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Background: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment., Objective: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages., Methods: We conducted differential analysis of the CSF proteome from control and relapsing-remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients., Results: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS., Conclusions: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS., (© The Author(s), 2015.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and is associated with increased disease activity. It has also been proposed that the lower the vitamin D levels are, the higher is the handicap., Methods: To refine the links between vitamin D insufficiency and disability in MS patients, a retrospective cohort analysis was performed including 181 patients prospectively followed without previous vitamin D supplementation, and age, gender, age at MS onset, MS type, MS activity, Expanded Disability Status Scale (EDSS) were analysed in correlation with plasma vitamin D levels., Results: Vitamin D levels were significantly higher in relapsing-remitting MS than in progressive forms of MS in multivariate analyses adjusted for age, ethnicity, gender, disease duration and season (P = 0.0487). Overall, there was a negative correlation between vitamin D level and EDSS score (P = 0.0001, r = -0.33). In relapsing-remitting MS, vitamin D levels were only correlated with disability scores for EDSS < 4 (P = 0.0012). Patients with >20 ng/ml of vitamin D were 2.78 times more likely to have an EDSS < 4 (P = 0.0011, 95% confidence interval 1.49-5.00)., Conclusion: Data support previous work suggesting that vitamin D deficiency is associated with higher risk of disability in MS. Vitamin D levels also correlated with the degree of disability in fully ambulatory patients with relapsing-remitting MS. These additional results support the pertinence of randomized controlled trials analysing the interest of an early vitamin D supplementation in MS patients to influence evolution of disability., (© 2014 EAN.)

Amyotrophic lateral sclerosis is sporadic (SALS) in 90% of cases and has complex environmental and genetic influences. Nogo protein inhibits neurite outgrowth and is overexpressed in muscle in ALS. Our aims were to study the reticulon 4 receptor gene RTN4R which encodes Nogo 1 receptor (NgR1) in SALS, to test if the variants were associated with variable expression of the gene and whether NgR1 protein expression was modified in a transgenic mouse model of ALS. We genotyped three single nucleotide polymorphisms (SNPs; rs701421, rs701427, and rs1567871) of the RTN4R gene in 364 SALS French patients and 430 controls. We examined expression of RTN4R mRNA by quantitative PCR in control post mortem human brain tissue. We determined the expression of NgR1 protein in spinal motor neurons from a SOD1 G86R ALS mouse model. We observed significant associations between SALS and RTN4R alleles. Messenger RNA expression from RTN4R in human cortical brain tissue correlated significantly with the genotypes of rs701427. NgR1 protein expression was reduced in Nogo A positive motor neurons from diseased transgenic animals. In conclusion, these observations suggest that a functional RTN4R gene variant is associated with SALS. This variant may act in concert with other genetic variants or environmental influences.

