CHCHD10 variants in amyotrophic lateral sclerosis: where Is the evidence?

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants

Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests

Amyotrophic lateral sclerosis: risk factors in the genome and exposome

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in progressive weakness and death in three to five years on average. In most patients there are no family members with ALS, and therefore an interplay of genetic and environmental risk factors is thought to be causal for disease development. Unfortunately many risk factors are still unknown and mechanisms of ALS development are not yet unraveled. This thesis presents multiple new risk factors for ALS, both genetic and environmental factors. Also previously postulated risk factors are checked in replication experiments. The finding of mutations in NEK1 as a novel risk factor points toward cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity as potential new disease mechanisms that needs to be followed up in future research. Also, a new approach was postulated towards investigating the exposome, the total of environmental factors. In this study many new environmental risk factors were found and for the first time the associations between risk factors could be determined. This exposome-wide study points towards different and independent environmental risk profiles that all lead to the same disease entity, ALS. It revealed that for instance the risk effect of smoking was independent of the effect of alcohol intake or a beneficial vascular risk profile. This thesis not only gives more insight in the risk factors for ALS, but also provides new insight in disease etiopathogenesis, thereby providing a basis for future treatment development

Amyotrophic lateral sclerosis: risk factors in the genome and exposome

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in progressive weakness and death in three to five years on average. In most patients there are no family members with ALS, and therefore an interplay of genetic and environmental risk factors is thought to be causal for disease development. Unfortunately many risk factors are still unknown and mechanisms of ALS development are not yet unraveled. This thesis presents multiple new risk factors for ALS, both genetic and environmental factors. Also previously postulated risk factors are checked in replication experiments. The finding of mutations in NEK1 as a novel risk factor points toward cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity as potential new disease mechanisms that needs to be followed up in future research. Also, a new approach was postulated towards investigating the exposome, the total of environmental factors. In this study many new environmental risk factors were found and for the first time the associations between risk factors could be determined. This exposome-wide study points towards different and independent environmental risk profiles that all lead to the same disease entity, ALS. It revealed that for instance the risk effect of smoking was independent of the effect of alcohol intake or a beneficial vascular risk profile. This thesis not only gives more insight in the risk factors for ALS, but also provides new insight in disease etiopathogenesis, thereby providing a basis for future treatment development

Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis

IMPORTANCE Because dietary intakemay influence pathophysiologic mechanisms in sporadic amyotrophic lateral sclerosis (ALS), the association between premorbid dietary intake and the risk of sporadic ALS will provide insight into which mechanisms are possibly involved in ALS pathophogenesis. OBJECTIVE To systematically determine the association between premorbid dietary intake and the risk of sporadic ALS. DESIGN, SETTING, AND PARTICIPANTS A population-based case-control studywas conducted in a general community setting in the Netherlands from January 1, 2006, to September 30, 2011. Analysis was conducted April 1, 2013, to November 15, 2014. All patients with a new diagnosis of possible, probable (laboratory supported), or definite ALS according to the revised El Escorial criteria were included and multiple sources were used to ensure complete case ascertainment. Of 986 eligible patients, 674 gave informed consent and returned a complete questionnaire; 2093 controls randomly selected from the general practitioners’ registers and frequency matched to the patients for sex and age were included. MAIN OUTCOMES AND MEASURES We studied the premorbid intake of nutrients in association with the risk of ALS by using a 199-item food frequency questionnaire adjusted for confounding factors and corrected for multiple comparisons while minimizing recall bias. RESULTS Presymptomatic total daily energy intake in patients, reported as mean (SD), was significantly higher compared with controls (2258 [730] vs 2119 [619] kcal/day; P <.01), and presymptomatic body mass index (calculated as weight in kilograms divided by height in meters squared) was significantly lower in patients (25.7 [4.0] vs 26.0 [3.7]; P = .02). With values reported as odds ratio (95%CI), higher premorbid intake of total fat (1.14; 1.07-1.23; P <.001), saturated fat (1.43; 1.25-1.64; P <.001), trans-fatty acids (1.03; 1.01-1.05; P <.001), and cholesterol (1.08; 1.05-1.12; P <.001) was associated with an increased risk of ALS; higher intake of alcohol (0.91; 0.84-0.99; P = .03) was associated with a decreased risk of ALS. These associations were independent of total energy intake, age, sex, body mass index, educational level, smoking, and lifetime physical activity. No significant associations between dietary intake and survival were found. CONCLUSIONS AND RELEVANCE The combination of independent positive associations of a low premorbid body mass index and a high fat intake together with prior evidence from ALS mouse models transgenic for SOD1 and earlier reports on premorbid body mass index support a role for increased resting energy expenditure before clinical onset of ALS

IgM anti-MAG(+/-) peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies

BackgroundInternational consensus on IgM +/- anti-MAG +/- PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM +/- anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM +/- anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AimsFunctional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. MethodsThe IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. ResultsThe final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. ConclusionThe constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies