muscle, we studied isolated extensor digitorum longus (fast-twitch) muscles from a specially developed alpha-actinin-3 knockout (KO) mouse. alpha-Actinin-3-deficient muscles showed similar levels of damage to wild-type (WT) muscles following lengthening contractions of 20% strain, suggesting that the presence or absence of alpha-actinin-3 does not significantly influence the mechanical stability of the sarcomere in the mouse. alpha-Actinin-3 deficiency does not result in any change in myosin heavy chain expression. However, compared with alpha-actinin-3-positive muscles, alpha-actinin-3-deficient muscles displayed longer twitch half-relaxation times, better recovery from fatigue, smaller cross-sectional areas, and lower twitch-to-tetanus ratios. We conclude that alpha-actinin-3 deficiency results in fast-twitch, glycolytic fibers developing slower-twitch, more oxidative properties. These changes in the contractile properties of fast-twitch skeletal muscle from alpha-actinin-3-deficient individuals would be detrimental to optimal sprint and power performance, but beneficial for endurance performance. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A MacArthur, Daniel G %A Seto, Jane T %A Chan, Stephen %A Quinlan, Kate G R %A Raftery, Joanna M %A Turner, Nigel %A Nicholson, Megan D %A Kee, Anthony J %A Hardeman, Edna C %A Gunning, Peter W %A Cooney, Gregory J %A Head, Stewart I %A Yang, Nan %A North, Kathryn N %T An Actn3 knockout mouse provides mechanistic insights into the association between alpha-actinin-3 deficiency and human athletic performance. %B Human Molecular Genetics %D 2008 %C United Kingdom %I Oxford University Press %V 17 %N 8 %P 1076-1086 %@ 1460-2083 %X A common nonsense polymorphism (R577X) in the ACTN3 gene results in complete deficiency of the fast skeletal muscle fiber protein alpha-actinin-3 in an estimated one billion humans worldwide. The XX null genotype is under-represented in elite sprint athletes, associated with reduced muscle strength and sprint performance in non-athletes, and is over-represented in endurance athletes, suggesting that alpha-actinin-3 deficiency increases muscle endurance at the cost of power generation. Here we report that muscle from Actn3 knockout mice displays reduced force generation, consistent with results from human association studies. Detailed analysis of knockout mouse muscle reveals reduced fast fiber diameter, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and enhanced recovery from fatigue, suggesting a shift in the properties of fast fibers towards those characteristic of slow fibers. These findings provide the first mechanistic explanation for the reported associations between R577X and human athletic performance and muscle function. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Clement, Emma %A Mercuri, Eugenio %A Godfrey, Caroline %A Smith, Janine %A Robb, Stephanie %A Kinali, Maria %A Straub, Volker %A Bushby, Kate %A Manzur, Adnan %A Talim, Beril %A Cowan, Frances %A Quinlivan, Ros %A Klein, Andrea %A Longman, Cheryl %A McWilliam, Robert %A Topaloglu, Haluk %A Mein, Rachael %A Abbs, Stephen %A North, Kathryn %A Barkovich, A James %A Rutherford, Mary %A Muntoni, Francesco %T Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. %B Annals of Neurology %D 2008 %C United States %I John Wiley & Sons, Inc. %V 64 %N 5 %P 573-582 %@ 0364-5134 %X OBJECTIVE: To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies). METHODS: Blinded review of magnetic resonance imaging brain scans from 27 patients with mutations in 1 of these 5 genes. RESULTS: Brain magnetic resonance images were normal in 3 of 27 patients; in another 5, only nonspecific abnormalities (ventricular dilatation, periventricular white matter abnormalities, or both) were seen. The remaining 19 patients had a spectrum of structural defects, ranging from complete lissencephaly in patients with Walker-Warburg syndrome to isolated cerebellar involvement. Cerebellar cysts and/or dysplasia and hypoplasia were the predominant features in four patients. Polymicrogyria (11/27) was more severe in the frontoparietal regions in 6, and had an occipitofrontal gradient in 2. Pontine clefts, with an unusual appearance to the corticospinal tracts, were seen in five patients with a muscle-eye-brain-like phenotype, three patients with POMGnT1, one with LARGE, and one with POMT2 mutations. Prominent cerebellar cysts were always seen with POMGnT1 mutations, but rarely seen in POMT1 and POMT2. Brainstem and pontine abnormalities were common in patients with POMT2, POMGnT1, and LARGE mutations. INTERPRETATION: Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Cairns, Anita G %A North, Kathryn N %T Cerebrovascular Dysplasia in Neurofibromatosis Type 1. %B Journal of neurology, neurosurgery, and psychiatry %D 2008 %C United Kingdom %I BMJ Publishing Group %V 79 %N 10 %P 1165-70 %@ 0022-3050 %X To assess the frequency and clinical characteristics of the increasingly recognised complication of cerebrovascular dysplasia in children with neurofibromatosis type 1 (NF1). %Z FOR Codes: 110906 %0 Journal Article %~ PubMed %A Au, Carol %A Butler, Tanya %A Egan, Jonathan %A Cooper, Sandra %A Lo, Harriet %A Compton, Alison %A North, Kathryn %A Winlaw, David %T Changes in skeletal muscle expression of AQP1 and AQP4 in dystrophinopathy and dysferlinopathy patients. %B Acta neuropathologica %D 2008 %C Germany %I Springer %V 116 %N 3 %P 235-46 %@ 0001-6322 %X Transmembrane water transport is mediated by aquaporins (AQPs), of which AQP1 and AQP4 are expressed in skeletal muscle. AQP4 expression is reduced in Duchenne muscular dystrophy (DMD) patients, and is reported to correlate with decreased alpha1-syntrophin and altered osmotic permeability. In this study, we assessed the relationship between AQP1, AQP4, dystrophin and alpha1-syntrophin in dystrophinopathy and dysferlinopathy patients. Muscle biopsies of patients with DMD (n = 8) and limb-girdle muscular dystrophy type 2B (LGMD2B; n = 5) were screened for AQP1 and AQP4 expression by real-time quantitative RT-PCR or Western blot and immunohistochemistry. AQP expression was further analyzed in primary myotubes derived from DMD and LGMD2B patients by cell culture and immunohistochemistry. AQP1 transcript and protein expression was significantly elevated in DMD biopsies, and was localized to the sarcolemma of muscle fibers and endothelia of muscle capillaries. AQP4 was significantly reduced despite normal dystrophin and alpha1-syntrophin in dysferlinopathy patients, while expression of AQP1 was variably upregulated. Expression of AQP1 and AQP4 was normal in patient-derived primary myotubes, suggesting that altered AQPs observed in biopsies are likely secondary to the dystrophic process. Our study shows that AQP4 downregulation can occur in muscular dystrophies with either normal or disrupted expression of dystrophin-associated proteins, and that this might be associated with upregulation of AQP1. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Young, Helen K %A Barton, Belinda A %A Waisbren, Susan %A Portales Dale, Lourdes %A Ryan, Monique M %A Webster, Richard I %A North, Kathryn N %T Cognitive and psychological profile of males with Becker muscular dystrophy. %B Journal of Child Neurology %D 2008 %C United States %I Sage Science Press %V 23 %N 2 %P 155-162 %@ 0883-0738 %X Duchenne and Becker muscular dystrophy are allelic X-linked disorders causing progressive muscle weakness in males. Duchenne muscular dystrophy is caused by absence of dystrophin in muscle and brain; boys with Duchenne muscular dystrophy have a static cognitive impairment with mean Full Scale IQ approximately 1 standard deviation below the mean. Less is known of the cognitive profile of males with Becker muscular dystrophy, which is associated with variable alterations in the amount or size of the dystrophin protein. The aim of this study was to describe the cognitive and psychological profile of males with Becker muscular dystrophy. This was a prospective cohort study. Clinical data collected included age at diagnosis and assessment, socioeconomic status, serum creatine kinase level, and site of gene deletion/mutation (by exon number). The following psychological tests were used to assess general intellectual functioning, academic achievement, incidence and nature of behavioral problems: The Wechsler Intelligence Scales, The Wide Range Achievement Test-Revised, The Developmental Test of Visual-Motor Integration, The Child Behavior Checklist, and The Conner''s Parent Rating Scale. Twenty-four males were enrolled. The Wechsler Full Scale IQ was normally distributed with a mean of 95.6 (SD 23.3), which did not differ significantly from the population mean. The frequency of learning difficulties for reading was 21%, for spelling was 32%, and for arithmetic was 26%, significantly higher than the frequency in the general population. The frequency of total behavioral problems in the clinical range was 67%, and the frequency of autism was 8.3%. Patients with Becker muscular dystrophy demonstrate a less homogeneous cognitive phenotype than that seen in Duchenne muscular dystrophy. Males with Becker muscular dystrophy have a high incidence of learning difficulties. Autism and behavioral and attention problems are also more common in Becker muscular dystrophy than in the general population. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Pace, Rishika A %A Peat, Rachel A %A Baker, Naomi L %A Zamurs, Laura %A Mörgelin, Matthias %A Irving, Melita %A Adams, Naomi E %A Bateman, John F %A Mowat, David %A Smith, Nicholas J C %A Lamont, Phillipa J %A Moore, Steven A %A Mathews, Katherine D %A North, Kathryn N %A Lamandé, Shireen R %T Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity. %B Annals of neurology %D 2008 %C United Kingdom %I Wiley-Blackwell %V 64 %N 3 %P 294-303 %@ 0364-5134 %X OBJECTIVE: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. METHODS: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. RESULTS: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. INTERPRETATION: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity. %Z FOR Codes: 60199 %0 Journal Article %~ PubMed %A Ilkovski, Biljana %A Mokbel, Nancy %A Lewis, Raymond %A Walker, Kendall %A Nowak, Kristen %A Domazetovska, Ana %A Laing, Nigel %A Fowler, Velia %A North, Kathryn %A Cooper, Sandra %T Disease Severity and Thin Filament Regulation in M9R TPM3 Nemaline Myopathy. %B Journal of neuropathology and experimental neurology %D 2008 %C United States %I Lippincott Williams and Wilkins %V 67 %N 9 %P 867-77 %@ 0022-3069 %X The mechanism of muscle weakness was investigated in an Australian family with an M9R mutation in TPM3 (alpha-tropomyosin(slow)). Detailed protein analyses of 5 muscle samples from 2 patients showed that nemaline bodies are restricted to atrophied Type 1 (slow) fibers in which the TPM3 gene is expressed. Developmental expression studies showed that alpha-tropomyosin(slow) is not expressed at significant levels until after birth, thereby likely explaining the childhood (rather than congenital) disease onset in TPM3 nemaline myopathy. Isoelectric focusing demonstrated that alpha-tropomyosin(slow) dimers, composed of equal ratios of wild-type and M9R-alpha-tropomyosin(slow), are the dominant tropomyosin species in 3 separate muscle groups from an affected patient. These findings suggest that myopathy-related slow fiber predominance likely contributes to the severity of weakness in TPM3 nemaline myopathy because of increased proportions of fibers that express the mutant protein. Using recombinant proteins and far Western blot, we demonstrated a higher affinity of tropomodulin for alpha-tropomyosin(slow) compared with beta-tropomyosin; the M9R substitution within alpha-tropomyosin(slow) greatly reduced this interaction. Finally, transfection of the M9R mutated and wild-type alpha-tropomyosin(slow) into myoblasts revealed reduced incorporation into stress fibers and disruption of the filamentous actin network by the mutant protein. Collectively, these results provide insights into the clinical features and pathogenesis of M9R-TPM3 nemaline myopathy. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Peat, Rachel A %A Gécz, Jozef %A Fallon, Justin R %A Tarpey, Patrick S %A Smith, Raffaella %A Futreal, Andrew %A Stratton, Michael R %A Lamandé, Shireen R %A Yang, Nan %A North, Kathryn N %T Exclusion of biglycan mutations in a cohort of patients with neuromuscular disorders. %B Neuromuscular disorders : NMD %D 2008 %C United Kingdom %I Elsevier %V 18 %N 8 %P 606-9 %@ 0960-8966 %X Biglycan has been considered a good candidate for neuromuscular disease based on direct interactions with collagen VI and alpha-dystroglycan, both of which are linked with congenital muscular dystrophy (CMD). We screened 83 patients with CMD and other neuromuscular disorders and six controls for mutations and variations in the biglycan sequence. We identified a number of novel sequence variations. After family analysis and control screening we found that none of these polymorphisms were disease-causing mutations. Thus mutations in biglycan are not a common cause of neuromuscular disorders in our cohort. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Burns, Joshua %A Bray, Paula %A Cross, Lauren A %A North, Kathryn N %A Ryan, Monique M %A Ouvrier, Robert A %T Hand involvement in children with Charcot-Marie-Tooth disease type 1A. %B Neuromuscular disorders : NMD %D 2008 %C United Kingdom %I Elsevier %V 18 %N 0 %P 970-3 %@ 0960-8966 %X Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand strength, function and disease-related symptoms in children with CMT1A. Intrinsic and extrinsic hand strength was measured by hand-held dynamometry, function by nine-hole peg test, and disease-related symptoms by interview and examination in 84 affected children aged 2-16 years. Hand weakness and dysfunction was present from the earliest stages of the disease. While hand strength and function measures tended to increase with age throughout childhood, at no point did they reach normal values. Day-to-day hand problems such as poor handwriting, weakness, pain and sensory symptoms also worsened with age. The hand is affected at all ages in children with CMT1A, but may be under-recognised in its early stages, potentially delaying therapy. %Z FOR Codes: 110321 110904 111403 %0 Journal Article %~ PubMed %A Lo, Harriet P %A Cooper, Sandra T %A Evesson, Frances J %A Seto, Jane T %A Chiotis, Maria %A Tay, Valerie %A Compton, Alison G %A Cairns, Anita G %A Corbett, Alistair %A Macarthur, Daniel G %A Yang, Nan %A Reardon, Katrina %A North, Kathryn N %T Limb-girdle muscular dystrophy: Diagnostic evaluation, frequency and clues to pathogenesis. %B Neuromuscular disorders : NMD %D 2008 %C United Kingdom. %I Elsevier Ltd. %V 18 %N 0 %P 34-44 %@ 0960-8966 %X We characterized the frequency of limb-girdle muscular dystrophy (LGMD) subtypes in a cohort of 76 Australian muscular dystrophy patients using protein and DNA sequence analysis. Calpainopathies (8%) and dysferlinopathies (5%) are the most common causes of LGMD in Australia. In contrast to European populations, cases of LGMD2I (due to mutations in FKRP) are rare in Australasia (3%). We have identified a cohort of patients in whom all common disease candidates have been excluded, providing a valuable resource for identification of new disease genes. Cytoplasmic localization of dysferlin correlates with fiber regeneration in a subset of muscular dystrophy patients. In addition, we have identified a group of patients with unidentified forms of LGMD and with markedly abnormal dysferlin localization that does not correlate with fiber regeneration. This pattern is mimicked in primary caveolinopathy, suggesting a subset of these patients may also possess mutations within proteins required for membrane targeting of dysferlin. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Compton, Alison G %A Albrecht, Douglas E %A Seto, Jane T %A Cooper, Sandra T %A Ilkovski, Biljana %A Jones, Kristi J %A Challis, Daniel %A Mowat, David %A Ranscht, Barbara %A Bahlo, Melanie %A Froehner, Stanley C %A North, Kathryn N %T Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy. %B American journal of human genetics %D 2008 %C United States %I University of Chicago Press %V 83 %N 6 %P 714-24 %@ 1537-6605 %X We have previously reported a group of patients with congenital onset weakness associated with a deficiency of members of the syntrophin-alpha-dystrobrevin subcomplex and have demonstrated that loss of syntrophin and dystrobrevin from the sarcolemma of skeletal muscle can also be associated with denervation. Here, we have further studied four individuals from a consanguineous Egyptian family with a lethal congenital myopathy inherited in an autosomal-recessive fashion and characterized by a secondary loss of beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. We performed homozygosity mapping and candidate gene analysis and identified a mutation that segregates with disease within CNTN1, the gene encoding for the neural immunoglobulin family adhesion molecule, contactin-1. Contactin-1 transcripts were markedly decreased on gene-expression arrays of muscle from affected family members compared to controls. We demonstrate that contactin-1 is expressed at the neuromuscular junction (NMJ) in mice and man in addition to the previously documented expression in the central and peripheral nervous system. In patients with secondary dystroglycanopathies, we show that contactin-1 is abnormally localized to the sarcolemma instead of exclusively at the NMJ. The cntn1 null mouse presents with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. We propose that loss of contactin-1 from the NMJ impairs communication or adhesion between nerve and muscle resulting in the severe myopathic phenotype. This disorder is part of the continuum in the clinical spectrum of congenital myopathies and congenital myasthenic syndromes. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Clarke, Nigel F %A Kolski, Hanna %A Dye, Danielle E %A Lim, Esther %A Smith, Robert L L %A Patel, Rakesh %A Fahey, Michael C %A Bellance, Rémi %A Romero, Norma B %A Johnson, Edward S %A Labarre-Vila, Annick %A Monnier, Nicole %A Laing, Nigel G %A North, Kathryn N %T Mutations in TPM3 are a common cause of congenital fiber type disproportion. %B Annals of Neurology %D 2008 %C United States %I John Wiley & Sons %V 63 %N 3 %P 329-337 %@ 0364-5134 %X OBJECTIVE: Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding alpha-tropomyosin(slow) (TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD. METHODS AND RESULTS: We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant. INTERPRETATION: Mutation of TPM3 is the most common cause of CFTD reported to date. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Egan, Jonathan R %A Butler, Tanya L %A Cole, Andrew D %A Aharonyan, Avetis %A Baines, David %A Street, Neil %A Navaratnam, Manchula %A Biecker, Oliver %A Zazulak, Carla %A Au, Carol G %A Tan, Yee Mun %A North, Kathryn N %A Winlaw, David S %T Myocardial ischemia is more important than the effects of cardiopulmonary bypass on myocardial water handling and postoperative dysfunction: A pediatric animal model. %B The Journal of Thoracic and Cardiovascular Surgery %D 2008 %C United States %I Mosby %V 136 %N 5 %P 1265-1273.e2 %@ 1097-685X %X OBJECTIVES: Low cardiac output state is the principal cause of morbidity after surgical intervention for congenital heart disease. Myocardial ischemia-reperfusion injury, apoptosis, capillary leak syndrome, and myocardial edema are associated factors. We established a clinically relevant model to examine relationships between myocardial ischemia, edema, and cardiac dysfunction and to assess the role of the water transport proteins aquaporins. METHODS: Sixteen lambs were studied. Seven were control animals not undergoing cardiopulmonary bypass, and 9 underwent bypass. Six had 90 minutes of aortic crossclamping with blood cardioplegia and moderate hypothermia. The remaining 3 underwent cardiopulmonary bypass without aortic crossclamping. Hemodynamic and biochemical data were recorded, and myocardial edema, apoptotic markers, and aquaporin expression were determined after death. RESULTS: The group undergoing