Introduction: Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the β-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS., Methods and Analysis: The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case-control study, in the subpopulation living in the identified areas, will gather information about patients' occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls., Ethics and Dissemination: The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories., Methods: The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference., Results: Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories., Conclusions: Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Amyotrophic lateral sclerosis (ALS) is an incurable paralytic disorder primarily typified by the selective and progressive degeneration of motoneurons in the brain and spinal cord. ALS causes muscle wasting and atrophy, resulting eventually in respiratory failure and death within 3-5 years of diagnosis. Vitamin D is a potent secosteroid hormone with diverse biological functions that include protection against neuronal damage. The detrimental consequences of vitamin D dietary deficiency have been documented in other neurodegenerative diseases. However, the protective effect of vitamin D on motoneuron and the influence of its levels on disease course remains elusive. Here we found that the biologically active form of vitamin D significantly potentiated the effect of neurotrophic factors and prevented motoneurons from a Fas-induced death, while electrophysiological properties of motoneurons were not affected. In ALS patients, we report that a severe vitamin D deficiency accelerates by 4 times the rate of decline and were associated with a marked shorter life expectancy. Our findings support a neuroprotective function of vitamin D on motoneurons and propose vitamin D as a reliable prognostic factor of ALS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in the SOD1 gene, number of genes linked to or promoting ALS had always growing. Among them, only four (SOD1, TARDBP, FUS and C9ORF72 genes) are unanimously recognized as convincing causative genetic factors for more than 60% of familial and probably 10% of sporadic ALS cases. Geographic origin of the studied populations tends to become one of the major items in the gene-ALS relationship: this was extremely stressed for C9ORF72. Concerning susceptibility genes factors, an increase of the risk of ALS is clearly shown for SMN1 and ATXN2 genes and accepted for some VEGF haplotypes. Finally, some modulating effects might also exist as underline for the relationships between ApoE and ALS that differ between European and North American studies. In inherited ALS, The European Federation of Neurological Societies (EFNS) edited rules that gave a legal frame to situations for which research of mutations were justified. Progress in the field of genetic raises major questions concerning the relevance of genetic studies from asymptomatic relatives. This first implies that the mutation identified in the proband case is perfectly characterized as a pathogenic mutation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these metals. Exposure to pesticides has been suggested to be linked to an increased risk of developing ALS. The mechanism of their toxicity is likely to be mediated by paraoxonases. These proteins are in charge of detoxifying the organism from toxins, and particularly organophosphates. To date, there are insufficient scientific data to suggest that exposure to electromagnetic fields may increase the risk of having ALS. We are particularly missing longitudinal cohorts to demonstrate that risk., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Importance: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge., Objective: To collect data from patients with MS switching from natalizumab to fingolimod., Design, Setting, and Participants: The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod., Main Outcomes and Measures: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod., Results: Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05)., Conclusions and Relevance: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Background and Purpose: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment., Methods: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y )., Results: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found., Conclusions: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

Background: Dietary exposure to the cyanotoxin BMAA is suspected to be the cause of amyotrophic lateral sclerosis in the Western Pacific Islands. In Europe and North America, this toxin has been identified in the marine environment of amyotrophic lateral sclerosis clusters but, to date, only few dietary exposures have been described., Objectives: We aimed at identifying cluster(s) of amyotrophic lateral sclerosis in the Hérault district, a coastal district from Southern France, and to search, in the identified area(s), for the existence of a potential dietary source of BMAA., Methods: A spatio-temporal cluster analysis was performed in the district, considering all incident amyotrophic lateral sclerosis cases identified from 1994 to 2009 by our expert center. We investigated the cluster area with serial collections of oysters and mussels that were subsequently analyzed blind for BMAA concentrations., Results: We found one significant amyotrophic lateral sclerosis cluster (p = 0.0024), surrounding the Thau lagoon, the most important area of shellfish production and consumption along the French Mediterranean coast. BMAA was identified in mussels (1.8 µg/g to 6.0 µg/g) and oysters (0.6 µg/g to 1.6 µg/g). The highest concentrations of BMAA were measured during summer when the highest picocyanobacteria abundances were recorded., Conclusions: While it is not possible to ascertain a direct link between shellfish consumption and the existence of this ALS cluster, these results add new data to the potential association of BMAA with sporadic amyotrophic lateral sclerosis, one of the most severe neurodegenerative disorder.

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Vitamin D deficiency is associated with a higher risk of multiple sclerosis and also with a higher relapse rate as well as a higher number of MRI lesions. Elders with vitamin D deficiency have worse cognitive performance. Vitamin D deficiency is a risk factor for developing Alzheimer's disease. Ischemic stroke are more frequent and more severe in patients with low vitamin D levels. Carotid atherosclerosis is more frequent and more severe in patients with vitamin D deficiency. Vitamin D deficiency is associated with a higher risk and worse prognosis of Parkinson's disease. In the different neurological disorders discussed herein, gene polymorphisms that could alter vitamin D metabolism are also associated with a higher incidence or a worse disease prognosis. Despite the links between vitamin D deficiency and the risks of developing neurological disorders, there is, to date, no proof that supplementation could alter the course of these diseases., (Copyright © 2013. Published by Elsevier Masson SAS.)

The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n = 468) and matched-controls (n = 394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio = 2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development., (© 2013 WILEY PERIODICALS, INC.)

The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Δ). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.

Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in many patients; the average time between symptom onset and diagnosis can reach 12 months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrollment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Mutations in the profilin 1 (PFN1) gene, encoding a member of the profilin family of small actin-binding proteins, have been recently reported in patients with familial amyotrophic lateral sclerosis (ALS). In this study we aimed to determine the prevalence of PFN1 mutations by sequencing the coding region of this gene in a cohort of 94 familial ALS patients from France and Quebec. No mutations were identified in our cohort suggesting that PFN1 gene mutations are a very rare cause of familial ALS among patients with predominantly European ancestry., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron diseases (MND), while frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia. Many ALS families segregating FTLD have been reported, particularly over the last decade. Recently, mutations in TARDBP, FUS/TLS, and C9ORF72 have been identified in both ALS and FTLD patients, while mutations in VCP, a FTLD associated gene, have been found in ALS families. Distinct variants located in the 3'-untranslated region (UTR) of the SIGMAR1 gene were previously reported in three unrelated FTLD or FTLD-MND families. We directly sequenced the coding and UTR regions of the SIGMAR1 gene in a targeted cohort of 25 individual familial ALS cases of Caucasian origin with a history of cognitive impairments. This screening identified one variant in the 3'-UTR of the SIGMAR1 gene in one ALS patient, but the same variant was also observed in 1 out of 380 control chromosomes. Subsequently, we screened the same samples for a C9ORF72 repeat expansion: 52% of this cohort was found expanded, including the sample with the SIGMAR1 3'-UTR variant. Consequently, coding and noncoding variants located in the 3'-UTR region of the SIGMAR1 gene are not the cause of FTLD-MND in our cohort, and more than half of this targeted cohort is genetically explained by C9ORF72 repeat expansions.

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

Multiple sclerosis (MS) is the main nontraumatic cause of handicap in young adults. Immunomodulators and treatments limiting lymphocyte migration have been proven efficient to treat relapsing-remitting MS. Subcutaneous IFN-β1a improve relapse rate and MRI parameters in a series of double-blind, placebo-controlled trials in relapsing-remitting MS patients. Similar results, and with a greater extent, were obtained when treating patients with a first demyelinating event suggestive of MS. Except for the rare liver toxicity, the drug is well tolerated and has no severe adverse reaction. When compared with intramuscular IFN-β1a, both relapse rate and MRI parameters were modulated in favor of the subcutaneous administration. Although the effect of subcutaneous IFN-β1a on disability progression is limited, the good tolerance profile together with the efficiency of the drug explain why this treatment, as well as the other interferons and glatiramer acetate, is a first-line therapy for relapsing-remitting MS.

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disorder in adults. This fatal condition, due to degeneration of upper and lower motor neurons in spinal and bulbar myotomes, leads to death from respiratory failure after median disease duration of 36 months. ALS is sporadic in more than 90% of cases and familial in the remaining cases. Most studies show male predominance with a gender ratio of 3:2, but gender differences are age related. The phenotype of ALS is also different in males and females with a predominance of limb onset in males and bulbar onset in females. While age and site of onset impact survival rate, and are both related to gender, gender by itself has not clearly been shown to have an effect on survival. Given this complex relationship between gender and ALS, we developed a hypothesis about hormone involvement in ALS aetiology by suggesting protective effect of oestrogens and adverse effect of androgens.

Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been recently identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with dementia. We report here the sequencing of the UBQLN2 gene in 590 ALS patients of French and French-Canadian ancestry. We identified two novel missense mutations (p.S155N and p.P189T) in two individuals with sporadic ALS. Bioinformatic analysis predicts that these missense mutations affect the normal protein's function. Importantly, these findings further highlight the importance of the proline residues located in the conserved domains of the ubiquilin-2 protein, suggesting that mutations affecting these residues are particularly relevant to the development of ALS. Our findings further support a causative role of the UBQLN2 gene in the pathogenesis of ALS and suggest that UBQLN2 mutations are rare in the French and French-Canadian population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD., Design: A repeat-primed polymerase chain reaction assay., Setting: Academic research., Participants: Affected and unaffected individuals from 4 ALS/FTD families., Main Outcome Measure: The amplified C9orf72 repeat expansion., Results: We show that the repeat is expanded in and segregated perfectly with the disease in these 4 pedigrees., Conclusion: Our findings further confirm the C9orf72 hexanucleotide repeat expansion as the causative mutation for c9ALS/FTD and strengthen the hypothesis that ALS and FTD belong to the same disease spectrum.

