%0 Journal Article
%~ PubMed
%A Collins, D
%A Angles, J M
%A Christodoulou, J
%A Spielman, D
%A Lindsay, S A
%A Boyd, J
%A Krockenberger, M B
%T Severe Subacute Necrotizing Encephalopathy (Leigh-like Syndrome) in American Staffordshire Bull Terrier Dogs.
%B Journal of Comparative Pathology
%D 2013
%C United Kingdom
%I Elsevier Ltd.
%V 148
%N 4
%P 345-353
%@ 1532-3129
%X 
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Tchan, M C
%A Wilcken, B
%A Christodoulou, J
%T The mild form of menkes disease: a 34 year progress report on the original case.
%B JIMD Reports
%D 2013
%C Germany
%I Springer
%V 9
%N 
%P 81-84
%@ 2192-8304
%X 
%Z FOR Codes: 60499


%0 Journal Article
%~ PubMed
%A Williamson, Sarah L
%A Giudici, Laura
%A Kilstrup-Nielsen, Charlotte
%A Gold, Wendy
%A Pelka, Gregory J
%A Tam, Patrick P L
%A Grimm, Andrew
%A Prodi, Dionigio
%A Landsberger, Nicoletta
%A Christodoulou, John
%T A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.
%B Human Genetics
%D 2012
%C Germany
%I Springer
%V 131
%N 2
%P 187-200
%@ 0340-6717
%X The X-linked cyclin-dependent kinase-like 5 (CDKL5) gene is an important molecular determinant of early-onset intractable seizures with infantile spasms and Rett syndrome-like phenotype. The gene encodes a kinase that may influence components of molecular pathways associated with MeCP2. In humans there are two previously reported splice variants that differ in the 5'' untranslated exons and produce the same 115??kDa protein. Furthermore, very recently, a novel transcript including a novel exon (16b) has been described. By aligning both the human and mouse CDKL5 proteins to the orthologs of other species, we identified a theoretical 107??kDa isoform with an alternative C-terminus that terminates in intron 18. In human brain and all other tissues investigated except the testis, this novel isoform is the major CDKL5 transcript. The detailed characterisation of this novel isoform of CDKL5 reveals functional and subcellular localisation attributes that overlap greatly, but not completely, with that of the previously studied human CDKL5 protein. Considering its predominant expression in the human and mouse brain, we believe that this novel isoform is likely to be of primary pathogenic importance in human diseases associated with CDKL5 deficiency, and suggest that screening of the related intronic sequence should be included in the molecular genetic analyses of patients with a suggestive clinical phenotype.
%Z FOR Codes: 60405 60407


%0 Book Section
%A Alodaib, Ahmad N
%A Carpenter, Kevin
%A Wiley, Veronica
%A Wotton, Tiffany
%A Christodoulou, John
%A Wilcken, Bridget
%T Homocysteine Measurement in Dried Blood Spot for Neonatal Detection of Homocystinurias
%B JIMD Reports - Case and Research Reports, 2012/2
%D 2012
%C Germany
%I Springer
%V 
%N 
%P 1-6
%@ 9783642280955
%X 
%Z FOR Codes: 110101 111401


%0 Book Section
%A De Greef, Elizabeth
%A Christodoulou, John
%A Alexander, Ian
%A Shun, Albert
%A O'Loughlin, Edward
%A Thorburn, David R
%A Jermyn, Vicki
%A Stormon, Michael
%T Mitochondrial Respiratory Chain Hepatopathies: Role of Liver Transplantation. A Case Series of Five Patients
%B JIMD Reports - Case and Research Reports, 2012/1
%D 2012
%C United Kingdom
%I Springer
%V 
%N 
%P 5-11
%@ 9783642257513
%X 
%Z FOR Codes: 111403


%0 Journal Article
%~ PubMed
%A Huppke, Peter
%A Brendel, Cornelia
%A Korenke, Georg Christoph
%A Marquardt, Iris
%A Donsante, Anthony
%A Yi, Ling
%A Hicks, Julia D
%A Steinbach, Peter J
%A Wilson, Callum
%A Elpeleg, Orly
%A Møller, Lisbeth Birk
%A Christodoulou, John
%A Kaler, Stephen G
%A Gärtner, Jutta
%T Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase.
%B Human Mutation
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 33
%N 8
%P 1207-1215
%@ 1059-7794
%X Copper (Cu) is a trace metal that readily gains and donates electrons, a property that renders it desirable as an enzyme cofactor but dangerous as a source of free radicals. To regulate cellular Cu metabolism, an elaborate system of chaperones and transporters has evolved, although no human Cu chaperone mutations have been described to date. We describe a child from a consanguineous family who inherited homozygous mutations in the SLC33A1, encoding an acetyl CoA transporter, and in CCS, encoding the Cu chaperone for superoxide dismutase. The CCS mutation, p.Arg163Trp, predicts substitution of a highly conserved arginine residue at position 163, with tryptophan in domain II of CCS, which interacts directly with superoxide dismutase 1 (SOD1). Biochemical analyses of the patient''s fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys7? (CCS homolog) yeast complementation support the pathogenicity of the mutation. Expression of CCS was reduced and binding of CCS to SOD1 impaired. As a result, this mutation causes reduced SOD1 activity and may impair other mechanisms important for normal Cu homeostasis. CCS-Arg163Trp represents the primary example of a human mutation in a gene coding for a Cu chaperone.
%Z FOR Codes: 111499 60408 110903


%0 Journal Article
%~ PubMed
%A Calvo, Sarah E
%A Compton, Alison G
%A Hershman, Steven G
%A Lim, Sze Chern
%A Lieber, Daniel S
%A Tucker, Elena J
%A Laskowski, Adrienne
%A Garone, Caterina
%A Liu, Shangtao
%A Jaffe, David B
%A Christodoulou, John
%A Fletcher, Janice M
%A Bruno, Damien L
%A Goldblatt, Jack
%A Dimauro, Salvatore
%A Thorburn, David R
%A Mootha, Vamsi K
%T Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.
%B Science Translational Medicine
%D 2012
%C United States
%I American Association for the Advancement of Scienc
%V 4
%N 118
%P 118ra10
%@ 1946-6242
%X Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings.
%Z FOR Codes: 111403 60412


%0 Journal Article
%~ PubMed
%A Huppke, Peter
%A Brendel, Cornelia
%A Kalscheuer, Vera
%A Korenke, Georg Christoph
%A Marquardt, Iris
%A Freisinger, Peter
%A Christodoulou, John
%A Hillebrand, Merle
%A Pitelet, Gaele
%A Wilson, Callum
%A Gruber-Sedlmayr, Ursula
%A Ullmann, Reinhard
%A Haas, Stefan
%A Elpeleg, Orly
%A Nürnberg, Gudrun
%A Nürnberg, Peter
%A Dad, Shzeena
%A Møller, Lisbeth Birk
%A Kaler, Stephen G
%A Gärtner, Jutta
%T Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin.
%B American Journal of Human Genetics
%D 2012
%C United States
%I Cell Press
%V 90
%N 1
%P 61-68
%@ 0002-9297
%X Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.
%Z FOR Codes: 60412


%0 Journal Article
%A Ho, Gladys
%A Gold, Wendy
%A Williamson, Sarah L
%A Christodoulou, John
%T Pathogenicity of C-terminal mutations in CDKL5
%B Journal of Pediatric Epilepsy
%D 2012
%C Netherlands
%I I O S Press
%V 1
%N 
%P 185-186
%@ 2146-457X
%X 
%Z FOR Codes: 110902


%0 Journal Article
%~ PubMed
%A Moran, Rocio
%A Kuilenburg, André B P
%A Duley, John
%A Nabuurs, Sander B
%A Retno-Fitri, Aditia
%A Christodoulou, John
%A Roelofsen, Jeroen
%A Yntema, Helger G
%A Friedman, Neil R
%A van Bokhoven, Hans
%A de Brouwer, Arjan P M
%T Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I.
%B American Journal of Medical Genetics. Part A
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 158A
%N 2
%P 455-460
%@ 1552-4833
%X We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected.
%Z FOR Codes: 60406


%0 Journal Article
%~ PubMed
%A Georgiou, Theodoros
%A Ho, Gladys
%A Vogazianos, Marios
%A Dionysiou, Maria
%A Nicolaou, Alexia
%A Chappa, Georgia
%A Nicolaides, Paola
%A Stylianidou, Goula
%A Christodoulou, John
%A Drousiotou, Anthi
%T The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening.
%B Clinical Biochemistry
%D 2012
%C United States
%I Elsevier Inc.
%V 45
%N 7-8
%P 588-592
%@ 1873-2933
%X The purpose of this study was to identify the mutations responsible for phenylalanine hydroxylase deficiency in Cypriot patients detected through neonatal screening.
%Z FOR Codes: 111499 60499


%0 Journal Article
%~ PubMed
%A Armani, Roksana
%A Archer, Hayley
%A Clarke, Angus
%A Vasudevan, Pradeep
%A Zweier, Christiane
%A Ho, Gladys
%A Williamson, Sarah
%A Cloosterman, Desiree
%A Yang, Nan
%A Christodoulou, John
%T Transcription factor 4 and myocyte enhancer factor 2C mutations are not common causes of Rett syndrome.
%B American Journal of Medical Genetics. Part A
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 158A
%N 4
%P 713-719
%@ 1552-4833
%X The systematic screening of Rett syndrome (RTT) patients for pathogenetic sequence variations has focused on three genes that have been associated with RTT or related clinical phenotypes, namely MECP2, CDKL5, and FOXG1. More recently, it has been suggested that phenotypes associated with TCF4 and MEF2C mutations may represent a form of RTT. Here we report on the screening of the TCF4 and MEF2C genes in a cohort of 81 classical, atypical, and incomplete atypical RTT patients harboring no known mutations in MECP2, CDKL5, and FOXG1 genes. No pathogenetic sequence variations were identified in the MEF2C gene in our cohort. However, a frameshift mutation in TCF4 was identified in a patient with a clinical diagnosis of "variant" RTT, in whom the clinical evolution later raised the possibility of Pitt-Hopkins syndrome. Although our results suggest that these genes are not commonly associated with RTT, we note the clinical similarity between RTT and Pitt-Hopkins syndrome, and suggest that RTT patients with no mutation identified in MECP2 be considered for molecular screening of the TCF4 gene.
%Z FOR Codes: 110903 111403


%0 Journal Article
%~ PubMed
%A Christodoulou, John
%T Trimethylaminuria: An under-recognised and socially debilitating metabolic disorder.
%B Journal of Paediatrics and Child Health
%D 2012
%C United Kingdom, Australia
%I Wiley-Blackwell Publishing Ltd.
%V 48
%N 3
%P E153-155
%@ 1034-4810
%X Primary flavin mono-oxygenase 3 deficiency, an inborn error of choline metabolism, leads to an accumulation of trimethylamine, which because of its associated pungent odour of rotting fish, is a socially crippling disorder. Although it often has its onset in early childhood, it may take years or even decades before the diagnosis is established. In this review the clinical biochemical and genetic features of the disorder are reported. The principles of therapy will also be covered, including dietary, pharmacological approaches, as well as techniques used to manipulate the gastrointestinal environment as a strategy to reduce the gastrointestinal load of trimethylamine.
%Z FOR Codes: 111403 110107


%0 Journal Article
%~ PubMed
%A Alodaib, A
%A Carpenter, K
%A Wiley, V
%A Sim, K
%A Christodoulou, J
%A Wilcken, B
%T An improved ultra performance liquid chromatography-tandem mass spectrometry method for the determination of alloisoleucine and branched chain amino acids in dried blood samples.
%B Annals of clinical biochemistry
%D 2011
%C United Kingdom
%I Royal Society of Medicine Press Ltd.
%V 48
%N 5
%P 468-70
%@ 1758-1001
%X Branched chain amino acid (BCAA) analysis is needed for the diagnosis and management of patients with maple syrup urine disease (MSUD). We report an improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of BCAAs and Allo-Ile in dried blood spot (DBS) samples.
%Z FOR Codes: 111403 60499 60101


%0 Journal Article
%~ PubMed
%A Ho, Gladys
%A Yonezawa, Atsushi
%A Masuda, Satohiro
%A Inui, Ken-Ichi
%A Sim, Keow G
%A Carpenter, Kevin
%A Olsen, Rikke K J
%A Mitchell, John J
%A Rhead, William J
%A Peters, Gregory
%A Christodoulou, John
%T Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B.
%B Human mutation
%D 2011
%C United States
%I John Wiley & Sons, Inc.
%V 32
%N 1
%P E1976-84
%@ 1059-7794
%X Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant. Two recently-identified riboflavin transporters G protein-coupled receptor 172B (GPR172B or RFT1) and riboflavin transporter 2 (C20orf54 or RFT2) were screened for mutations. Two missense sequence variations, c.209A>G [p.Q70R] and c.886G>A [p.V296M] were found in GPR172B. In vitro functional studies of both missense variations showed that riboflavin transport was unaffected by these variations. Quantitative real-time PCR revealed a de novo deletion in GPR172B spanning exons 2 and 3 in one allele from the mother. We postulate that haploinsufficiency of this riboflavin transporter causes mild riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, resulted in the transient riboflavin-responsive disease seen in her newborn infant. This is the first report of a genetic defect in riboflavin transport in humans.
%Z FOR Codes: 111403 110107