cardiopulmonary bypass with aortic crossclamping had a low cardiac output state, with early postoperative tachycardia, hypotension, increased serum lactate levels, and impaired tissue oxygen delivery (P < .05) compared with the group undergoing cardiopulmonary bypass without aortic crossclamping. The lambs undergoing cardiopulmonary bypass with aortic crossclamping had increased myocardial water (P < .05) compared with those not undergoing cardiopulmonary bypass and a 2-fold increase in aquaporin 1 mRNA expression (P < .05) compared with those not undergoing cardiopulmonary bypass and those undergoing cardiopulmonary bypass without aortic crossclamping. CONCLUSIONS: A temporal association between hemodynamic dysfunction, myocardial edema, and increased aquaporin 1 expression was demonstrated. Cardiopulmonary bypass without ischemia was associated with minimal edema, negligible myocardial dysfunction, and static aquaporin expression. Ischemic reperfusion injury is the main cause of myocardial edema and myocardial dysfunction, but a causal relationship between edema and dysfunction remains to be proved. %Z FOR Codes: 110323 110201 %0 Journal Article %~ PubMed %A Rose, Kristy J %A Burns, Joshua %A Ryan, Monique M %A Ouvrier, Robert A %A North, Kathryn N %T Reliability of quantifying foot and ankle muscle strength in very young children. %B Muscle & Nerve %D 2008 %C United States %I Elsevier Science Inc %V 37 %N 5 %P 626-631 %@ 1097-4598 %X Preschool-age children with neuromuscular disorders are often excluded from clinical trials due to the lack of reliable and objective strength measures. We evaluated the reliability of measuring foot and ankle muscle strength in 60 healthy children age 2-4 years. The strength of foot inversion and eversion, ankle plantarflexion, and dorsiflexion was measured using a hand-held dynamometer. Intrarater and interrater reliability of two assessors was determined for each muscle group using intraclass correlation coefficients (ICCs), 95% confidence intervals (CIs), and standard error of measurement (SEM). For all muscle groups intrarater (ICC(2,2) = 0.85-0.94, 95% CI = 0.75-0.96, SEM = 1.5-4.7 N) and interrater (ICC(2,1) = 0.88-0.96, 95% CI = 0.81-0.98, SEM = 1.2-4.6 N) reliability was high for all children. As expected, reliability was generally highest in 3- and 4-year-old children and lowest in 2-year-old children. Hand-held dynamometry can reliably measure foot and ankle strength in very young children and may help aid in diagnosis and in characterizing disease progression in disorders affecting the foot and ankle. %Z FOR Codes: 110905 111403 %0 Book Section %A North, Kathryn %A Laing, Nigel G %T Skeletal Muscle Alpha-Actin Diseases %B The Sarcomere and Skeletal Muscle Disease %D 2008 %C United States %I Springer %V %N %P 15-27 %@ 978-0-387-84846-4 %E Laing, Nigel G %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Amsili, Shira %A Zer, Hagit %A Hinderlich, Stephan %A Krause, Sabine %A Becker-Cohen, Michal %A MacArthur, Daniel G %A North, Kathryn N %A Mitrani-Rosenbaum, Stella %T UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) binds to alpha-actinin 1: novel pathways in skeletal muscle? %B PloS one %D 2008 %C United States %I Public Library of Science %V 3 %N 6 %P e2477 %@ 1932-6203 %X BACKGROUND: Hereditary inclusion body myopathy (HIBM) is a rare neuromuscular disorder caused by mutations in GNE, the key enzyme in the biosynthetic pathway of sialic acid. While the mechanism leading from GNE mutations to the HIBM phenotype is not yet understood, we searched for proteins potentially interacting with GNE, which could give some insights about novel putative biological functions of GNE in muscle. METHODOLOGY/PRINCIPAL FINDINGS: We used a Surface Plasmon Resonance (SPR)-Biosensor based assay to search for potential GNE interactors in anion exchanged fractions of human skeletal muscle primary culture cell lysate. Analysis of the positive fractions by in vitro binding assay revealed alpha-actinin 1 as a potential interactor of GNE. The direct interaction of the two proteins was assessed in vitro by SPR-Biosensor based kinetics analysis and in a cellular environment by a co-immunoprecipitation assay in GNE overexpressing 293T cells. Furthermore, immunohistochemistry on stretched mouse muscle suggest that both GNE and alpha-actinin 1 localize to an overlapping but not identical region of the myofibrillar apparatus centered on the Z line. CONCLUSIONS/SIGNIFICANCE: The interaction of GNE with alpha-actinin 1 might point to its involvement in alpha-actinin mediated processes. In addition these studies illustrate for the first time the expression of the non-muscle form of alpha-actinin, alpha-actinin 1, in mature skeletal muscle tissue, opening novel avenues for its specific function in the sarcomere. Although no significant difference could be detected in the binding kinetics of alpha-actinin 1 with either wild type or mutant GNE in our SPR biosensor based analysis, further investigation is needed to determine whether and how the interaction of GNE with alpha-actinin 1 in skeletal muscle is relevant to the putative muscle-specific function of alpha-actinin 1, and to the muscle-restricted pathology of HIBM. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A North, Kathryn %T What's new in congenital myopathies? %B Neuromuscular disorders : NMD %D 2008 %C United Kingdom %I Elsevier %V 18 %N 6 %P 433-42 %@ 0960-8966 %X The congenital myopathies are defined by distinctive morphologic abnormalities in skeletal muscle. Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes, with increasing availability of genetic and prenatal diagnosis. Identification of the disease genes, in combination with a reappraisal of muscle pathology and the development of tissue culture and animal models is now providing insights into disease pathogenesis and, for the first time, suggesting avenues for the development of specific therapies. This review highlights some of the major recent advances in each of these areas and demonstrates how a morphological classification of the congenital myopathies into subgroups remains useful for future research into gene discovery and understanding of disease mechanism. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A North, Kathryn %T Why is alpha-Actinin-3 Deficiency So Common in the General Population? The Evolution of Athletic Performance. %B Twin Research and Human Genetics %D 2008 %C Australia %I Australian Academic Press Pty. Ltd %V 11 %N 4 %P 384-394 %@ 1832-4274 %X Abstract ''We can now explain how this common genetic variation influences athletic performance as well as why it has become so common in the general population. There is a fascinating link between factors that influence survival in ancient humans and the factors that contribute to athletic abilities in modern man.'' The human ACTN3 gene encodes the protein alpha-actinin-3, a component of the contractile apparatus in fast skeletal muscle fibers. In 1999, we identified a common polymorphism in ACTN3 (R577X) that results in absence of alpha-actinin-3 in more than one billion people worldwide, despite the ACTN3 gene being highly conserved during human evolution. In 2003, we demonstrated that ACTN3 genotype influences elite athletic performance, and the association between ACTN3 genotype and skeletal muscle performance has since been replicated in athletes and non-athlete cohorts. We have also studied the evolution of the R577X allele during human evolution and demonstrated that the null (X) allele has undergone strong, recent positive selection in Europeans and Asian populations. We have developed an Actn3 knockout mouse model that replicates alpha-actinin-3 deficiency in humans and has already provided insight into the role of alpha-actinin-3 in the regulation of skeletal muscle metabolism, fibre size, muscle mass and contractile properties. In particular, mouse muscle lacking alpha-actinin-3 uses energy more efficiently, with the fast fibers displaying metabolic and contractile properties of slow oxidative fibers. While this favors endurance activities, the trade off is that the muscle cannot generate the rapid contractions needed to excel in sprinting. We propose that the shift towards more efficient aerobic muscle metabolism associated with alpha-actinin-3 deficiency also underlies the adaptive benefit of the 577X allele. Our future studies will focus on the effect of ACTN3 genotype on response to exercise and ageing, and the onset and severity of muscle disease phenotype. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A MacArthur, Daniel G %A North, Kathryn N %T ACTN3: A genetic influence on muscle function and athletic performance. %B Exercise and sport sciences reviews %D 2007 %C United States %I Lippincott Williams & Wilkins %V 35 %N 1 %P 30-34 %@ 0091-6331 %X A common variant of the ACTN3 gene, R577X, results in complete deficiency of the alpha-actinin-3 protein in the fast skeletal muscle fibers of more than a billion humans worldwide. We review the evidence that this genetic variant is strongly associated with elite athlete status and with normal variation in human muscle strength and sprinting speed. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Watt, Sharon %A Shores, E Arthur %A North, Kathryn %T An Examination of Lexical and Sublexical Reading Skills in Children with Neurofibromatosis Type 1. %B Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence %D 2007 %C United States %I Lippincott Williams & Wilkins %V 14 %N 0 %P 401-18 %@ 0929-7049 %X Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with a high frequency of cognitive and learning difficulties. Based on discrepancies between IQ and academic achievement, approximately 17% of children with NF1 have been classified as having reading impairments. In this study, the lexical and sublexical reading skills of children with NF1 (n = 30) were examined using the Castles'' Word/Non-Word Test (modified version), together with measures of neuropsychological functioning and academic achievement. Twenty children (67%) demonstrated deficits in one or more reading subskills, with 75% of these meeting criteria for phonological dyslexia and 20% classified with mixed dyslexia. These findings indicate that a large proportion of children with NF1 may be characterized by a specific difficulty with the sublexical procedure, suggesting a difficulty employing spelling-to-sound rules to assemble a pronunciation when reading. In line with previous studies, the present findings also suggest that discrepancy-based methods may not be sufficiently sensitive to identify children who experience reading difficulties. %Z FOR Codes: 110999 %0 Journal Article %~ Isi %A Jamurtas, A %A Wilson, RH %A Pitsiladis, YP %A MacArthur, DG %A Tsiokanos, A %A Bailey, MES %A Yang, N %A Moran, CN %A North, K %T Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks %B EUROPEAN JOURNAL OF HUMAN GENETICS %D 2007 %C UK %I Nature Publishing %V 15 %N %P 88-93 %@ 1018-4813 %X %Z FOR Codes: 111603 %0 Journal Article %~ PubMed %A Dulai, Sukhdeep %A Briody, Julie %A Schindeler, Aaron %A North, Kathryn N %A Cowell, Christopher T %A Little, David G %T Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort. %B Journal of pediatric orthopedics %D 2007 %C United States %I Lippincott Williams & Wilkins %V 27 %N 4 %P 472-475 %@ 0271-6798 %X Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3000 live births. It is well documented to be associated with bony deformities and other orthopaedic problems. Based on our observation that NF1 patients undergoing orthopaedic surgery often had osteopenic bone, we performed a study to assess the bone mineral density of a cohort of children with NF1 without orthopaedic defects.Twenty-three patients were recruited from the neurofibromatosis clinic. The bone mineral density of the total body, lumbar spine, and proximal femur was measured using dual-energy x-ray absorptiometry. Quantitative ultrasound was used to measure broadband ultrasonic attenuation at both heels. The group''s mean dual-energy x-ray absorptiometry sex- and age-matched Z scores were below normal (-0.8 +/- 1.1, -0.8 +/- 1.2, -0.7 +/- 0.8, -0.6 +/- 1.1, -0.6 +/- 0.9, -0.6 +/- 1.1 for the total body, arms, legs, lumbar spine, and right and left femoral neck, respectively; all P < 0.01). Although some individuals had normal bone mass, 30% had total body Z scores below -1.5. The mean heel broadband ultrasonic attenuation Z score was also lower than normal (-0.8 +/- 0.6; P < 0.001).Children with NF1 have a general tendency toward osteopenia, suggesting an abnormal underlying bone phenotype. This may be relevant when considering operative intervention and, if better understood, may partially explain poor bone healing associated with NF1. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Ryan, Monique M %A Sy, Catherine %A Rudge, Sian %A Ellaway, Carolyn %A Ketteridge, David %A Roddick, Laurence G %A Iannaccone, Susan T %A Kornberg, Andrew J %A North, Kathryn N %T Dietary L-Tyrosine Supplementation in Nemaline Myopathy. %B Journal of child neurology %D 2007 %C United States %I Sage Science Press %V 23 %N 0 %P 609-13 %@ 0883-0738 %X Nemaline myopathy is defined by the presence of nemaline bodies, or rods, on muscle biopsy. Facial and bulbar weakness in nemaline myopathy cause chewing and swallowing difficulties, recurrent aspiration, and poor control of oral secretions. This article discusses 5 patients (4 infants and 1 adolescent) with nemaline myopathy who received dietary supplementation with L-tyrosine (250 to 3000 mg/day). All 4 infants were reported to have an initial decrease in sialorrhoea and an increase in energy levels. The adolescent showed improved strength and exercise tolerance. No adverse effects of treatment were observed. Dietary tyrosine supplementation may improve bulbar function, activity levels, and exercise tolerance in nemaline myopathy. %Z FOR Codes: %0 Journal Article %~ PubMed %A Eisenberg, Iris %A Eran, Alal %A Nishino, Ichizo %A Moggio, Maurizio %A Lamperti, Costanza %A Amato, Anthony A %A Lidov, Hart G %A Kang, Peter B %A North, Kathryn N %A Mitrani-Rosenbaum, Stella %A Flanigan, Kevin M %A Neely, Lori A %A Whitney, Duncan %A Beggs, Alan H %A Kohane, Isaac S %A Kunkel, Louis M %T Distinctive patterns of microRNA expression in primary muscular disorders. %B Proceedings of the National Academy of Sciences of the United States of America %D 2007 %C US %I National Academy of Sciences %V 104 %N 43 %P 17016-17021 %@ 1091-6490 %X The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA-miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology. %Z FOR Codes: %0 Journal Article %~ PubMed %A Cooper, Sandra T %A Kizana, Eddy %A Yates, Jonathon D %A Lo, Harriet P %A Yang, Nan %A Wu, Zhan He %A Alexander, Ian E %A North, Kathryn N %T Dystrophinopathy carrier determination and detection of protein deficiencies in muscular dystrophy using lentiviral MyoD-forced myogenesis. %B Neuromuscular disorders : NMD %D 2007 %C United Kingdom. %I Elsevier Ltd. %V 17 %N 4 %P 276-284 %@ 0960-8966 %X The objective of this study is to expand the applications of MyoD-forced myogenesis for research and diagnosis of human muscle disorders using a lentiviral vector (LVhMyoD) for efficient trans-differentiation of patient primary cells. LVhMyoD transduced cells readily formed striated, multinucleate myotubes expressing a wide range of genes associated with muscular dystrophy (dystrophin, dysferlin, sarcoglycans, caveolin-3) and congenital myopathy (nebulin, actin, desmin, tropomyosin, troponin). We demonstrate that MyoD gene-modified fibroblasts reproduce protein deficiencies associated with different forms of muscular dystrophy, and confirm that LVhMyoD gene-modified chorionic villus can be used successfully to determine the dystrophin status of the developing fetus, augmenting prenatal diagnosis of dystrophinopathy patients. Using muscle-specific cDNA derived from LVhMyoD gene-modified patient cells, we identified a female carrier bearing a large dystrophin deletion and a previously unidentified non-coding splice-site mutation within dystrophin in a Becker muscular dystrophy patient. This study highlights the significant potential of lentiviral MyoD-forced myogenesis for study of a wide range of human muscle disorders; a field constrained by the limited availability of human tissue. LVhMyoD gene-modified patient cells provide a renewable source of mutant protein and muscle-specific mRNA, facilitating accelerated mutation screening of large genes, molecular analyses of splicing abnormalities and study of disease-causing mutations. %Z FOR Codes: 110311 %0 Book Section %A Macarthur, Daniel G %A North, Kathryn %T Genes and human elite athletic performance %B East African running: toward a cross-disciplinary perspective %D 2007 %C United States %I Routledge %V %N %P 217-233 %@ 978-0-203-09934-6 %E Pitsiladis, Yannis %E Bale, John %E Sharp, Craig %E Noakes, Timothy %X %Z FOR Codes: %0 Journal Article %~ PubMed %A Domazetovska, Ana %A Ilkovski, Biljana %A Kumar, Vikash %A Valova, Valentina A %A Vandebrouck, Aurelie %A Hutchinson, David O %A Robinson, Phillip J %A Cooper, Sandra T %A Sparrow, John C %A Peckham, Michelle %A North, Kathryn N %T Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness. %B Annals of neurology %D 2007 %C United States %I John Wiley & Sons, Inc %V 62 %N 6 %P 597-608 %@ 0364-5134 %X Mutations in the alpha-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes. Mutations at Val163 in ACTA1 result in pure intranuclear rod myopathy; however, the molecular mechanisms by which mutations at Val163 lead to intranuclear rod formation and muscle weakness are unknown. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Macarthur, Daniel G %A Seto, Jane T %A Raftery, Joanna M %A Quinlan, Kate G %A Huttley, Gavin A %A Hook, Jeff W %A Lemckert, Frances A %A Kee, Anthony J %A Edwards, Michael R %A Berman, Yemima %A Hardeman, Edna C %A Gunning, Peter W %A Easteal, Simon %A Yang, Nan %A North, Kathryn N %T Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. %B Nature genetics %D 2007 %C US %I Nature Publishing Group %V 39 %N 10 %P 1261-5 %@ 1061-4036 %X More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Domazetovska, Ana %A Ilkovski, Biljana %A Cooper, Sandra T %A Ghoddusi, Majid %A Hardeman, Edna C %A Minamide, Laurie S %A Gunning, Peter W %A Bamburg, James R %A North, Kathryn N %T Mechanisms underlying intranuclear rod formation. %B Brain : a journal of neurology %D 2007 %C UK %I Oxford University Press %V 130 %N Pt 12 %P 3275-84 %@ 0006-8950 %X Specific mutations within the alpha-skeletal actin gene (ACTA1) result in intranuclear rod myopathy (IRM), characterized by rod-like aggregates containing actin and alpha-actinin-2 inside the nucleus of muscle cells. The mechanism leading to formation of intranuclear aggregates containing sarcomeric proteins and their impact on cell function and contribution to disease pathogenesis is unknown. In this study, we transfected muscle and non-muscle cells with mutants of alpha-skeletal actin (Val163Leu, Val163Met) associated with intranuclear rod myopathy. By live-cell imaging we demonstrate that nuclear aggregates of actin form within the nuclear compartment, rather than entering the nucleus after formation in the cytoplasm, and are highly motile and dynamic structures. Thus, the nuclear environment supports the polymerization of actin and the movement and coalescence of the polymerized actin into larger structures. We show that the organization of actin within these aggregates is influenced by the binding of alpha-actinin, and that alpha-actinin is normally present in the nucleus of muscle and non-muscle cells. Furthermore, we demonstrate that, under conditions of cell stress (cytoskeletal disruption and ATP depletion), WT skeletal actin forms aggregates within the nucleus that are similar in morphology to those formed by the mutant actin, suggesting a common pathogenic mechanism for aggregate formation. Finally, we show that the presence of intranuclear actin aggregates significantly decreases the mitotic index and hence impacts on the function of the cell. Intranuclear aggregates thus likely contribute to the pathogenesis of muscle weakness in intranuclear rod myopathy. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Baker, Naomi L %A Mörgelin, Matthias %A Pace, Rishika A %A Peat, Rachel A %A Adams, Naomi E %A Gardner, R J McKinlay %A Rowland, Lewis P %A Miller, Geoffrey %A De Jonghe, Peter %A Ceulemans, Berten %A Hannibal, Mark C %A Edwards, Matthew %A Thompson, Elizabeth M %A Jacobson, Richard %A Quinlivan, Ros C M %A Aftimos, Salim %A Kornberg, Andrew J %A North, Kathryn N %A Bateman, John F %A Lamandé, Shireen R %T Molecular consequences of dominant Bethlem myopathy collagen VI mutations. %B Annals of neurology %D 2007 %C United States %I John Wiley & Sons, Inc %V 62 %N 4 %P 390-405 %@ 0364-5134 %X OBJECTIVE: Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown. METHODS: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. RESULTS: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients. INTERPRETATION: The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle. %Z FOR Codes: %0 Journal Article %~ PubMed %A Koy, A %A Ilkovski, B %A Laing, N %A North, K %A Weis, J %A Neuen-Jacob, E %A Mayatepek, E %A Voit, T %T Nemaline myopathy with exclusively intranuclear rods and a novel mutation in ACTA1 (Q139H). %B Neuropediatrics %D 2007 %C Germany %I Georg Thieme Verlag %V 38 %N 6 %P 282-286 %@ 0174-304X %X Nemaline myopathies (NM) are a rare group of muscle disorders, but represent one of the most common forms of congenital myopathy. The clinical picture ranges from severe muscular hypotonia often leading to death during childhood to mild forms with long life expectancy. Diagnosis is made by muscle biopsy showing characteristic sarcoplasmic and sometimes intranuclear rod bodies. So far, disease-associated mutations have been detected in six genes without any simple correlation between genotype and phenotype or histological findings. We report a patient with a phenotype typical of congenital onset nemaline myopathy and exclusively intranuclear rods. Mutation analysis revealed a new heterozygous missense mutation in exon 3 of the ACTA1 gene (Q139H). Molecular modelling predicts that substitution of Q139 for H139 alters the amino acid side chains and hydrogen bonding which may alter the nucleotide binding cleft by adding ''bulk'' to the mutated molecule. Two-dimensional gel electrophoresis demonstrates that mutant actin Q139H is expressed at approximately half the level of wild-type actin in the patient''s muscle. We speculate that these alterations, although not directly affecting the nuclear export signal, negatively interfere with the nuclear export of the mutated protein and thereby cause retention of mutant actin and intranuclear rod formation. %Z FOR Codes: 110902 %0 Journal Article %~ PubMed %A Young, H K %A Lowe, A %A Fitzgerald, D A %A Seton, C %A Waters, K A %A Kenny, E %A Hynan, L S %A Iannaccone, S T %A North, K N %A Ryan, M M %T Outcome of noninvasive ventilation in children with neuromuscular disease. %B Neurology %D 2007 %C US %I Lippincott Williams & Wilkins %V 68 %N 3 %P 198-201 %@ 0028-3878 %X OBJECTIVE: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. METHODS: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. RESULTS: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. CONCLUSION: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life. %Z FOR Codes: 110904 110203 %0 Journal Article %~ PubMed %A Godfrey, Caroline %A Clement, Emma %A Mein, Rachael %A Brockington, Martin %A Smith, Janine %A Talim, Beril %A Straub, Volker %A Robb, Stephanie %A Quinlivan, Ros %A Feng, Lucy %A Jimenez-Mallebrera, Cecilia %A Mercuri, Eugenio %A Manzur, Adnan Y %A Kinali, Maria %A Torelli, Silvia %A Brown, Susan C %A Sewry, Caroline A %A Bushby, Kate %A Topaloglu, Haluk %A North, Kathryn %A Abbs, Stephen %A Muntoni, Francesco %T Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. %B Brain : a journal of neurology %D 2007 %C United Kingdom. %I Oxford University Press %V 130 %N pt 10 %P 2725-35 %@ 1460-2156 %X Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Hyman, Shelley L %A Gill, Deepak S %A Shores, Edwin Arthur %A Steinberg, Adam %A North, Kathryn N %T T2-Hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. %B Journal of neurology, neurosurgery, and psychiatry %D 2007 %C United Kingdom %I BMJ Publishing Group %V 78 %N 10 %P 1088-91 %@ 0022-3050 %X Neurofibromatosis type 1 (NF1) is a single gene disorder associated with a high frequency of cognitive deficits and a complex cognitive phenotype. These cognitive deficits have been associated with focal areas of high signal intensity on T2 weighted MRI images but the relationship remains controversial. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Yang, Nan %A Macarthur, Daniel %A Wolde, Bezabhe %A Onywera, Vincent %A Boit, Michael %A Lau, Sau %A Wilson, Richard %A Scott, Robert %A Pitsiladis, Yannis %A North, Kathryn %T The ACTN3 R577X Polymorphism in East and West African Athletes. %B Medicine and science in sports and exercise %D 2007 %C USA. %I Lippincott Williams & Wilkins. %V 39 %N 11 %P 1985-1988 %@ 0195-9131 %X PURPOSE:: To determine the frequency of the ACTN3 R577X polymorphism (functional R allele and nonfunctional X allele) in a variety of African populations and to examine its influence on the success of elite East African endurance runners and West African sprinters. METHODS:: The R577X polymorphism was genotyped in 198 Ethiopian controls and 76 elite Ethiopian endurance athletes, 158 Kenyan controls and 284 elite Kenyan endurance runners, and 60 Nigerian controls and 62 elite Nigerian power athletes. Statistical analyses were performed by exact tests of population differentiation, using Arlequin, version 3. Analyses were carried out using 1 x 10 Markov chain steps, and 1 x 10 dememorization steps. RESULTS:: The frequency of the X allele was extremely low among Kenyans and Nigerians ( approximately 1% homozygosity) and higher in Ethiopians ( approximately 11% homozygosity). The low baseline frequencies of the three populations tested mean that any associations with sprint performance would likely be obscured. In Ethiopians, where baseline levels of 577XX were about 11%, there was no increased frequency in the endurance athletes. CONCLUSION:: Our data suggest that alpha-actinin-3 deficiency is not a major influence on performance in African athletes. %Z FOR Codes: 111601 %0 Journal Article %~ PubMed %A Peat, R A %A Smith, J M %A Compton, A G %A Baker, N L %A Pace, R A %A Burkin, D J %A Kaufman, S J %A Lamandé, S R %A North, K N %T The diagnosis and etiology of congenital muscular dystrophy. %B Neurology %D 2007 %C US %I Lippincott Williams & Wilkins %V 71 %N 0 %P 312-21 %@ 0028-3878 %X We aimed to determine the frequency of all known forms of congenital muscular dystrophy (CMD) in a large Australasian cohort. %Z FOR Codes: 110999 %0 Journal Article %~ PubMed %A Clarke, Nigel F %A