Background: Substantial efforts have been deployed in the past decade to identify the genetic causes of amyotrophic lateral sclerosis (ALS), and we hypothesized here that mutations in SORT1 or aberrant SORT1 splicing reduce progranulin level and promote neurodegeneration., Methods: We sequenced the coding exons of SORT1 in a cohort of 112 unrelated individuals with familial ALS. We also tested for aberrant SORT1 splicing by RT-PCR using RNA samples from cell lines expressing six different ALS-associated TARDBP mutations., Results: We identified one unique missense and two unique silent mutations in our cohort. None are predicted to have functional effects. No aberrant SORT1 splicing event was observed., Conclusions: SORT1 mutations are not a common cause of familial ALS, and the influence of TARDBP mutations on SORT1 splicing still needs to be clarified., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations., Methods: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations., Results: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months)., Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.

Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

Mutations in UBQLN2 encoding ubiquilin-2 have recently been identified in families with dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. Ubiquilin-2 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. All the previously reported UBQLN2 mutations were localized in 1 of the 12 PXX domains of ubiquilin-2 protein. We sequenced UBQLN2 in 130 French patients with familial ALS (FALS) and absence of male-to-male transmission and the PXX domain in 240 more patients with sporadic ALS (SALS). We identified, at the heterozygote state, the c.1500&#95;1508delCATAGGCCC, p.Gly502&#95;Ile504del, in 1 affected woman. This deletion presumably leads to the in-frame deletion of 1 PXX repeat in the protein. This variant did not segregate with the disease in the corresponding family and was also detected in 1/380 control subject. Our results suggest that UBQLN2 gene mutations are rare in French ALS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS., Methods: We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations., Results: The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene (SOD1, TARDBP, FUS) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1, p=0.002 vs TARDBP, p=0.011 vs FUS, p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1, p=0.04 vs TARDBP, p=0.004 vs FUS, p=0.03 vs other FALS). C9ORF72-linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72-negative SALS (p=0.0006)., Conclusions: Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes.

Background. Uveitis is 20 times more frequent in multiple sclerosis (MS) patients than in the general population. Methods. A retrospective study of local multiple sclerosis (n = 700) and uveitis cohorts (n = 450) described the ophthalmological and neurological characteristics of patients with multiple sclerosis and uveitis. Results. Uveitis and multiple sclerosis were associated in seven patients. The time intervals between diagnoses of MS and uveitis ranged from 6 months to 15 years. Analysis of the patients' characteristics revealed that multiple sclerosis was associated with an older age of onset than usually expected, that is, 39 years. Uveitis was bilateral in three cases and mainly posterior (5/10). Five patients presented with acute optic neuritis (two in one eye and three in both eyes). All eyes presenting with acute optic neuritis were also affected by uveitis (P = 0.02), though not simultaneously. Conclusion. The ipsilateral association between optic neuritis and uveitis in this series of patients with multiple sclerosis may suggest a reciprocal potentiation between optic neuritis and uveitis in multiple sclerosis.