%0 Journal Article
%~ PubMed
%A Tucker, Elena J
%A Hershman, Steven G
%A Köhrer, Caroline
%A Belcher-Timme, Casey A
%A Patel, Jinal
%A Goldberger, Olga A
%A Christodoulou, John
%A Silberstein, Jonathon M
%A McKenzie, Matthew
%A Ryan, Michael T
%A Compton, Alison G
%A Jaffe, Jacob D
%A Carr, Steven A
%A Calvo, Sarah E
%A RajBhandary, Uttam L
%A Thorburn, David R
%A Mootha, Vamsi K
%T Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation.
%B Cell Metabolism
%D 2011
%C United States
%I Cell Press
%V 14
%N 3
%P 428-434
%@ 1932-7420
%X The metazoan mitochondrial translation machinery is unusual in having a single tRNA(Met) that fulfills the dual role of the initiator and elongator tRNA(Met). A portion of the Met-tRNA(Met) pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA(Met) (fMet-tRNA(met)), which is used for translation initiation; however, the requirement of formylation for initiation in human mitochondria is still under debate. Using targeted sequencing of the mtDNA and nuclear exons encoding the mitochondrial proteome (MitoExome), we identified compound heterozygous mutations in MTFMT in two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-tRNA(Met) levels and an abnormal formylation profile of mitochondrially translated COX1. Our findings demonstrate that MTFMT is critical for efficient human mitochondrial translation and reveal a human disorder of Met-tRNA(Met) formylation.
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Duley, John A
%A Christodoulou, John
%A de Brouwer, Arjan P M
%T The PRPP synthetase spectrum: what does it demonstrate about nucleotide syndromes?
%B Nucleosides, nucleotides & nucleic acids
%D 2011
%C United States
%I Taylor & Francis Inc.
%V 30
%N 12
%P 1129-39
%@ 1532-2335
%X Defects in X-linked phosphoribosylpyrophosphate synthetase 1 (PRPS1) manifest as follows: (1) PRS-I enzyme "superactivity" (gain-of-function mutations affecting allosteric regions); (2) PRS-I overexpression (which may be linked to miRNA mutation); (3) severe PRS-I deficiency/Arts syndrome (missense mutations producing loss-of-function); (4) moderate PRS-I deficiency/Charcot-Marie-Tooth disease-5 (less severe loss-of-function mutations); and (5) mild PRS-I deficiency/Deafness-2 (mutations producing slight destabilization). Similar to Lesch-Nyhan disease, PRPS1-related disorders arise from phosphoribosyl-pyrophosphate (PRPP)-dependent nucleotide "depletion" of purine nucleotides (e.g., ATP, GTP). S-adenosylmethionine (SAMe) appears to partially alleviate purine depletion via a PRPP-independent path. Synthesis of pyrimidine nucleotides is PRPP dependent, with uridine monophosphate synthase deficiency producing pyrimidine nucleotide depletion. But pyrimidine salvage from uridine does not require PRPP, and this nucleoside is transported freely to pyrimidine-depleted tissues. Regulation of nicotinamide nucleotides is less clear; synthesis from pyridine nucleobases is PRPP dependent. Nucleotide "depletion" contrasts with nucleotide "toxicity," exemplified by the purine disorders adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies or by pyrimidine nucleotidase deficiency. These are characterized by the accumulation of one or more abnormal nucleotides such as succinyl- or deoxy-nucleotides or their metabolites, which interrupt other nucleotide or related pathways or are toxic to specific cell types. Theoretically, purine toxicity disorders would not be ameliorated by SAMe therapy, and this was confirmed for one adenylosuccinate lyase-deficient child. Nucleotide defects may also be seen as an aspect of mitochondrial disease, with SAMe-based mitochondrial therapy perhaps meriting further investigation.
%Z FOR Codes: 110105


%0 Journal Article
%~ PubMed
%A Harikrishnan, K N
%A Bayles, Richard
%A Ciccotosto, Giuseppe D
%A Maxwell, Scott
%A Cappai, Roberto
%A Pelka, Gregory J
%A Tam, Patrick P L
%A Christodoulou, John
%A El-Osta, Assam
%T Alleviating transcriptional inhibition of the norepinephrine slc6a2 transporter gene in depolarized neurons.
%B The Journal of Neuroscience
%D 2010
%C United States
%I Society for Neuroscience
%V 30
%N 4
%P 1494-1501
%@ 1529-2401
%X Recent studies have brought to light additional experimental information, namely, that the MeCP2 protein complex is not only capable of associating with members of the ATPase-dependent bromodomain family, but also found on nonmethylated genomic sequences. These unexpected results are indicative of a multifunctional role for MeCP2, more importantly; our view of the molecular mechanisms that regulate gene activity may not be necessarily distinguishable. Depolarized mouse neuronal cortical cells were examined for increased Slc6a2 mRNA synthesis, changes in CpG methylation status using bisulfite sequencing, and binding of MeCP2 and Smarca2 on the Slc6a2 promoter sequence by chromatin immunopurification strategies. Increased Slc6a2 gene expression in response to membrane depolarization was strongly correlated with the dissociation of MeCP2 and Smarca2 complex on the unmethylated gene. We identified that gene expression in neuronal cortical cells involves increased histone hyperacetylation on the Slc6a2 promoter, which is commensurate with the recruitment of SP1 and RNA Polymerase II and is inversely correlated with H3K9 trimethylation. We hypothesize that the MeCP2 corepressor is capable of associating with multiple forms of SWI/SNF to remodel chromatin for important regulatory roles. The results of our experiments indicate that these proteins are asymmetrically bound to chromatin independent of DNA methylation and not inevitably diametrically opposed. These results now begin to offer a new perspective on the mechanism of Slc6a2 gene regulation.
%Z FOR Codes: 60199 110902


%0 Journal Article
%A de Brouwer, Arjan PM
%A Dudley, John A
%A Christodoulou, John
%T Arts Syndrome
%B GeneReviews
%D 2010
%C United States
%I University of Washington
%V NBK2591
%N 
%P 0
%@ 0000-0000
%X 
%Z FOR Codes: 110902


%0 Journal Article
%~ PubMed
%A White, Rose
%A Ho, Gladys
%A Schmidt, Swetlana
%A Scheffer, Ingrid E
%A Fischer, Alexandra
%A Yendle, Simone C
%A Bienvenu, Thierry
%A Nectoux, Juliette
%A Ellaway, Carolyn J
%A Darmanian, Artur
%A Tong, Xingzhang
%A Cloosterman, Desiree
%A Bennetts, Bruce
%A Kalra, Veena
%A Fullston, Tod
%A Gecz, Jozef
%A Cox, Timothy C
%A Christodoulou, John
%T Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders.
%B Twin Research and Human Genetics
%D 2010
%C Australia
%I Australian Academic Press Pty. Ltd.
%V 13
%N 2
%P 168-178
%@ 1832-4274
%X Abstract Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.
%Z FOR Codes: 60410


%0 Journal Article
%~ PubMed
%A Gibson, Joanne H
%A Slobedman, Barry
%A Kn, Harikrishnan
%A Williamson, Sarah L
%A Minchenko, Dimitri
%A El-Osta, Assam
%A Stern, Joshua L
%A Christodoulou, John
%T Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain.
%B BMC Neuroscience
%D 2010
%C United Kingdom
%I BioMed Central Ltd.
%V 11
%N 1
%P 53
%@ 1471-2202
%X ABSTRACT: BACKGROUND: The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. RESULTS: Using microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1) or are involved in synaptic vesicle cycling (dynamin 1). RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP) analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression. CONCLUSIONS: This study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implicated in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited.
%Z FOR Codes: 60410 111403 60499


