%0 Journal Article %~ PubMed %A Solski, Jennifer A %A Yang, Shu %A Nicholson, Garth A %A Luquin, Natasha %A Williams, Kelly L %A Fernando, Ruvini %A Pamphlett, Roger %A Blair, Ian P %T A novel TARDBP insertion/deletion mutation in the flail arm variant of amyotrophic lateral sclerosis. %B Amyotrophic Lateral Sclerosis %D 2012 %C United Kingdom %I Informa Healthcare %V 13 %N 5 %P 465-470 %@ 1471-180X %X Phenotypic variation in amyotrophic lateral sclerosis (ALS) is common, and one atypical form is the flail arm variant (FAV). Some classic ALS patients carry TARDBP mutations, and so we sought to establish whether TARDBP mutations are also present in the FAV of ALS. Mutation analysis of TARDBP, the gene encoding TDP-43, was performed in cohorts of classic and FAV ALS patients. An analysis of mutation effects was performed in patient fibroblasts. Results showed that a novel heterozygous in-frame insertion/deletion (indel), c.1158_1159delAT; c.1158_1159insCACCAACC, was identified in a highly conserved region encoding the glycine-rich area of TDP-43 in a patient with FAV. This indel was confirmed in the proband''s mother, an obligate carrier, and was absent from 480 ethnically-matched control individuals. Transcription of the mutant allele was confirmed. Under induced stress, indel-mutant fibroblasts showed a loss of normal nuclear TDP-43 immunoreactivity and formation of cytoplasmic inclusions of TDP-43, consistent with features seen in affected neurons. In conclusion, TARDBP missense mutations have previously been reported in classic ALS and frontotemporal lobar degeneration. The identification of a TARDBP indel mutation in a patient with FAV extends the spectrum of mutations and further supports the role of TDP-43 in a range of neurodegenerative phenotypes. %Z FOR Codes: 60410 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Morahan, Julia M %A Luquin, Natasha %A Yu, Bing %T An approach to finding brain-situated mutations in sporadic Parkinson's disease. %B Parkinsonism & related disorders %D 2012 %C United Kingdom %I Elsevier Ltd %V 18 %N 1 %P 82-5 %@ 1873-5126 %X Sporadic Parkinson''s disease (PD) is thought to have a major genetic component, but the variants involved remain mostly unknown. One possible reason for the difficulty in finding mutations underlying PD is that rare predominantly brain-situated somatic mutations underlie the disease; these mutations would be missed by analysing blood DNA only. To test the feasibility of looking for somatic mutations in PD brain tissue, we compared copy number variants (CNVs) between 8 PD and 26 control brains using Affymetrix 6.0 arrays. The median number of CNVs per brain, and the overall proportion of amplifications and deletions, were similar in PD and control brains. In 7 of the 8 PD brains, however, a total of 45 CNVs were found that were not present in control brains. Twelve of these CNVs overlapped with one or more genes, some of which are involved in pathways suspected in the pathogenesis of PD, or are rare. This study shows that PD brain CNVs can be detected, and raises the possibility that brain-situated mutations could underlie some cases of PD. A method of undertaking a definitive study of brain somatic mutations in PD, using massively parallel sequencing and multiple tissues, is suggested. %Z FOR Codes: 1109 604 %0 Journal Article %~ PubMed %A Pamphlett, R %T Exposure to environmental toxins and the risk of sporadic motor neuron disease: an expanded Australian case-control study. %B European Journal of Neurology %D 2012 %C United States %I Wiley-Blackwell Publishing Ltd. %V 19 %N 10 %P 1343-1348 %@ 1468-1331 %X BACKGROUND AND PURPOSE: It remains unclear what role environmental toxins play in sporadic motor neuron disease (SMND) and its most common subtype, amyotrophic lateral sclerosis (SALS). Most previous studies of this issue have contained only small numbers of SMND cases. We sought to re-examine possible associations between toxins and SMND in a large Australian case-control study. METHODS: Questionnaire data were available from 787 patients with SMND (614 with SALS) and 778 non-related controls. Individuals were asked whether they had been exposed to metals or chemicals/solvents at work or to herbicides/pesticides. Chi-square tests with odds ratios and 95% confidence intervals were calculated for responses, and significance levels were corrected for multiple testing. RESULTS: Men were more likely to acquire SALS if they worked with metals (OR??=??1.95, 95% CI??=??1.24-3.07) or chemicals/solvents (OR??=??1.96, 95% CI??=??1.46-2.61) or if they had been exposed to herbicides or pesticides (OR??=??1.77, 95% CI??=??1.30-2.39). Women who had worked with chemicals or solvents also appeared to be at increased risk of acquiring SALS (OR??=??1.71, 95% CI??=??1.22-2.40). CONCLUSIONS: These results support previous reports that exposures to metals or chemicals are associated with SMND. A suggested protocol for future multinational studies of environmental toxins and SMND is presented. %Z FOR Codes: 1109 1103 %0 Journal Article %~ PubMed %A Majounie, Elisa %A Renton, Alan E %A Mok, Kin %A Dopper, Elise G P %A Waite, Adrian %A Rollinson, Sara %A Chiņ, Adriano %A Restagno, Gabriella %A Nicolaou, Nayia %A Simon-Sanchez, Javier %A van Swieten, John C %A Abramzon, Yevgeniya %A Johnson, Janel O %A Sendtner, Michael %A Pamphlett, Roger %A Orrell, Richard W %A Mead, Simon %A Sidle, Katie C %A Houlden, Henry %A Rohrer, Jonathan D %A Morrison, Karen E %A Pall, Hardev %A Talbot, Kevin %A Ansorge, Olaf %A , Chromosome 9-ALS/FTD Consortium %A , French research network on FTLD/FTLD/ALS %A , ITALSGEN Consortium %A Hernandez, Dena G %A Arepalli, Sampath %A Sabatelli, Mario %A Mora, Gabriele %A Corbo, Massimo %A Giannini, Fabio %A Calvo, Andrea %A Englund, Elisabet %A Borghero, Giuseppe %A Floris, Gian Luca %A Remes, Anne M %A Laaksovirta, Hannu %A McCluskey, Leo %A Trojanowski, John Q %A Van Deerlin, Vivianna M %A Schellenberg, Gerard D %A Nalls, Michael A %A Drory, Vivian E %A Lu, Chin-Song %A Yeh, Tu-Hsueh %A Ishiura, Hiroyuki %A Takahashi, Yuji %A Tsuji, Shoji %A Le Ber, Isabelle %A Brice, Alexis %A Drepper, Carsten %A Williams, Nigel %A Kirby, Janine %A Shaw, Pamela %A Hardy, John %A Tienari, Pentti J %A Heutink, Peter %A Morris, Huw R %A Pickering-Brown, Stuart %A Traynor, Bryan J %T Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. %B Lancet Neurology %D 2012 %C United Kingdom %I The Lancet Publishing Group %V 11 %N 4 %P 323-330 %@ 1474-4465 %X We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Fang, Fang %T Season and weather patterns at time of birth in amyotrophic lateral sclerosis. %B Amyotrophic Lateral Sclerosis %D 2012 %C United Kingdom %I Informa Healthcare %V 13 %N 5 %P 459-464 %@ 1471-180X %X Studies in the northern hemisphere suggest that the numbers of amyotrophic lateral sclerosis (ALS) births vary depending on the season of the year. We wished to determine if a southern hemisphere study would show the same seasonal changes, and whether particular weather conditions were associated with the numbers of ALS births. Birth data from a case-control study of Australian residents were used to relate monthly birth rates of ALS to the seasons and weather conditions. The results were compared with previous studies in Japan, Sweden and Switzerland. Four hundred and ninety-one Australian sporadic ALS patients and 629 controls (partners, friends, and community volunteers) completed a self-reported questionnaire that included dates of birth. Australian ALS birth rates increased between late summer and early winter, and decreased between mid-winter and early summer. Similar patterns were seen in Japan and Sweden. Monthly average humidity correlated positively with the numbers of ALS births in Australia, Sweden, and Japan. In conclusion, seasonal differences in ALS birth rates in the southern hemisphere are similar to those in two out of three northern hemisphere countries. Early life factors related to weather conditions, such as increased humidity leading to more infectious diseases and allergens, need to be further investigated in ALS. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Ward, Elizabeth Cochran %T Smoking is not a risk factor for sporadic amyotrophic lateral sclerosis in an Australian population. %B Neuroepidemiology %D 2012 %C Switzerland %I S. Karger AG %V 38 %N 2 %P 106-113 %@ 1423-0208 %X Controversy persists as to whether smoking is a risk factor for sporadic amyotrophic lateral sclerosis (SALS), the most common form of sporadic motor neuron disease (SMND). We therefore undertook a large case-control study of smoking and SALS in Australia. %Z FOR Codes: 1103 1109 1117 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Cheong, Pak Leng %A Trent, Ronald J %A Yu, Bing %T Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. %B Neuroreport %D 2012 %C United States %I Lippincott Williams & Wilkins %V 23 %N 9 %P 556-559 %@ 0959-4965 %X Abnormally expanded C9orf72 hexanucleotide repeats are found in up to 7% of patients with sporadic amyotrophic lateral sclerosis (SALS). It is not known whether the sporadic nature of the disease represents incomplete penetrance of the phenotype or expansion of the repeat in the SALS patient. The sizes of C9orf72 hexanucleotide repeats were measured in blood DNA of 43 SALS patients and their parents who had no symptoms of ALS. Two SALS patients (4.7%) had abnormally expanded (>30 repeats) C9orf72 repeats. Both of their fathers (one with dementia) also had abnormally expanded repeats. Nine