Introduction: Demyelinating disease affecting both the central and the peripheral nervous systems has rarely been reported., Case Report: A 30-year-old man, presented with ataxia and diffuse areflexia due to polyneuropathy fullfilling demyelination criteria. His medical history was notable for central nervous system demyelination compatible with multiple sclerosis. He improved transiently with intravenous immunoglobulin and then stabilized with methotrexate., Conclusion: This case report distinguishes a new kind of inflammatory disease affecting both central and peripheral nervous system. It seems to be different from multiple sclerosis and chronic immune demyelinating polyneuropathy, because of high hyperproteinorachia and absence of oligoclonal bands in the cerebrospinal fluid., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective:   Several association studies have identified possible susceptibility factors for sporadic amyotrophic lateral sclerosis (SALS). Studies on the APOE gene provided conflicting results, especially about the effect on bulbar onset. We assessed the possible role of APOE gene in a large cohort of patients with ALS and matched controls., Methods:   The APOE alleles were determined in 1482 patients with SALS and 955 controls and analysed by univariate and multivariate statistics, taking into account gender, site-of-onset and age-at-onset., Results:   Patients with bulbar onset were more likely to be women [odds ratio (OR)=2.17; 95% CI: 1.74-2.72] and to be older (OR=3.47; 95% CI: 2.58-4.67). The ε4-carriers were more frequent in the bulbar-onset group than in the limb-onset group (OR=1.39 bulbar onset versus limb onset; 95% CI: 1.08-1.80) but this association was observed amongst men (OR=1.78; 95% CI: 1.25-2.53) and not women (OR=1.09; 95% CI: 0.75-1.59)., Conclusion:   Our study provides evidence for a contribution of the ε4 allele in the occurrence of bulbar-onset ALS amongst men. We propose that men are normally protected by androgens against bulbar onset and that the ε4 allele inhibits this protection, perhaps by interfering with the androgen pathway., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Familial amyotrophic lateral sclerosis (FALS) cases linked to SOD1 mutations may sometimes present with unusual clinical features such as pure lower motor neuron involvement or sensory signs. The authors describe a FALS pedigree with the L144F SOD1 mutation in which all cases had respiratory involvement as a first symptom. Although atypical clinical features are not rare in ALS families, this is the first pedigree with respiratory-onset in three affected members. This unusual presentation led to delayed diagnosis in the proband and highlights the fact that respiratory-onset can occur in familial ALS cases carrying SOD1 mutation.

Objective: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS., Design: Case-control study., Setting: France and Quebec, Canada., Participants: A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin., Results: We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases., Conclusions: Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.

Background: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies., Objective: To describe HRS patients and compare them with NMO patients., Methods: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database., Results: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup., Conclusion: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.

Objective: To identify novel disease-causing genes for amyotrophic lateral sclerosis (ALS)., Design, Setting, and Patients: We carried out a systematic mutation screening of the entire coding regions of 29 candidate genes encoding critically important proteins for proper differentiation and development of corticospinal motor neurons in 190 patients with familial and sporadic ALS., Main Outcome Measures: We focused our analysis on coding variants and evaluated the distribution of nonsynonymous and synonymous variants in our cohort of patients with ALS., Results: We identified 40 novel nonsynonymous variants and showed a significant excess of unique nonsynonymous variants in our cohort of patients with ALS, which suggests the presence of ALS-predisposing mutations., Conclusions: Using a multifaceted approach based on the functional prediction of missense variants, the conservation of the altered amino acid, and the cosegregation of the variants identified in familial cases, we identified several promising novel genes for ALS such as LUM and CRYM. We have also highlighted the analytical challenges of large-scale sequencing screens to detect disease-causing variants.

Chromogranins interact with mutant forms of superoxide dismutase 1 (SOD1) responsible for a portion of familial amyotrophic lateral sclerosis (ALS). A particular variation (P413L) in the chromogranin B gene, CHGB, has been recently associated with an earlier age at onset in both familial and sporadic ALS. The aim of our study was to evaluate the P413L chromogranin variation in French patients with sporadic amyotrophic lateral sclerosis. We developed a High Resolution DNA Melting (HRM) protocol to analyse the P413L variation in the CHGB gene in 540 French patients with sporadic ALS and 504 controls. The clinical characteristics of patients were analysed in relation to their genotype. Results showed that our study on a large cohort of French-Caucasian patients with SALS and controls failed to confirm an increased frequency of the 413L variant in SALS patients. This frequency was 5.3% in the SALS population and 5.5% in the control group. Moreover, we did not observe a previous observation of a difference of age at onset between T-allele carriers and non-carriers (median age of onset 60.4 vs. 62.0 years of age, respectively). Thus, our findings do not support the 413L variant of rs742710 as a risk factor for sporadic ALS in the French population.

Background: Dysregulation of iron homeostasis is one possible pathophysiological mechanism involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). SLC11A2 gene encodes the divalent metal transport 1 (DMT1) mediating iron transport in cerebral endosomal compartments. The objective of the study was to analyze DMT1 as a possible risk or modulating factor in sporadic ALS (SALS)., Methods: We performed a case-control association study on an intronic polymorphism (rs407135) previously analyzed in another neurodegenerative disease, Alzheimer's disease. This polymorphism was studied by DNA sequencing in 579 French patients with SALS and 517 healthy matched individuals. The clinical characteristics of patients were analyzed in relation to their genotypes., Results: We observed that the C allele of rs407135 in SLC11A2 was associated with a shorter disease duration in SALS patients with onset in the legs [Hazard ratio: 1.5 [1.1-2.1] (p=0.02)]. These results are in line with previous observations suggesting that bulbar and spinal motor neurons have different metabolic regulation and gene expression profiles., Conclusions: Our findings support an implication for iron metabolism in ALS and suggest that the genotype of the SLC11A2 gene could modulate the duration of the disease in French SALS patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage.

Mutations in the OPTN gene are well known to be associated with the development of glaucoma. Recently, unique variations in the same gene have been reported in familial and sporadic Japanese cases of amyotrophic lateral sclerosis (ALS). We set out to evaluate the frequency of OPTN mutations in a sample of our familial and sporadic ALS cohorts. All coding exons of the OPTN gene were amplified and sequenced in 95 unrelated familial ALS (FALS) and 95 sporadic ALS (SALS) cases of European descent. Two variants were newly identified in 2 individual FALS cases. Unique variations in the OPTN gene are rare in FALS cases and were not identified in any SALS patients, all of European descent., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Genetic studies have led, thus far, to the identification of 12 loci and 9 genes for familial ALS (FALS). Although the distribution and impact of superoxide dismutase 1 mutations has been extensively examined for over a decade, the recently identified FALS-associated FUS gene has been less studied. Therefore, we set out to screen our collection of FALS cases for FUS mutations. All 15 exons of FUS were amplified and sequenced in 154 unrelated FALS cases and 475 ethnically matched healthy individuals. One substitution located in the acceptor splice site of intron 14 was identified in all affected members of a large family, causing the skipping of the last 13 amino acids of the protein and the translation of 7 novel amino acids, resulting from the new translation of a part of the 3' untranslated region. Our study identified a new splicing mutation in the highly conserved C-terminal of the FUS protein. Thus far most FUS mutations are missenses, and our findings, combined with those of others, confirm the importance of the C-terminal portion of the protein, adding additional support for FUS mutations having a critical role in ALS.

Mutations in OPTN gene encoding optineurin have recently been identified at the homozygote and heterozygote state in Japanese families with slowly progressive amyotrophic lateral sclerosis (ALS). OPTN had previously been involved in adult primary open angle glaucoma (POAG). We sequenced the coding exons of OPTN in 126 French patients with familial ALS (FALS). We identified, at the heterozygote state, the nonsense c.382&#95;383insAG variant (also called 691&#95;692insAG), alternatively reported as a causative mutation for primary open angle glaucoma (POAG) or a rare polymorphism and the new p.Arg96Leu variant in a family with dominant ALS. Western blot experiments on the patients' lymphoblasts showed that the former variant led to a loss of function and the latter did not cause protein accumulation. Our results do not confirm the contribution of OPTN in ALS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

NMO-IgG is a specific biomarker of neuromyelitis optica (NMO) that targets the aquaporin-4 (AQP4) water channel protein. The current gold standard for NMO-IgG identification is indirect immunofluorescence (IIF). Our aim in this study was to develop a new quantitative cell-based assay (CBA) and to propose a rational strategy for anti-AQP4 Ab identification and quantification. We observed an excellent correlation between the CBA and IIF for NMO-IgG/anti-AQP4 detection. The CBA appeared more sensitive than IIF but on the other hand, IIF allows the simultaneous detection of various auto-Abs, underlining the complementarity between both methods. In conclusion, we propose to use IIF for the screening of patients at diagnosis in order to identify auto-Abs targeting the central nervous system. A highly sensitive, AQP4 specific and quantitative assay such as our CBA could be used thereafter to specifically identify the target of the Ab and to monitor its serum concentration under treatment., (Copyright © 2010 Elsevier Inc. All rights reserved.)