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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)

Objectives: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved., Methods: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed., Results: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1 , TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years., Conclusion: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family., Objectives: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients., Patients and Methods: Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected., Results: Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers., Conclusions: While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance.

Importance: Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population., Objectives: To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers., Design, Setting, and Participants: The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9-) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017., Main Outcomes and Measures: Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9- individuals., Results: Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9- individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9- individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9- individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts., Conclusions and Relevance: Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers., Trial Registration: clinicaltrials.gov Identifier: NCT02590276.

Mutations in CHCHD10 have been reported as the cause of a large panel of neurologic disorders. To confirm the contribution of this gene to amyotrophic lateral sclerosis (ALS) disease, we analyzed the 4 coding exons of CHCHD10 by Sanger sequencing in a cohort of 118 French familial ALS already excluded for all known ALS-related genes. We did not find any pathogenic mutation suggesting that CHCHD10 is not a major genetic cause of familial ALS, in France., (Copyright © 2016 Elsevier Inc. All rights reserved.)

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease including about 15% of genetically determined forms. A de novo mutation in the SS18L1 (also known as CREST or KIAA0693) gene encoding the calcium-responsive transactivator and/or neuronal chromatin remodeling complex subunit has recently been identified by exome sequencing of 47 sporadic ALS trios. This Q388stop mutation deleting the last 9 amino acids was shown to impair activity-dependent dendritic outgrowth. A missense mutation (c.369T>G, p.Ileu123Met) was also found in 1 of 62 ALS families previously screened for other ALS-related genes and not carrying any mutation. To confirm the contribution of SS18L1 to ALS, we sequenced the 11 coding exons and exon-intron boundaries in 87 familial ALS (FALS). We identified 2 variants: the c.660_668del, p.Gln222_Ser224del in a patient devoid of mutation in any ALS related genes and the c.790G>A, p.Ala264Thr in a patient carrying a p.Arg96Leu variant in the OPTN gene. As these variants were not found in Single Nucleotide Polymorphism databases and were absent from 180 controls they could be new SS18L1 mutations causing ALS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We report on a patient belonging to a large family with autosomal-dominant amyotrophic lateral sclerosis, who developed asymmetrical akineto-rigid symptoms at 33 years of age. He had no signs of lower motor neuron disease after four years of follow-up. All seven ALS patients from this family harboured a mutation located in the fourth intron of the SOD1 gene. The proband also harboured the same mutation, associated with a 40% decrease in SOD1 erythrocyte activity. This case report suggests that SOD1 mutations might be associated with marked phenotypic variability (ALS or early onset Parkinsonism in this family).

Background: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3)., Methods: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics., Results: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients., Conclusions: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders.

BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.