Chorea is a pleiotropic clinical feature of mutated fused-in-sarcoma in amyotrophic lateral sclerosis.

Around 10% of all amyotrophic lateral sclerosis (ALS) cases are familial and around 3-5% are fused-in-sarcoma (FUS)-related in Europe. We report a 43-year-old patient with a pathogenic FUS mutation (c.1561C>G p.(Arg521Gly) who presented at our clinic with chorea and subsequently with progressive symptoms of classical ALS. As a result of progressive upper and lower motor neurone deterioration, chorea disappeared and death occurred 2.5 years after the onset of the first manifestations. This first description adds chorea as a possible pleiotropic clinical feature in FUS-related ALS. It further warrants to systematically ask and check for chorea in ALS patients and their relatives.

Author Correction: Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.

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Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study.

BACKGROUND AND PURPOSE: Previous studies, mostly case reports and uncontrolled studies, provide a low level of evidence for the hypothesized link between Lyme disease and amyotrophic lateral sclerosis (ALS). In order to make evidence-based recommendations regarding testing for Borrelia burgdorferi antibodies in the diagnostic work-up for ALS, the objective of this study was to explore the evidence for an association between these antibodies and ALS in a case-control design including age-, gender- and residency-matched controls. METHODS: A total of 491 patients with ALS were matched to 982 controls. IgG titers against B. burgdorferi were determined by an enzyme-linked immunosorbent assay and, in the case of positivity or borderline results, a western blot was performed. Conditional logistic regression and Fisher's exact tests were used to compare the antibody titers or positivity between patients and controls. RESULTS: No difference in seroprevalence of Borrelia was found between patients (4.1%) and controls (5.9%). Clinical characteristics and survival were similar between seropositive and seronegative patients. Moreover, patients with a spinal onset were not more frequently seropositive compared with patients with a bulbar onset (P = 0.47), and neither were patients with a short diagnostic delay of <6 months compared with controls (P = 0.69). None of the 20 patients with a diagnostic delay of <3 months tested positive for IgM antibodies, suggestive of a recent infection. CONCLUSION: This large case-control study provides evidence for a lack of association between B. burgdorferi antibodies and ALS, and therefore does not support the inclusion of routine testing for these antibodies in the diagnostic work-up in patients with classical ALS.

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis.

BACKGROUND: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results. METHODS: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3. RESULTS: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1ß, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005). CONCLUSIONS: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1ß, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

BACKGROUND: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS: Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.

ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.

SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

SMN1 gene duplications are associated with sporadic ALS.

OBJECTIVE: To investigate the role of SMN1 and SMN2 copy number variation and point mutations in amyotrophic lateral sclerosis (ALS) pathogenesis in a large population. METHODS: We conducted a genetic association study including 847 patients with ALS and 984 controls. We used multiplexed ligation-dependent probe amplification (MLPA) assays to determine SMN1 and SMN2 copy numbers and examined effects on disease susceptibility and disease course. Furthermore, we sequenced SMN genes to determine if SMN mutations were more prevalent in patients with ALS. A meta-analysis was performed with results from previous studies. RESULTS: SMN1 duplications were associated with ALS susceptibility (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.34-3.20, p = 0.001). A meta-analysis with previous data including 3,469 individuals showed a similar effect: OR 1.85, 95% CI 1.18-2.90, p = 0.008). SMN1 deletions and SMN2 copy number status were not associated with ALS. SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. We found no enrichment of SMN point mutations in patients with ALS. CONCLUSIONS: Our data provide firm evidence for a role of common SMN1 duplications in ALS, and raise new questions regarding the disease mechanisms involved.

Family history of neurodegenerative and vascular diseases in ALS: a population-based study.

OBJECTIVE: To determine whether the frequency of Parkinson disease (PD), dementia, and vascular diseases in relatives of patients with amyotrophic lateral sclerosis (ALS) differs from the frequency of those diseases in relatives of controls, providing further information about the association between these diseases. METHODS: We studied the occurrence of neurodegenerative and vascular diseases in families of patients with ALS in a prospective, population-based, case-control study in the Netherlands between 2006 and 2009, using the recurrence risk λ. Family history data were obtained by asking participants to fill in questionnaires. RESULTS: A total of 635 patients and 1,616 controls were included. The frequency of dementia was mildly increased only among parents and siblings of patients with sporadic ALS (λ1.32; 95 confidence interval [CI] 1.10-1.59), not among grandparents, or aunts and uncles. The risk of PD was not elevated (any relative: λ 0.91; 95% CI 0.70-1.17). Among relatives of patients with familial ALS, no significantly increased risk of neurodegenerative diseases was found. A reduced risk of vascular diseases was found in relatives of patients with sporadic ALS (stroke: λ 0.90; 95% CI 0.80-1.01 and myocardial infarction: λ 0.86; 95% CI 0.79-0.94), and in relatives of patients with familial ALS (stroke: λ 0.88; 95% CI 0.61-1.27 and myocardial infarction: λ 0.61; 95% CI 0.43-0.86). CONCLUSIONS: This large, prospective, population-based study showed that familial aggregation of ALS, dementia, and PD is substantially lower than previously thought. The lowered risk of vascular diseases in relatives of patients with ALS supports the view that a beneficial vascular risk profile increases ALS susceptibility.

Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that results in progressive muscle weakness and limits survival to 2-5 years after disease onset. Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS. METHODS: We determined ATXN2 CAG repeat size in 1,948 sporadic and familial ALS cases and 2,002 controls from Belgium and the Netherlands. RESULTS: In controls, the maximal ATXN2 repeat size was 31. In sporadic ALS, a significant amount of longer repeat sizes (≥ 32, range 32-39) were encountered (in 0.5% or 10/1,845 ALS cases, vs 0% in controls, p = 0.0006). Receiver operating characteristic analysis showed that a cutoff of ≥ 29 appeared optimal to discriminate ALS from control (p = 0.036, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.04-3.64). A meta-analysis with the previously published results from the United States showed that the association between a repeat length of ≥ 29 and ALS became stronger (p < 0.0001, OR 2.93, 95% CI 1.73-4.98). In unexplained familial ALS, we found an intermediate repeat expansion of 31 and a homozygous repeat expansion of 33 each in 1.1% of families. The phenotype of patients with ALS with expanded repeat sizes ranged from rapidly progressive typical ALS to slowly progressive ALS with reduced sensory nerve action potentials. CONCLUSION: Our data reveal a novel genetic overlap between ALS and SCA2.

Beneficial vascular risk profile is associated with amyotrophic lateral sclerosis.

OBJECTIVES: Reports of increased amyotrophic lateral sclerosis (ALS) with hyperlipidaemia and elevated plasma homocysteine levels as well as cigarette-smoking and polymorphisms in angiogenic genes suggest a role for altered vascular homeostasis in ALS pathogenesis. The authors assessed the association between vascular risk factors and ALS. METHODS: Traditional cardiovascular risk factors (smoking, hypertension, hypercholesterolaemia, diabetes and body mass index (BMI)) and cardiovascular disease prior to ALS onset established by a questionnaire were compared in 334 patients and 538 age- and sex-matched controls. Biochemical assessments (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), hs-CRP, and homocysteine) at diagnosis were measured in blood samples of 303 patients with ALS and compared with prospectively collected data from 2100 population-based controls. RESULTS: Patients with ALS used cholesterol-lowering agents less frequently (OR=0.6, p=0.008) and had a lower BMI (OR=0.9, p=0.001), a lower LDL/HDL ratio (women: OR=0.5, p<0.001; men: OR=0.4, p<0.001) and lower homocysteine levels (women: OR=0.9, p=0.02; men: OR=0.9, p<0.001). The mean LDL and TC levels were significantly lower among patients with a lower functional vital capacity percentage of predicted (FVC). In the univariate analysis, a higher LDL/HDL ratio correlated with increased survival (HR=0.9, p=0.04); after adjusting for the confounders age, site and FVC, no difference was observed. CONCLUSIONS: Vascular risk factors, measured clinically and biochemically, were not associated with increased ALS. Instead, patients reported less use of cholesterol-lowering medication and had a lower premorbid BMI and favourable lipid profile-all findings consistent with the hypothesis that a higher metabolic rate plays a role in ALS.

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy.

