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1.  Valosin-containing protein mutations in sporadic amyotrophic lateral sclerosis 
Neurobiology of Aging  2012;33(9):2231.e1-2231.e6.
We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
doi:10.1016/j.neurobiolaging.2012.04.005
PMCID: PMC3391327  PMID: 22572540
Amyotrophic lateral sclerosis; valosin-containing protein; mutations; sporadic disease
2.  Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease 
Brain  2012;135(9):2875-2882.
Brown–Vialetto–Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown–Vialetto–Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown–Vialetto–Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown–Vialetto–Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.
doi:10.1093/brain/aws161
PMCID: PMC3437022  PMID: 22740598
motor neuron disease; ALS; riboflavin; BVVL; SLC52A2
3.  A candidate gene for autoimmune myasthenia gravis 
Neurology  2012;79(4):342-347.
Objective:
We sought to identify a causative mutation in a previously reported kindred with parental consanguinity and 5 of 10 siblings with adult-onset autoimmune myasthenia gravis.
Methods:
We performed genome-wide homozygosity mapping, and sequenced all known genes in the one region of extended homozygosity. Quantitative and allele-specific reverse transcriptase PCR (RT-PCR) were performed on a candidate gene to determine the RNA expression level in affected siblings and controls and the relative abundance of the wild-type and mutant alleles in a heterozygote.
Results:
A region of shared homozygosity at chromosome 13q13.3–13q14.11 was found in 4 affected siblings and 1 unaffected sibling. A homozygous single nucleotide variant was found in the 3′-untranslated region of the ecto-NADH oxidase 1 gene (ENOX1). No other variants likely to be pathogenic were found in genes in this region or elsewhere. The ENOX1 sequence variant was not found in 764 controls. Quantitative RT-PCR showed that expression of ENOX1 decreased to about 20% of normal levels in lymphoblastoid cells from individuals homozygous for the variant and to about 50% in 2 unaffected heterozygotes. Allele-specific RT-PCR showed a 55%–60% reduction in the level of the variant transcript in heterozygous cells due to reduced mRNA stability.
Conclusion:
These results indicate that this sequence variant in ENOX1 may contribute to the familial autoimmune myasthenia in these patients.
doi:10.1212/WNL.0b013e318260cbd0
PMCID: PMC3400092  PMID: 22744667
5.  Frequency of the C9ORF72 hexanucleotide repeat expansion in ALS and FTD in diverse populations: a cross-sectional study 
Lancet Neurology  2012;11(4):323-330.
Background
A hexanucleotide repeat expansion in the C9ORF72 gene has recently been shown to cause a large proportion of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD).
Methods
We screened 4,448 patients diagnosed with ALS and 1,425 patients diagnosed with FTD drawn from diverse populations for the hexanucleotide expansion using a repeat-primed PCR assay. ALS and FTD were diagnosed according to the El Escorial and Lund-Manchester criteria respectively. Familial status was based on self-reported family history of similar neurodegenerative diseases at the time of sample collection. Haplotype data of 262 patients carrying the expansion were compared with the known Finnish founder risk haplotype across the chromosomal locus. Age-related penetrance was calculated by the Kaplan-Meier method using data from 603 individuals carrying the expansion.
Findings
The mutation was observed among 7·0% (n = 236 of 3,377) of Caucasians, 4·1% (n = 2 of 49) of African-Americans, and 8·3% (n = 6 of 72) of Hispanic individuals diagnosed with sporadic ALS, whereas the rate was 6·0% (n = 59 of 981) among Caucasians diagnosed with sporadic FTD. Among Asians, 5·0% (n = 1 of 20) of familial ALS and 66·6% (n = 2 of 3) of familial FTD cases carried the repeat expansion. In contrast, mutations were not observed among patients of Native American (n = 3 sporadic ALS), Indian (n = 31 sporadic ALS, n = 31 sporadic FTD), and Pacific Islander (n = 90 sporadic ALS) ethnicity. All patients with the repeat expansion carried, either partially or fully, the founder haplotype suggesting that the expansion occurred on a single occasion in the past (~1,500 years ago). The pathogenic expansion was non-penetrant below 35 years of age, increasing to 50·0% penetrance by 58 years of age, and was almost fully penetrant by 80 years of age.
Interpretation
We confirm that a common single Mendelian genetic lesion is implicated in a large proportion of sporadic and familial ALS and FTD. Testing for this pathogenic expansion will be important in the management and genetic counseling of patients with these fatal neurodegenerative diseases.
Funding
See Acknowledgements.
doi:10.1016/S1474-4422(12)70043-1
PMCID: PMC3322422  PMID: 22406228
6.  Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases 
Neurology  2012;79(2):127-131.
Objective:
Genetic heterogeneity is common in many neurologic disorders. This is particularly true for the hereditary ataxias where at least 36 disease genes or loci have been described for spinocerebellar ataxia and over 100 genes for neurologic disorders that present primarily with ataxia. Traditional genetic testing of a large number of candidate genes delays diagnosis and is expensive. In contrast, recently developed genomic techniques, such as exome sequencing that targets only the coding portion of the genome, offer an alternative strategy to rapidly sequence all genes in a comprehensive manner. Here we describe the use of exome sequencing to investigate a large, 5-generational British kindred with an autosomal dominant, progressive cerebellar ataxia in which conventional genetic testing had not revealed a causal etiology.
Methods:
Twenty family members were seen and examined; 2 affected individuals were clinically investigated in detail without a genetic or acquired cause being identified. Exome sequencing was performed in one patient where coverage was comprehensive across the known ataxia genes, excluding the known repeat loci which should be examined using conventional analysis.