SALS patients had intermediate-normal repeat sizes (7-30 repeats); in each of these, one parent had a similar repeat size. In the remaining 32 SALS patients, the repeat sizes were low-normal (<7 repeats). There was no evidence of repeat instability leading to abnormal numbers of repeats in any SALS patient in this trio cohort. Our results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related SALS. %Z FOR Codes: 1109 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Morahan, Julia M %T Copy number imbalances in blood and hair in monozygotic twins discordant for amyotrophic lateral sclerosis. %B Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia %D 2011 %C United Kingdom %I Churchill Livingstone %V 18 %N 9 %P 1231-4 %@ 1532-2653 %X Chromosomal copy number association studies in patients with amyotrophic lateral sclerosis (ALS) using blood DNA have so far been inconclusive. We employed genome-wide screening to look for copy number imbalances (CNIs) between blood and hair DNA from three ALS-discordant monozygotic twin pairs and two phenotypically normal monozygotic twin pairs. Genome-wide chromosomal copy number was estimated using AffyMetrix 6.0 GeneChips. CNIs were sought both between twin pairs and between blood and hair DNA from the same individuals. Two blood CNIs were found in one ALS-discordant twin pair. In another ALS-discordant twin pair, seven hair CNIs were detected. CNIs were also found between blood and hair in three individuals. Imbalances in blood copy number appear to be rare in monozygotic twin pairs, but hair may harbour more CNIs than blood. Copy number differences between blood and hair from the same individuals appear to be common. Since brain and hair share a common ectodermal origin, hair may be a more suitable tissue than blood to estimate somatic copy number variation in the brain. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Jew, Stephen Kum %T Inorganic mercury within motor neurons does not cause the TDP-43 changes seen in sporadic ALS. %B Toxicology letters %D 2011 %C Ireland %I Elsevier Ireland Ltd %V 201 %N 1 %P 58-61 %@ 1879-3169 %X Heavy metals have long been suspected to be involved in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), but evidence for their toxic effects on motor neurons is limited. Characteristic mislocalisation of TDP-43 is seen in the motor neurons of patients with SALS, resulting in a lack of nuclear staining and cytoplasmic inclusions. To find out if a heavy metal can cause these TDP-43 changes, mice were exposed to varying doses of mercuric chloride or mercury vapor. Sections of spinal cord were then immunostained with phosphorylation-dependent and independent TDP-43 antibodies. All mercury-exposed mice had mercury granules in their motor neurons, even up to 2 years after exposure. However, the pathognomic changes in TDP-43 that are seen in SALS were not present in the motor neurons of these mice. The results do not therefore support a hypothesis of inorganic mercury-induced damage to motor neurons leading to SALS. This experimental model could be further used to test which of the environmental toxicants implicated in SALS may in fact cause the disease. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Morahan, Julia M %A Luquin, Natasha %A Yu, Bing %T Looking for differences in copy number between blood and brain in sporadic amyotrophic lateral sclerosis. %B Muscle & nerve %D 2011 %C United States %I John Wiley & Sons, Inc. %V 44 %N 4 %P 492-8 %@ 0148-639X %X Most analyses of blood DNA in sporadic neuromuscular disorders have been inconclusive. This may be because some genetic variants occur only in brain tissue. We therefore looked for copy number variants (CNVs) in both blood and brain in patients with sporadic amyotrophic lateral sclerosis (SALS). %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Masters, Colin L %A Kril, Jillian J %A Halliday, Glenda M %A Pamphlett, Roger %A Collins, Steven %A Hill, Andrew F %A McLean, Catriona %T Overview and recent advances in neuropathology. Part 2: Neurodegeneration. %B Pathology %D 2011 %C United Kingdom, Australia %I Wolters Kluwer UK Ltd. %V 43 %N 2 %P 93-102 %@ 0031-3025 %X The sections in the following review cover six main neurodegenerative diseases. The first article on Alzheimer''s disease (AD) outlines the major evidence available to date that links A?