%0 Journal Article
%~ PubMed
%A Hynes, Kim
%A Tarpey, Patrick
%A Dibbens, Leanne M
%A Bayly, Marta A
%A Berkovic, Samuel F
%A Smith, Raffaella
%A Al Raisi, Zahyia
%A Turner, Samantha J
%A Brown, Natasha J
%A Desai, Tarishi D
%A Haan, Eric
%A Turner, Gillian
%A Christodoulou, John
%A Leonard, Helen
%A Gill, Deepak
%A Stratton, Michael R
%A Gecz, Jozef
%A Scheffer, Ingrid E
%T Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families.
%B Journal of medical genetics
%D 2010
%C United Kingdom
%I BMJ Group
%V 47
%N 3
%P 211-6
%@ 0022-2593
%X Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder affecting heterozygous females and sparing hemizygous males. Mutations in the protocadherin 19 (PCDH19) gene have been identified in seven unrelated families with EFMR.
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Relf, Bronwyn L
%A Larkin, Emma K
%A Torres, Carina DE
%A Baur, Louise A
%A Christodoulou, John
%A Waters, Karen A
%T Genome-wide linkage of obstructive sleep apnoea and high-density lipoprotein cholesterol in a Filipino family: bivariate linkage analysis of obstructive sleep apnoea.
%B Journal of sleep research
%D 2010
%C United Kingdom, Unit
%I Wiley-Blackwell Publishing Ltd.
%V 19
%N 2
%P 349-57
%@ 1365-2869
%X Increasing evidence supports an association between obstructive sleep apnoea (OSA) and metabolic syndrome (MeS) in both children and adults, suggesting a genetic component. However, the genetic relationship between the diseases remains unclear. We performed a bivariate linkage scan on a single Filipino family with a high prevalence of OSA and MeS to explore the genetic pathways underlying these diseases. A large rural family (n = 50, 50% adults) underwent a 10-cM genome-wide scan. Fasting blood was used to measure insulin, triglycerides, total cholesterol and high density lipoprotein (HDL) cholesterol. Attended overnight polysomnography was used to quantify the respiratory disturbance index (RDI), a measure of sleep apnoea. Body mass index z-scores and insulin resistance scores were calculated. Bivariate multipoint linkage analyses were performed on RDI and MeS components. OSA prevalence was 46% (n = 23; nine adults, 14 children) in our participants. MeS phenotype was present in 40% of adults (n = 10) and 48% of children (n = 12). Linkage peaks with a logarithm of odds (LOD) score >3 were demonstrated on chromosome 19q13.4 (LOD = 3.04) for the trait pair RDI and HDL cholesterol. Candidate genes identified in this region include the killer cell immunoglobulin-like receptor genes. These genes are associated with modulating inflammatory responses in reaction to cellular stress and initiation of atherosclerotic plaque formation. We have identified a novel locus for genetic links between RDI and lipid factors associated with MeS in a chromosomal region containing genes associated with inflammatory responses.
%Z FOR Codes: 60405 110203


%0 Journal Article
%~ PubMed
%A Riley, Lisa G
%A Cooper, Sandra
%A Hickey, Peter
%A Rudinger-Thirion, Joëlle
%A McKenzie, Matthew
%A Compton, Alison
%A Lim, Sze Chern
%A Thorburn, David
%A Ryan, Michael T
%A Giegé, Richard
%A Bahlo, Melanie
%A Christodoulou, John
%T Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia-MLASA Syndrome.
%B American journal of human genetics
%D 2010
%C United States
%I Cell Press
%V 87
%N 1
%P 52-9
%@ 0002-9297
%X Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The YARS2 gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA.
%Z FOR Codes: 110904 111403 110311


%0 Journal Article
%~ PubMed
%A de Brouwer, Arjan P M
%A van Bokhoven, Hans
%A Nabuurs, Sander B
%A Arts, Willem Frans
%A Christodoulou, John
%A Duley, John
%T PRPS1 mutations: four distinct syndromes and potential treatment.
%B American Journal of Human Genetics
%D 2010
%C United States
%I Cell Press
%V 86
%N 4
%P 506-518
%@ 0002-9297
%X Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Chung, Seo-Kyung
%A Vanbellinghen, Jean-François
%A Mullins, Jonathan G L
%A Robinson, Angela
%A Hantke, Janina
%A Hammond, Carrie L
%A Gilbert, Daniel F
%A Freilinger, Michael
%A Ryan, Monique
%A Kruer, Michael C
%A Masri, Amira
%A Gurses, Candan
%A Ferrie, Colin
%A Harvey, Kirsten
%A Shiang, Rita
%A Christodoulou, John
%A Andermann, Frederick
%A Andermann, Eva
%A Thomas, Rhys H
%A Harvey, Robert J
%A Lynch, Joseph W
%A Rees, Mark I
%T Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia.
%B Journal of Neuroscience
%D 2010
%C United States
%I Society for Neuroscience
%V 30
%N 28
%P 9612-9620
%@ 1529-2401
%X Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha1 or heteromeric alpha1beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.
%Z FOR Codes: 110904 60499 111403


%0 Journal Article
%~ PubMed
%A , Jeffrey L. Neul
%A Kaufmann, Walter E
%A Glaze, Daniel G
%A Christodoulou, John
%A Clarke, Angus J
%A Bahi-Buisson, Nadia
%A Leonard, Helen
%A Bailey, Mark E S
%A Schanen, N Carolyn
%A Zappella, Michele
%A Renieri, Alessandra
%A Huppke, Peter
%A Percy, Alan K
%A , RettSearch Consortium
%T Rett syndrome: revised diagnostic criteria and nomenclature.
%B Annals of Neurology
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 68
%N 6
%P 944-950
%@ 1531-8249
%X Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.
%Z FOR Codes: 110902


%0 Journal Article
%~ Isi
%A Bebbington, A.
%A Percy, A.
%A Christodoulou, J.
%A Ravine, D.
%A Ho, G.
%A Jacoby, P.
%A Anderson, A.
%A Pineda, M.
%A Ben Zeev, B.
%A Bahi-Buisson, N.
%A Smeets, E.
%A Leonard, H.
%T Updating the profile of C-terminal MECP2 deletions in Rett syndrome
%B Journal of Medical Genetics
%D 2010
%C United Kingdom
%I BMJ Group
%V 47
%N 
%P 242-248
%@ 0022-2593
%X 
%Z FOR Codes: 111403 110903


%0 Journal Article
%~ PubMed
%A Bijarnia, Sunita
%A Shaw, Peter
%A Vimpani, Anne
%A Smith, Robert
%A Pacey, Verity
%A O'Grady, Helen
%A Christodoulou, John
%A Sillence, David
%T Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome.
%B Journal of Paediatrics and Child Health
%D 2009
%C United Kingdom, Australia
%I Wiley-Blackwell Publishing Ltd.
%V 45
%N 7-8
%P 469-472
%@ 1034-4810
%X We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant.
%Z FOR Codes: 60499 111403


%0 Journal Article
%~ PubMed
%A Shanti, B
%A Silink, M
%A Bhattacharya, K
%A Howard, N
%A Carpenter, K
%A Fietz, M
%A Clayton, P
%A Christodoulou, J
%T Congenital disorder of glycosylation type Ia: Heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency.
%B Journal of Inherited Metabolic Disease
%D 2009
%C Netherlands
%I Springer Netherlands
%V 0
%N 0
%P 0
%@ 0141-8955
%X We describe three patients with congenital disorder of glycosylation (CDG) type Ia, all of whom had persistent hyperinsulinaemic hypoglycaemia responding to diazoxide therapy as a common feature. The first patient, an infant girl, presented with recurrent vomiting, failure to thrive, liver impairment, hypothyroidism and a pericardial effusion. The second patient, also female, had a milder disease with single organ involvement, presenting as isolated hyperinsulinaemic hypoglycaemia, not associated with any cognitive impairment. The third patient, a boy presented with multi-organ manifestations including congenital hypothyroidism, persistent hyperinsulinaemic hypoglycaemia, coagulopathy, olivopontocerebellar hypoplasia and recurrent pancreatitis. All three patients had a type 1 serum transferrin isoform pattern, and were subsequently found to have low phosphomannomutase activity, confirming the diagnosis of CDG type Ia. Our findings emphasize that CDG should be considered as a differential diagnosis in patients with persistent hyperinsulinaemic hypoglycaemia and that it may even occasionally be the leading symptom in CDG Ia.
%Z FOR Codes: 60499 111403


%0 Journal Article
%~ PubMed
%A Wilcken, Bridget
%A Haas, Marion
%A Joy, Pamela
%A Wiley, Veronica
%A Bowling, Francis
%A Carpenter, Kevin
%A Christodoulou, John
%A Cowley, David
%A Ellaway, Carolyn
%A Fletcher, Janice
%A Kirk, Edwin P
%A Lewis, Barry
%A McGill, Jim
%A Peters, Heidi
%A Pitt, James
%A Ranieri, Enzo
%A Yaplito-Lee, Joy
%A Boneh, Avihu
%T Expanded Newborn Screening: Outcome in Screened and Unscreened Patients at Age 6 Years.
%B Pediatrics
%D 2009
%C United States
%I American Academy of Pediatrics
%V 124
%N 2
%P e241-e248
%@ 1098-4275
%X OBJECTIVE: Tandem mass spectrometry is widely applied to routine newborn screening but there are no long-term studies of outcome. We studied the clinical outcome at six years of age in Australia. METHODS: In a cohort study, we analyzed the outcome at 6 years for patients detected by screening or by clinical diagnosis among >2 million infants born from 1994 to 1998 (1 017 800, all unscreened) and 1998 to 2002 (461 500 screened, 533 400 unscreened) recording intellectual and physical condition, school placement, other medical problems, growth, treatment, diet, and hospital admissions. Results were analyzed separately for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and other disorders, and grouped patients as those who presented clinically or died in the first 5 days of life; patients presented later or diagnosed by screening, and those with substantially benign disorders. RESULTS: Inborn errors, excluding phenylketonuria, were diagnosed in 116 of 1 551 200 unscreened infants (7.5/100 000 births) and 70 of 461 500 screened infants (15.2/100 000 births). Excluding MCADD, 21 unscreened patients with metabolic disorders diagnosed after 5 days of life died or had a significant intellectual or physical handicap (1.35/100 000 population) compared with 2 of the screened cohort (0.43/100 000; odds ratio: 3.1 [95% CI: 0.73-13.32]). Considering the likely morbidity or mortality among the expected number of never-diagnosed unscreened patients, there would be a significant difference. Growth distribution was normal in all cohorts. CONCLUSION: Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.
%Z FOR Codes: 111403 111704 60499


%0 Journal Article
%~ PubMed
%A Hamvas, Aaron
%A Nogee, Lawrence M
%A Wegner, Daniel J
%A Depass, Kelcey
%A Christodoulou, John
%A Bennetts, Bruce
%A McQuade, Leon R
%A Gray, Peter H
%A Deterding, Robin R
%A Carroll, Travis R
%A Kammesheidt, Anja
%A Kasch, Laura M
%A Kulkarni, Shashikant
%A Cole, F Sessions
%T Inherited Surfactant Deficiency Caused by Uniparental Disomy of Rare Mutations in the Surfactant Protein-B and ATP Binding Cassette, Subfamily A, Member 3 Genes.
%B The Journal of pediatrics
%D 2009
%C United States
%I Mosby, Inc
%V 155
%N 6
%P 854-859.e1
%@ 0022-3476
%X To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure.
%Z FOR Codes: 60499 111403


%0 Journal Article
%~ PubMed
%A Zeev, B Ben
%A Bebbington, A
%A Ho, G
%A Leonard, H
%A de Klerk, N
%A Gak, E
%A Vecsler, M
%A Vecksler, M
%A Christodoulou, J
%T The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome.
%B Neurology
%D 2009
%C United States
%I Lippincott Williams & Wilkins
%V 72
%N 14
%P 1242-1247
%@ 0028-3878
%X BACKGROUND: Rett syndrome (RTT) is caused by mutations in the transcriptional repressor methyl CpG-binding protein 2 (MECP2). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis, and plasticity, and it has been shown that BDNF expression is regulated by MeCP2 through a complex interaction. A common polymorphism of BDNF (Val66Met [p.V66M]) has been found to correlate with severity and course of several neuropsychiatric disorders. METHODS: We examined the association between disease severity score, assessed by the modified Percy score, and BDNF polymorphism, using regression methods, in 125 mutation-positive patients with RTT from the Australian Rett Syndrome Database and an Israeli cohort. RESULTS: Those who were heterozygous (Val/Met) had slightly more severe disease than those who were homozygous for the wild-type (Val/Val) BDNF polymorphism (increased severity score 2.1, p = 0.09). In those with p.R168X, a commonly occurring MECP2 mutation in RTT, there was a 6-point increase in severity score for those who were heterozygous for the BDNF polymorphism, both unadjusted (p = 0.02) and adjusted for age (p = 0.03). Individuals with the p.R168X mutation and heterozygous for the BDNF polymorphism were also at an increased risk of seizure onset (hazard ratio 5.3, 95% confidence interval 1.6-17.7) compared with those homozygous for the wild-type BDNF allele. CONCLUSIONS: In addition to mutation type and degree of X-chromosome skewing, the common brain-derived neurotrophic factor (BDNF) polymorphism appears to be another genetic modifier of Rett syndrome (RTT) severity. This suggests that BDNF function may play a significant role in the pathogenesis of RTT.
%Z FOR Codes: 110904


%0 Journal Article
%A de Brouwer, Arjan PM
%A Duley, John A
%A Christodoulou, John
%T Arts Syndrome
%B GeneReviews
%D 2008
%C United States
%I GeneTests
%V 0
%N 
%P 0
%@ 0
%X 
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Ho, G
%A Walter, J
%A Christodoulou, J
%T Costeff optic atrophy syndrome: New clinical case and novel molecular findings.
%B Journal of inherited metabolic disease
%D 2008
%C Netherlands
%I Springer
%V 31 Suppl 2
%N 0
%P S419-23
%@ 0141-8955
%X 3-Methylglutaconic aciduria (MGA) encompasses a heterogeneous group of disorders, often coinciding with elevated levels of urinary 3-methylglutaric acid. Type I MGA is a disorder of leucine metabolism, while the biological basis for the MGA is unclear for the other types (MGA types II-V). MGA type III (Costeff optic atrophy syndrome, autosomal recessive optic atrophy-3 or optic atrophy plus syndrome, OMIM 258501) is distinguished by early bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, ataxia, and occasional cognitive deficits. It is caused by homozygous mutations in the optic atrophy 3 gene (OPA3). We present a case of a patient with MGA who has infantile-onset optic atrophy, ataxia, extrapyramidal movements and spasticity, but with normal intellect. Sequencing of the patient''s DNA revealed a homozygous nonsense mutation c.415C>T (p.Q139X) in exon 2 of transcript 2 of the OPA3 gene, as well as a common silent polymorphism c.231T>C in the same exon. This is the first nonsense mutation found in OPA3. The molecular findings in OPA3 are also reviewed, including mutations in OPA3 that result in autosomal dominant optic atrophy and cataract (ADOAC). The recessive mode of inheritance of MGA type III as a result of the p.Q139X mutation is supported by the carrier status of the unaffected father.
%Z FOR Codes: 110311 110399


%0 Journal Article
%~ PubMed
%A Kondo, Mari
%A Gray, Laura J
%A Pelka, Gregory J
%A Christodoulou, John
%A Tam, Patrick P L
%A Hannan, Anthony J
%T Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome--Mecp2 gene dosage effects and BDNF expression.
%B The European journal of neuroscience
%D 2008
%C UK
%I Blackwell Publishing Ltd
%V 27
%N 12
%P 3342-50
%@ 0953-816X
%X Rett syndrome, commonly associated with mutations of the methyl CpG-binding protein 2 (MECP2) gene, is characterised by an apparently normal early postnatal development followed by deterioration of acquired cognitive and motor coordination skills in early childhood. To evaluate whether environmental factors may influence the disease outcome of Rett syndrome, we tested the effect of environmental enrichment from 4 weeks of age on the behavioural competence of mutant mice harboring a Mecp2 (tm1Tam)-null allele. Our findings show that enrichment improves motor coordination in heterozygous Mecp2+/- females but not Mecp2-/y males. Standard-housed Mecp2+/- mice had an initial motor coordination deficit on the accelerating rotarod, which improved with training then deteriorated in subsequent weeks. Enrichment resulted in a significant reduction in this coordination deficit in Mecp2+/- mice, returning the performance to wild-type levels. Brain-derived neurotrophic factor (BDNF) protein levels were 75 and 85% of wild-type controls in standard-housed and environmentally enriched Mecp2+/- cerebellum, respectively. Mecp2-/y mice showed identical deficits of cerebellar BDNF (67% of wild-type controls) irrespective of their housing environment. Our findings demonstrate a positive impact of environmental enrichment in a Rett syndrome model; this impact may be dependent on the existence of one functional copy of Mecp2.
%Z FOR Codes: 110999


%0 Journal Article
%~ PubMed
%A Bijarnia, S
%A Wiley, V
%A Carpenter, K
%A Christodoulou, J
%A Ellaway, C
%A Wilcken, B
%T Glutaric aciduria type I: outcome following detection by newborn screening.
%B Journal of inherited metabolic disease
%D 2008
%C Netherlands
%I Springer
%V 31
%N 4
%P 503-7
%@ 0141-8955
%X Glutaric aciduria type I (GA I), a cerebral organic acidaemia with the potential for severe neurological consequences, can now be detected by tandem mass spectrometry newborn screening. Early detection with implementation of careful management strategies appears to lessen the likelihood of neurological damage. We assessed the outcome in all 10 GA I patients detected in New South Wales during the last decade. Three patients were detected clinically and 7 by newborn screening. Diagnosis was confirmed by detection of significantly elevated urinary 3-hydroxybutyrate and glutarate in urine, isolated elevation of glutarylcarnitine in plasma, typical clinical and MRI findings in several, and mutation analysis or enzyme analysis on cultured skin fibroblasts in 4 cases. The birth frequency was 1:90,000. Following diagnosis, treatment was initiated in all children with oral carnitine (100 mg/kg per day) and a low-protein diet supplemented with a lysine-free, low-tryptophan amino acid formula. Disability was assessed in fields of motor, cognitive and speech development and scored according to Kyllerman. Clinically diagnosed patients were all symptomatic, with severity scores (out of 9) of 3, 5 and 9. Six of seven patients detected by newborn screening are asymptomatic, 4 being aged 2-6 years. One patient had a severe decompensation at 7 months, despite full management advice and treatment, and later died. Our data support previous findings that early diagnosis reduces neurological complications, but show that even with early diagnosis and careful management severe complications may ensue in some.
%Z FOR Codes: 111403


%0 Journal Article
%~ PubMed
%A Singh, Jasmine
%A Saxena, Alka
%A Christodoulou, John
%A Ravine, David
%T MECP2 genomic structure and function: insights from ENCODE.
%B Nucleic acids research
%D 2008
%C United Kingdom
%I Oxford University Press
%V 36
%N 0
%P 6035-47
%@ 0305-1048
%X MECP2, a relatively small gene located in the human X chromosome, was initially described with three exons transcribing RNA from which the protein MeCP2 was translated. It is now known to have four exons from which two isoforms are translated; however, there is also evidence of additional functional genomic structures within MECP2, including exons potentially transcribing non-coding RNAs. Accompanying the recognition of a higher level of intricacy within MECP2 has been a recent surge of knowledge about the structure and function of human genes more generally, to the extent that the definition of a gene is being revisited. It is timely now to review the published and novel functional elements within MECP2, which is proving to have a complexity far greater than was previously thought.
%Z FOR Codes: 111403 110903 110105


