Objective
To define the genetic landscape of amyotrophic lateral sclerosis (ALS) and assess the contribution of possible oligogenic inheritance, we aimed to comprehensively sequence 17 known ALS ...genes in 391 ALS patients from the United States.
Methods
Targeted pooled‐sample sequencing was used to identify variants in 17 ALS genes. Fragment size analysis was used to define ATXN2 and C9ORF72 expansion sizes. Genotype–phenotype correlations were made with individual variants and total burden of variants. Rare variant associations for risk of ALS were investigated at both the single variant and gene level.
Results
A total of 64.3% of familial and 27.8% of sporadic subjects carried potentially pathogenic novel or rare coding variants identified by sequencing or an expanded repeat in C9ORF72 or ATXN2; 3.8% of subjects had variants in >1 ALS gene, and these individuals had disease onset 10 years earlier (p = 0.0046) than subjects with variants in a single gene. The number of potentially pathogenic coding variants did not influence disease duration or site of onset.
Interpretation
Rare and potentially pathogenic variants in known ALS genes are present in >25% of apparently sporadic and 64% of familial patients, significantly higher than previous reports using less comprehensive sequencing approaches. A significant number of subjects carried variants in >1 gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis. ANN NEUROL 2015;77:100–113
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS
) will provide key information for optimising clinical trials in this patient ...population.
To establish an updated natural history of ALS
.
Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.
Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1
), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1
) for analysis.
Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1
and SOD1
(p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1
. SOD1
survival probability (median survival 1.2 years) was significantly decreased compared with SOD1
(median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1
compared with SOD1
participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1
compared with SOD1
(p=0.02).
SOD1
is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS
patient population.
Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In ...this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.
Abstract Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by ...which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.
The Scale for the Assessment and Rating of Ataxia (SARA) is a semi-quantitative assessment used to evaluate ataxia. The goal of these studies was to assess and evaluate the utility of this instrument ...in a Healthy Volunteer (HV) group and subjects with Schizophrenia (SCZ).
Two studies were completed to collect SARA data, in a HV group and in a stable SCZ group. 177 HVs (18–65 years) and 16 SCZs (18–58 years) provided written consent and were assessed using the SARA. Of 177 HV subjects, 88 had 2 SARA assessments (within 2 days of initial visit) while all 16 SCZ had 3 SARA assessments (within 14 days of initial visit).
For the HV group, the mean score ± Std for the SARA on visit-1 was 0.39 ± 0.72, and 0.34 ± 0.64 for visit-2. The Pearson correlation coefficient between visit-1 and visit-2 was 0.7486 and an ICC of 0.743. For the SCZ group, the mean score for the SARA was 0.63 ± 0.65 on visit-1, 0.84 ± 1.19 on visit-2, and 0.84 ± 0.94 on visit-3. The Pearson correlation coefficient between visit-1 and visit-2 was 0.6545, between visit-1 and visit-3 was 0.6635 and between visit-2 and visit-3 was 0.7613 and an ICC of 0.650. There was no significant difference in baseline SARA scores between the HV and SCZ group p = .063. A statistically significant positive association between age and total SARA scores was observed in HV (r = 0.345) and SCZ (r = 0.676).
A strong association was observed in both the HV and SCZ groups in the reassessment of signs of ataxia using the SARA scale. Both groups demonstrated minimal signs of ataxia, with no statistically significant difference between the two groups in their visit-1 scores.
•Participants with schizophrenia and controls demonstrate low ataxia scores•The two groups do not significantly differ in their baseline scores•The SARA showed good test-retest reliability in both groups•Positive association observed between age and ataxia symptoms in both groups
Motor Neuron Diseases (MNDs) are neurological disorders characterized by the selective and progressive degeneration of motor neurons. Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou ...Gehrig's disease, is the most common. ALS causes diffuse muscle weakness and death secondary to respiratory failure. The diagnosis is made clinically, supported by electrodiagnostic testing. Although medications are limited, careful attention to breathing, nutrition, and patient mobility can have a major, positive impact on the course of the disease.
Hexanucleotide repeat expansions in
C9ORF72
are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which ...expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the
C9ORF72
gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the
C9ORF72
expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.
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