-amyloid peptide as a proximal cause of AD. The article also highlights how an initial finding of the protein content of the amyloid plaque seen in the brains of patients with AD has led to many very significant findings in the neuroscience field. The next section outlines the many and recent advances that have occurred in the field of frontotemporal lobar degeneration (FTLD), including the most recent finding related to the fused sarcoma gene (FUS) and the newest nomenclature whereby the FTLD is subtyped according to the presence of specific proteins seen at a microscopic level. The section on Lewy bodies outlines the latest advances in the relationship between the anatomical distribution of Lewy bodies and disease phenotype. The following section includes an overview of current known genetic links with familial causes of motor neuron disease (MND) and an update on the areas being researched into the causes of sporadic MND. The presence of TDP-43 within inclusions and its new diagnostic role in MND are discussed. The final article on prion diseases gives an overview of human prion diseases, including the phenotypic spectrum, epidemiology and diagnostic investigations relevant to disease. %Z FOR Codes: 110903 110316 110308 %0 Journal Article %~ PubMed %A Pamphlett, Roger %T The "somatic-spread" hypothesis for sporadic neurodegenerative diseases. %B Medical hypotheses %D 2011 %C United Kingdom %I Churchill Livingstone %V 77 %N 4 %P 544-7 %@ 1532-2777 %X The major neurodegenerative diseases (Alzheimer''s disease, Parkinson''s disease and amyotrophic lateral sclerosis) share in common a mostly sporadic occurrence, a focal onset of pathology, and spread from the initial site of injury to adjacent regions of the nervous system. The sporadic nature and focal onset of these diseases can be explained either by somatic mutations (arising in either of two models of cell lineage) or environmental agents, both of which affect a small number of neurons. The genetic or environmental agent then changes the conformation of a vital protein in these neurons. Spread of the diseases occurs by the misfolded proteins being transferred to adjacent neurons. Clinical and pathological details of one neurodegenerative disorder, amyotrophic lateral sclerosis, are presented to show how the pathogenesis of a typical neurodegenerative disease can be explained by this "somatic-spread" hypothesis. Ultrasensitive techniques will be needed to detect the initiating genetic or environmental differences that are predicted to be present in only a few cells. %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Pamphlett, Roger %A Morahan, Julia M %A Yu, Bing %T Using case-parent trios to look for rare de novo genetic variants in adult-onset neurodegenerative diseases. %B Journal of Neuroscience Methods %D 2011 %C Netherlands %I Elsevier BV %V 197 %N 2 %P 297-301 %@ 0165-0270 %X Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA samples are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases. %Z FOR Codes: 60410 %0 Journal Article %~ PubMed %A Luquin, Natasha %A Yu, Bing %A Trent, Ronald J %A Pamphlett, Roger %T DHPLC can be used to detect low-level mutations in amyotrophic lateral sclerosis. %B Amyotrophic Lateral Sclerosis %D 2010 %C United Kingdom %I Informa Healthcare %V 11 %N 1-2 %P 76-82 %@ 1471-180X %X Somatic mutations have been suggested as a cause of sporadic amyotrophic lateral sclerosis (SALS). These mutations can be difficult to detect since they may involve only a small percentage of cells within the tissue, so we devised a method to detect low mutation levels in brain DNA. Different proportions of a known SOD1 mutation were prepared to determine the sensitivity of DHPLC. The fraction containing the mutant signal was collected and re-amplified (''enriched'') to increase sensitivity and to dideoxy sequence the mutation. The combined technique was used to screen all exons and the promoter of SOD1 in 23 SALS brains. DHPLC could detect a known SOD1 mutation in 5% of a sample of brain tissue. Using our enrichment technique doubled the height of the mutant sequencing signal, which allowed identification of an unknown mutation in 10% of brain tissue. No SOD1 mutations were found in the SALS brains using this technique. In conclusion, combining DHPLC and sequencing doubles the sensitivity of sequencing alone and can detect low levels of known and unknown mutations in brain DNA. No SALS SOD1 somatic mutations were detected, but DHPLC would be useful in looking for somatic mutations in other SALS candidate genes. %Z FOR Codes: 60408 %0 Journal Article %~ PubMed %A Pamphlett, Roger %T Study of 962 patients indicates progressive muscular atrophy is a form of ALS. %B Neurology %D 2010 %C United States %I Lippincott Williams & Wilkins %V 74 %N 23 %P 1926; author reply 1926-7 %@ 1526-632X %X %Z FOR Codes: 110904 %0 Journal Article %~ PubMed %A Morahan, Julia M %A Yu, Bing %A Trent, Ronald J %A Pamphlett, Roger %T A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis. %B Amyotrophic lateral sclerosis %D 2009 %C United Kingdom %I Informa %V 10 %N 5-6 %P 418-429 %@ 1471-180X %X Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p