%0 Journal Article
%~ PubMed
%A Sugiana, Canny
%A Pagliarini, David J
%A McKenzie, Matthew
%A Kirby, Denise M
%A Salemi, Renato
%A Abu-Amero, Khaled K
%A Dahl, Hans-Henrik M
%A Hutchison, Wendy M
%A Vascotto, Katherine A
%A Smith, Stacey M
%A Newbold, Robert F
%A Christodoulou, John
%A Calvo, Sarah
%A Mootha, Vamsi K
%A Ryan, Michael T
%A Thorburn, David R
%T Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease.
%B American journal of human genetics
%D 2008
%C Div John Wiley & Sons Inc,605 Third Ave, New York, Ny, 10158-0012
%I Wiley-Liss
%V 83
%N 4
%P 468-78
%@ 1537-6605
%X Complex I (NADH:ubiquinone oxidoreductase) is the first and largest multimeric complex of the mitochondrial respiratory chain. Human complex I comprises seven subunits encoded by mitochondrial DNA and 38 nuclear-encoded subunits that are assembled together in a process that is only partially understood. To date, mutations causing complex I deficiency have been described in all 14 core subunits, five supernumerary subunits, and four assembly factors. We describe complex I deficiency caused by mutation of the putative complex I assembly factor C20orf7. A candidate region for a lethal neonatal form of complex I deficiency was identified by homozygosity mapping of an Egyptian family with one affected child and two affected pregnancies predicted by enzyme-based prenatal diagnosis. The region was confirmed by microcell-mediated chromosome transfer, and 11 candidate genes encoding potential mitochondrial proteins were sequenced. A homozygous missense mutation in C20orf7 segregated with disease in the family. We show that C20orf7 is peripherally associated with the matrix face of the mitochondrial inner membrane and that silencing its expression with RNAi decreases complex I activity. C20orf7 patient fibroblasts showed an almost complete absence of complex I holoenzyme and were defective at an early stage of complex I assembly, but in a manner distinct from the assembly defects caused by mutations in the assembly factor NDUFAF1. Our results indicate that C20orf7 is crucial in the assembly of complex I and that mutations in C20orf7 cause mitochondrial disease.
%Z FOR Codes: 110999 110899


%0 Journal Article
%~ PubMed
%A Alexander, I E
%A Cunningham, S C
%A Logan, G J
%A Christodoulou, J
%T Potential of AAV vectors in the treatment of metabolic disease.
%B Gene Therapy
%D 2008
%C United Kingdom
%I Nature Publishing Group
%V 15
%N 11
%P 831-839
%@ 1476-5462
%X Inborn errors of metabolism are collectively common, frequently severe and in many instances difficult or impossible to treat. Accordingly, there is a compelling need to explore novel therapeutic modalities, including gene therapy, and examine multiple phenotypes where the risks of experimental therapy are outweighed by potential benefits to trial participants. Among available gene delivery systems recombinant AAV shows special promise for the treatment of metabolic disease given the unprecedented efficiencies achieved in transducing key target tissues, such as liver and muscle, in small animal models. To date over 30 metabolic disease phenotypes have been investigated in small animal studies with complete phenotype correction being achieved in a substantial proportion. Achieving adequately widespread transduction within the central nervous system, however, remains a major challenge, and will be critical to realization of the therapeutic potential of gene therapy for many of the most clinically troubling metabolic disease phenotypes. Despite the relatively low immunogenicity of AAV vectors, immune responses are also emerging as a factor requiring special attention as efforts accelerate toward human clinical translation. Four metabolic disease phenotypes have reached phase I or I/II trials with one, targeting lipoprotein lipase deficiency, showing exciting early evidence of efficacy.
%Z FOR Codes: 110107 100401


%0 Journal Article
%~ PubMed
%A Cotton, R G H
%A Auerbach, A D
%A Brown, A F
%A Carrera, P
%A Christodoulou, J
%A Claustres, M
%A Compton, J
%A Cox, D W
%A De Baere, E
%A den Dunnen, J T
%A Greenblatt, M
%A Fujiwara, M
%A Hilbert, P
%A Jani, A
%A Lehvaslaiho, H
%A Nebert, D W
%A Verma, I
%A Vihinen, M
%A , Members of the Human Genome Variation Society
%A , Human Variome Project Diagnostic Laboratory Working Group
%T A structured simple form for ordering genetic tests is needed to ensure coupling of clinical detail (phenotype) with DNA variants (genotype) to ensure utility in publication and databases.
%B Human mutation
%D 2007
%C United States
%I John Wiley & Sons
%V 28
%N 10
%P 931-932
%@ 1098-1004
%X Researchers and clinicians ideally need instant access to all the variation in their gene/locus of interest to efficiently conduct their research and genetic healthcare to the highest standards. Currently much key data resides in the laboratory books or patient records around the world, as there are many impediments to submitting this data. It would be ideal therefore if a semiautomated pathway was available, with a minimum of effort, to make the deidentified data publicly available for others to use. The Human Variome Project (HVP) meeting listed 96 recommendations to work toward this situation. This article is planned to initiate a strategy to enhance the collection of phenotype and genotype data from the clinician/diagnostic laboratory nexus. Thus, the aim is to develop universally applicable forms that people can use when investigating patients for each inherited disease, to assist in satisfying many of the recommendations of the HVP Meeting [Cotton et al., 2007]. We call for comment and collaboration in this article.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A de Brouwer, Arjan P M
%A Williams, Kelly L
%A Duley, John A
%A van Kuilenburg, Andre B P
%A Nabuurs, Sander B
%A Egmont-Petersen, Michael
%A Lugtenberg, Dorien
%A Zoetekouw, Lida
%A Banning, Martijn J G
%A Roeffen, Melissa
%A Hamel, Ben C J
%A Weaving, Linda
%A Ouvrier, Robert A
%A Donald, Jennifer A
%A Wevers, Ron A
%A Christodoulou, John
%A van Bokhoven, Hans
%T Arts Syndrome Is Caused by Loss-of-Function Mutations in PRPS1.
%B American journal of human genetics
%D 2007
%C United States
%I Univ Chicago Press
%V 81
%N 3
%P 507-518
%@ 1537-6605
%X Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.
%Z FOR Codes: 110903 110905


%0 Journal Article
%~ PubMed
%A Singh-Grewal, Davinder
%A Chaitow, Jeffrey
%A Aksentijevich, Ivona
%A Christodoulou, John
%T Coexistent MEFV and CIAS1 mutations manifesting as familial Mediterranean fever plus deafness.
%B Annals of the rheumatic diseases
%D 2007
%C United Kingdom
%I BMJ Publishing Group
%V 66
%N 11
%P 1541
%@ 0003-4967
%X 
%Z FOR Codes: 111799


%0 Journal Article
%~ PubMed
%A Archer, Hayley
%A Evans, Julie
%A Leonard, Helen
%A Colvin, Lyn
%A Ravine, David
%A Christodoulou, John
%A Williamson, Sarah
%A Charman, Tony
%A Bailey, Mark E S
%A Sampson, Julian
%A de Klerk, Nicholas
%A Clarke, Angus
%T Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation.
%B Journal of medical genetics
%D 2007
%C UK
%I BMJ Publishing Group
%V 44
%N 2
%P 148-152
%@ 1468-6244
%X INTRODUCTION: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. METHODS: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. RESULTS: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. CONCLUSIONS: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Hardwick, Simon A
%A Reuter, Kirsten
%A Williamson, Sarah L
%A Vasudevan, Vidya
%A Donald, Jennifer
%A Slater, Katrina
%A Bennetts, Bruce
%A Bebbington, Ami
%A Leonard, Helen
%A Williams, Simon R
%A Smith, Robert L
%A Cloosterman, Desiree
%A Christodoulou, John
%T Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband.
%B European journal of human genetics : EJHG
%D 2007
%C United Kingdom
%I Nature Publishing Group
%V 15
%N 12
%P 1218-29
%@ 1018-4813
%X Comprehensive genetic screening programs have led to the identification of pathogenic methyl-CpG-binding protein 2 (MECP2) mutations in up to 95% of classical Rett syndrome (RTT) patients. This high rate of mutation detection can partly be attributed to specialised techniques that have enabled the detection of large deletions in a substantial fraction of otherwise mutation-negative patients. These cases would normally be missed by the routine PCR-based screening strategies. Here, we have identified large multi-exonic deletions in 12/149 apparently mutation-negative RTT patients using multiplex ligation-dependent probe amplification (MLPA). These deletions were subsequently characterised using real-time quantitative PCR (qPCR) and long-range PCR with the ultimate aim of defining the exact nucleotide positions of the breakpoints and rearrangements. We detected an apparent deletion in one further patient using MLPA; however, this finding was contradicted by subsequent qPCR and long-range PCR results. The patient group includes an affected brother and sister with a large MECP2 deletion also present in their carrier mother. The X chromosome inactivation pattern of all female patients in this study was determined, which, coupled with detailed clinical information, allowed meaningful genotype-phenotype correlations to be drawn. This study reaffirms the view that large MECP2 deletions are an important cause of both classical and atypical RTT syndrome, and cautions that apparent deletions detected using high-throughput diagnostic techniques require further characterisation.
%Z FOR Codes: 110903 110311 111403