Results:
A novel p.Arg26Gly change in the PRKCG gene, mutated in SCA14, was identified. This variant was confirmed using Sanger sequencing and showed segregation with disease in the entire family.
Conclusions:
This work demonstrates the utility of exome sequencing to rapidly screen heterogeneous genetic disorders such as the ataxias. Exome sequencing is more comprehensive, faster, and significantly cheaper than conventional Sanger sequencing, and thus represents a superior diagnostic screening tool in clinical practice.
doi:10.1212/WNL.0b013e31825f048e
PMCID: PMC3390538  PMID: 22675081
7.  Large proportion of amyotrophic lateral sclerosis cases in Sardinia are due to a single founder mutation of the TARDBP gene 
Archives of neurology  2011;68(5):594-598.
Objective
To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.
Design
Population-based, prospective cohort study.
Patients
A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.
Intervention
Patients underwent mutational analysis for SOD1, FUS, and TARDBP.
Results
Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94–single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.
Conclusions
The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
doi:10.1001/archneurol.2010.352
PMCID: PMC3513278  PMID: 21220647
8.  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD 
Renton, Alan E. | Majounie, Elisa | Waite, Adrian | Simón-Sánchez, Javier | Rollinson, Sara | Gibbs, J. Raphael | Schymick, Jennifer C. | Laaksovirta, Hannu | van Swieten, John C. | Myllykangas, Liisa | Kalimo, Hannu | Paetau, Anders | Abramzon, Yevgeniya | Remes, Anne M. | Kaganovich, Alice | Scholz, Sonja W. | Duckworth, Jamie | Ding, Jinhui | Harmer, Daniel W. | Hernandez, Dena G. | Johnson, Janel O. | Mok, Kin | Ryten, Mina | Trabzuni, Danyah | Guerreiro, Rita J. | Orrell, Richard W. | Neal, James | Murray, Alex | Pearson, Justin | Jansen, Iris E. | Sondervan, David | Seelaar, Harro | Blake, Derek | Young, Kate | Halliwell, Nicola | Callister, Janis | Toulson, Greg | Richardson, Anna | Gerhard, Alex | Snowden, Julie | Mann, David | Neary, David | Nalls, Michael A. | Peuralinna, Terhi | Jansson, Lilja | Isoviita, Veli-Matti | Kaivorinne, Anna-Lotta | Hölttä-Vuori, Maarit | Ikonen, Elina | Sulkava, Raimo | Benatar, Michael | Wuu, Joanne | Chiò, Adriano | Restagno, Gabriella | Borghero, Giuseppe | Sabatelli, Mario | Heckerman, David | Rogaeva, Ekaterina | Zinman, Lorne | Rothstein, Jeffrey | Sendtner, Michael | Drepper, Carsten | Eichler, Evan E. | Alkan, Can | Abdullaev, Zied | Pack, Svetlana D. | Dutra, Amalia | Pak, Evgenia | Hardy, John | Singleton, Andrew | Williams, Nigel M. | Heutink, Peter | Pickering-Brown, Stuart | Morris, Huw R. | Tienari, Pentti J. | Traynor, Bryan J.
Neuron  2011;72(2):257-268.
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
doi:10.1016/j.neuron.2011.09.010
PMCID: PMC3200438  PMID: 21944779
9.  Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study 
Lancet Neurology  2012;11(4):323-330.
Summary
Background
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).
Methods
We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings
In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation
A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
Funding
Full funding sources listed at end of paper (see Acknowledgments).
doi:10.1016/S1474-4422(12)70043-1
PMCID: PMC3322422  PMID: 22406228
10.  Exome sequencing reveals VCP mutations as a cause of familial ALS 
Neuron  2010;68(5):857-864.
Summary
Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget’s disease and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically-proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1–2% of familial ALS, and represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
doi:10.1016/j.neuron.2010.11.036
PMCID: PMC3032425  PMID: 21145000
11.  SCA15 due to large ITPR1 deletions in a cohort of 333 Caucasian families with dominant ataxia 
Archives of neurology  2011;68(5):637-643.
Objectives
to determine the frequency and the phenotypical spectrum of SCA15 patients.
Methods
in the index cases of 333 families with autosomal dominant cerebellar ataxia (ADCA) negative for CAG repeat expansions in coding exons (SCA1,2,3,6,7,17 and dentatorubropallidoluysian atrophy), we searched for heterozygous rearrangements in ITPR1. Taqman PCR (258 index cases) or SNP genome-wide genotyping (75 index cases) were used.
Results
a deletion of ITPR1 was found in 6/333 (1.8%) families, corresponding to 13 SCA15 patients. Age at onset ranged from 18 to 66 years with a mean of 35±16 years. The symptom at onset was mainly cerebellar gait ataxia, except for one patient presenting with isolated upper limb tremor. Although we tested a large cohort of families irrespective of their phenotype, the main clinical features of SCA15 patients were homogeneous and characterized by a very slowly progressive gait and limb cerebellar ataxia with dysarthria. However, pyramidal signs (two patients), and mild cognitive problems (two patients) were occasionally present. Ocular alterations consisted of nystagmus, mainly horizontal and gaze-evoked (ten patients), and saccadic pursuit (seven patients). Radiological findings showed global or predominant vermian cerebellar atrophy in all patients.
Conclusions
In this series ITPR1 deletions are rare and account for ~1% of all ADCA. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present in a minority of patients.
doi:10.1001/archneurol.2011.81
PMCID: PMC3142680  PMID: 21555639

Results 1-11 (11)