Ilkovski, Biljana %A Cooper, Sandra %A Valova, Valentina A %A Robinson, Phillip J %A Nonaka, Ikuya %A Feng, Juan-Juan %A Marston, Steven %A North, Kathryn %T The pathogenesis of ACTA1-related congenital fiber type disproportion. %B Annals of neurology %D 2007 %C United States %I John Wiley & Sons, Inc %V 61 %N 6 %P 552-61 %@ 0364-5134 %X Mutations in ACTA1 have been associated with a variety of changes in muscle histology that likely result from fundamental differences in the way that ACTA1 mutations disrupt muscle function. Recently, we reported three patients with congenital fiber type disproportion (CFTD) caused by novel heterozygous missense mutations in ACTA1 (D292V, L221P, P332S) with marked type 1 fiber hypotrophy as the only pathological finding on muscle biopsy. We have investigated the basis for the histological differences between these CFTD patients and patients with ACTA1 nemaline myopathy (NM). %Z FOR Codes: 110311 110311 110311 %0 Journal Article %~ PubMed %A Barton, B %A North, K %T The self-concept of children and adolescents with neurofibromatosis type 1. %B Child: care, health and development %D 2007 %C United Kingdom %I Blackwell Publishing Ltd. %V 33 %N 4 %P 401-408 %@ 0305-1862 %X BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder associated with cognitive deficits, learning problems, medical complications and cosmetic disfigurement. Despite the wide-ranging impact of NF1, very few studies have examined the psychosocial adjustment of individuals with NF1, and in particular, self-concept. The aims of this study were threefold: (i) to examine the self-concept of children and adolescents with NF1; (ii) to compare the self-concept of children with NF1 (NF1 only), children with NF1 and learning difficulties [NF1 + LA (low achievement)], and children with NF1 and attention deficit hyperactivity disorder (ADHD) (NF1 + ADHD); and (iii) to examine the academic self-concept of these three groups relative to objective criteria - academic achievement and teacher ratings of academic competence. METHODS: Measures of self-concept, academic achievement and intelligence were administered to 49 children and 26 adolescents with NF1. Parents and teachers completed behavioural rating scales. RESULTS: The majority of children and adolescents with NF1 reported positive global self-concept, with some exceptions on specific domains. Children and adolescents with NF1 reported significantly poorer self-concept for physical abilities. Adolescents also reported significantly poorer self-concept for mathematics and general self when compared with normative mean values. Clinical severity of NF1 was not a significant predictor of self-concept for physical appearance or physical abilities. Despite a significant difference between NF1 only, NF1 + LA and NF1 + ADHD groups on measures of academic achievement and teacher ratings of academic competence, there was no significant difference between the groups for academic domains of self-concept, or any other domain of self-concept. All three groups reported inflated academic self-perceptions relative to objective criteria. CONCLUSION: Children and adolescents with NF1 are most likely to develop negative self-concepts about their physical and sporting abilities. Inflated academic self-perceptions are discussed in light of the positive illusory bias, which may serve as an adaptive or protective function. %Z FOR Codes: 110311 %0 Journal Article %~ PubMed %A Vlahovich, Nicole %A Schevzov, Galina %A Nair-Shaliker, Visalini %A Ilkovski, Biljana %A Artap, Stanley T %A Joya, Josephine E %A Kee, Anthony J %A North, Kathryn N %A Gunning, Peter W %A Hardeman, Edna C %T Tropomyosin 4 defines novel filaments in skeletal muscle associated with muscle remodelling/regeneration in normal and diseased muscle. %B Cell motility and the cytoskeleton %D 2007 %C United States %I John Wiley & Sons, Inc. %V 65 %N 0 %P 73-85 %@ 0886-1544 %X The organisation of structural proteins in muscle into highly ordered sarcomeres occurs during development, regeneration and focal repair of skeletal muscle fibers. The involvement of cytoskeletal proteins in this process has been documented, with nonmuscle gamma-actin found to play a role in sarcomere assembly during muscle differentiation and also shown to be up-regulated in dystrophic muscles which undergo regeneration and repair [Lloyd et al.,2004; Hanft et al.,2006]. Here, we show that a cytoskeletal tropomyosin (Tm), Tm4, defines actin filaments in two novel compartments in muscle fibers: a Z-line associated cytoskeleton (Z-LAC), similar to a structure we have reported previously [Kee et al.,2004], and longitudinal filaments that are orientated parallel to the sarcomeric apparatus, present during myofiber growth and repair/regeneration. Tm4 is upregulated in paradigms of muscle repair including induced regeneration and focal repair and in muscle diseases with repair/regeneration features, muscular dystrophy and nemaline myopathy. Longitudinal Tm4-defined filaments also are present in diseased muscle. Transition of the Tm4-defined filaments from a longitudinal to a Z-LAC orientation is observed during the course of muscle regeneration. This Tm4-defined cytoskeleton is a marker of growth and repair/regeneration in response to injury, disease state and stress in skeletal muscle. %Z FOR Codes: 111601 %0 Journal Article %~ PubMed %A Peat, Rachel A %A Baker, Naomi L %A Jones, Kristi J %A North, Kathryn N %A Lamandé, Shireen R %T Variable penetrance of COL6A1 null mutations: Implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families. %B Neuromuscular disorders : NMD %D 2007 %C United Kingdom. %I Elsevier Ltd. %V 17 %N 7 %P 547-557 %@ 0960-8966 %X Collagen VI mutations cause mild Bethlem myopathy and severe, progressive Ullrich congenital muscular dystrophy (UCMD). We identified a novel homozygous COL6A1 premature termination mutation in a UCMD patient that causes nonsense-mediated mRNA decay. Collagen VI microfibrils cannot be detected in muscle or fibroblasts. The parents are heterozygous carriers of the mutation and their fibroblasts produce reduced amounts of collagen VI. The molecular findings in the parents are analogous to those reported for a heterozygous COL6A1 premature termination mutation that causes Bethlem myopathy. However, the parents of our UCMD proband are clinically normal. The proband''s brother, also a carrier, has clinical features consistent with a mild collagen VI phenotype. Following a request for prenatal diagnosis in a subsequent pregnancy we found the fetus was a heterozygous carrier indicating that it would not be affected with severe UCMD. COL6A1 premature termination mutations exhibit variable penetrance necessitating a cautious approach to genetic counselling. %Z FOR Codes: 110311