%0 Journal Article
%~ PubMed
%A Chan, Philip A
%A Duraisamy, Sekhar
%A Miller, Peter J
%A Newell, Joan A
%A McBride, Carole
%A Bond, Jeffrey P
%A Raevaara, Tiina
%A Ollila, Saara
%A Nyström, Minna
%A Grimm, Andrew J
%A Christodoulou, John
%A Oetting, William S
%A Greenblatt, Marc S
%T Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR).
%B Human Mutation
%D 2007
%C United States
%I John Wiley & Sons, Inc.
%V 28
%N 7
%P 683-693
%@ 1098-1004
%X The human genome contains frequent single-basepair variants that may or may not cause genetic disease. To characterize benign vs. pathogenic missense variants, numerous computational algorithms have been developed based on comparative sequence and/or protein structure analysis. We compared computational methods that use evolutionary conservation alone, amino acid (AA) change alone, and a combination of conservation and AA change in predicting the consequences of 254 missense variants in the CDKN2A (n = 92), MLH1 (n = 28), MSH2 (n = 14), MECP2 (n = 30), and tyrosinase (TYR) (n = 90) genes. Variants were validated as either neutral or deleterious by curated locus-specific mutation databases and published functional data. All methods that use evolutionary sequence analysis have comparable overall prediction accuracy (72.9-82.0%). Mutations at codons where the AA is absolutely conserved over a sufficient evolutionary distance (about one-third of variants) had a 91.6 to 96.8% likelihood of being deleterious. Three algorithms (SIFT, PolyPhen, and A-GVGD) that differentiate one variant from another at a given codon did not significantly improve predictive value over conservation score alone using the BLOSUM62 matrix. However, when all four methods were in agreement (62.7% of variants), predictive value improved to 88.1%. These results confirm a high predictive value for methods that use evolutionary sequence conservation, with or without considering protein structural change, to predict the clinical consequences of missense variants. The methods can be generalized across genes that cause different types of genetic disease. The results support the clinical use of computational methods as one tool to help interpret missense variants in genes associated with human genetic disease.
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Chiong, M A
%A Carpenter, K
%A Christodoulou, J
%T Low citrulline may not be diagnostic of ornithine transcarbamylase deficiency: a case report.
%B Journal of inherited metabolic disease
%D 2007
%C Netherlands
%I Springer-Verlag Dordrecht
%V 30
%N 3
%P 405-405
%@ 0141-8955
%X A newborn boy with family history of severe ornithine transcarbamylase (OTC) deficiency was investigated prospectively and managed aggressively at birth based on an existing protocol for at risk neonates. Undetectable citrulline levels at birth suggested that the infant was affected; however, normal plasma glutamine and urine orotic acid levels confused the diagnosis to some extent. Mutation testing confirmed that the patient did not have OTC deficiency. Thus the low plasma citrulline level did not validate our initial biochemical suspicion of OTC deficiency, and this highlights the importance of considering all available clinical, biochemical and molecular evidence in determining disease status.
%Z FOR Codes: 110101 111403 110311


%0 Journal Article
%~ Isi
%A Nagarajan, L
%A de Klerk, N
%A Ravine, D
%A Christodoulou, J
%A Leonard, H
%A Jian, L
%T Seizures in Rett syndrome: An overview from a one-year calendar study
%B EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
%D 2007
%C United Kingdom
%I WB Saunders Co. Ltd.
%V 11
%N 5
%P 310-317
%@ 1090-3798
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Schindeler, Suzanne
%A Ghosh-Jerath, Suparna
%A Thompson, Susan
%A Rocca, Antonella
%A Joy, Pamela
%A Kemp, Allan
%A Rae, Caroline
%A Green, Kathryn
%A Wilcken, Bridget
%A Christodoulou, John
%T The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study.
%B Molecular genetics and metabolism
%D 2007
%C United States
%I Academic Press
%V 91
%N 1
%P 48-54
%@ 1096-7192
%X OBJECTIVE: To determine the effects of large neutral amino acid (LNAA) supplements on brain and plasma phenylalanine (Phe) levels and other metabolites in early treated subjects with classical phenylketonuria (PKU), and to investigate the relationship between these metabolites and neuropsychological performance. METHODS: This was a prospective, double blind, cross over study consisting of four two-week phases with a 4 week washout period. Sixteen subjects (7 males), with classical PKU were recruited into the study and completed all 4 phases. Each phase consisted of either the LNAA supplement or placebo, and either the patient''s usual medical product or not. Subjects were instructed to follow their usual Phe restricted diet, maintain energy intake and complete a 3-day food record during each phase. At the end of each phase, brain Phe and other metabolites were measured by proton magnetic resonance spectroscopy (MRS), and plasma amino acids quantified. A detailed neuropsychological assessment was performed on the same day as the MRS and plasma collection. RESULTS: There was no correlation between plasma and brain Phe, but few of the plasma Phe readings were over 1200 micromol/L. Plasma Phe decreased with LNAA supplementation when patients were not taking their medical formula. LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and cognitive flexibility. Measures of attention were better on medical product, with or without LNAA supplements. CONCLUSIONS: LNAA supplementation was associated with a trend to a lowering of plasma Phe levels. LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and flexibility. For individuals already complying with diet and PKU medical product, additional supplementation with LNAA is of limited value. LNAA supplementation may be of benefit to those unable to comply with PKU medical product by reducing plasma Phe, perhaps by competing with Phe at the level of transport across the gut.
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Chiong, M A
%A Sim, K G
%A Carpenter, K
%A Rhead, W
%A Ho, G
%A Olsen, R K J
%A Christodoulou, J
%T Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency.
%B Molecular genetics and metabolism
%D 2007
%C United States
%I Academic Press
%V 92
%N 1-2
%P 109-14
%@ 1096-7192
%X A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant''s birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother''s defect in riboflavin metabolism remains to be established.
%Z FOR Codes: 111403 110311 110101