OBJECTIVE: Identification and examination of all patients with multifocal motor neuropathy (MMN) in the Netherlands to document the clinical spectrum and response to IV immunoglobulin (IVIg) and to determine correlates of outcome. METHODS: A national cross-sectional descriptive study was performed. Ninety-seven patients were identified; 88 participated. Logistic regression analysis was used to study determinants of outcome. RESULTS: Age at onset was younger in men than in women (38 vs 45 years, p = 0.05). Onset of weakness was in distal arm (61%) or distal leg (34%), and occasionally in the upper arm (5%). Initial diagnosis was motor neuron disease in one-third of patients. Brisk, but not pathologic, reflexes in weakened muscles were found in 8%. Conduction blocks were most frequently detected in the ulnar (80%) and median (77%) nerves, but occasionally only between Erb and axilla (6%), or in the musculocutaneous nerve (1%). Ninety-four percent responded to IVIg therapy: nonresponders had longer disease duration before the first treatment (p = 0.03). Seventy-six percent received IVIg maintenance treatment at the time of this study (median duration 6 years; range 0-17): the median dose increased over the years from 12 to 17 g per week (p < 0.01). Independent determinants of more severe weakness and disability were axon loss (p < 0.001; p < 0.0001) and longer disease duration without IVIg (p = 0.03; p = 0.07). CONCLUSION: The results of this study may help aid recognition the clinical picture of MMN. Early IVIg treatment may help to postpone axonal degeneration and permanent deficits. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IVIg improves muscle strength of patients with MMN and disability (defined as an increase of >or=1 Medical Research Council grade in at least 2 muscle groups without decrease in other muscle groups) in 94% (95% confidence interval, 86.8%-97.4%) of patients.

[Amyotrophic lateral sclerosis]. / Amyotrofische laterale sclerose.

Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally.

Increased frequency of HLA-DRB1*15 in patients with multifocal motor neuropathy.

OBJECTIVES: The favorable response to treatment with IV immunoglobulins and the presence of IgM antibodies to the glycolipid GM1 are indications that inflammation underlies multifocal motor neuropathy (MMN) pathogenesis. We investigated the association of MMN with human leukocyte antigen (HLA) class I and II antigens. METHODS: HLA class I and II antigens of 74 Dutch patients with MMN and 700 controls were determined in a case-control study. Associations of HLA types with MMN disease characteristics were investigated. RESULTS: Compared with controls, patients with MMN had higher frequencies of HLA-DRB1*15 (41 vs 24%, p = 0.0017). Disease characteristics were not associated with specific HLA types. CONCLUSIONS: Similar associations were found in patients with multiple sclerosis and women with chronic immune-mediated demyelinating neuropathy, which may suggest that these demyelinating disorders share pathogenic mechanisms.

Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes.

OBJECTIVE: To investigate the frequency of autosomal recessive paraplegin mutations in patients with sporadic adult-onset upper motor neuron (UMN) syndromes. METHODS: We analyzed the paraplegin gene in 98 Dutch patients with a sporadic adult-onset UMN syndrome. Inclusion criteria were a progressive UMN syndrome, adult onset, duration >6 months, and negative family history. Exclusion criteria were clinical or electrophysiologic evidence of lower motor neuron loss and evidence of other causes using a predefined set of laboratory tests, including analysis of the spastin gene. RESULTS: Seven patients had homozygous or compound heterozygous pathogenic paraplegin mutations: six patients had UMN symptoms restricted to the legs and one had UMN symptoms in legs and arms. No mutations were found in the 33 patients with UMN involvement of the bulbar region. Age at onset was lower in the seven patients with paraplegin mutations (37 years, range 34-42) than in the 91 patients without mutations (51 years, range 18-77, p = 0.001). Three of the seven patients with paraplegin mutations and none of the patients without mutations developed cerebellar signs during follow-up. CONCLUSIONS: Paraplegin mutations are a frequent cause of sporadic spastic paraparesis.

Lifetime occupation, education, smoking, and risk of ALS.

OBJECTIVE: To investigate the association between cigarette smoking, level of education, occupation, and the occurrence of sporadic amyotrophic lateral sclerosis (ALS). METHODS: A total of 364 patients and 392 controls completed a questionnaire covering smoking habits, level of education, and occupational history. Main occupations were coded according to the International Standard Classification of Occupations and compared between patients and controls. RESULTS: The univariate analysis showed an increased risk of developing ALS among current cigarette smokers (OR = 1.7; 95% CI = 1.1 to 2.6; p = 0.01), those with a low level of education (elementary school) (OR = 2.2; 95% CI = 1.2 to 3.8; p < 0.01), and among women whose main occupation was classified as crafts and related trades workers (OR = 8.4; 95% CI = 1.0 to 70.1; p = 0.05). Multivariate analysis (with covariates age, smoking, education, and occupation) showed an increased risk for current smokers of cigarettes (OR = 1.6; 95% CI = 1.0 to 2.5; p = 0.04). CONCLUSIONS: Occupation, education, and cigarette smoking are risk factors for amyotrophic lateral sclerosis, but only smoking appeared independently associated.

Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis.

BACKGROUND: To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS). METHODS: Patients referred to our clinic during 2001-2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case-control study (132 patients and 220 healthy controls). A food-frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking). RESULTS: A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B2, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS. CONCLUSION: A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically.