Controversies and priorities in amyotrophic lateral sclerosis

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events

A genome-wide association study in multiple system atrophy

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with .5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p , 1 3 1026, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA.We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis

Measurement of event-shape observables in Z→ℓ+ℓ− events in pp collisions at √ s=7 TeV with the ATLAS detector at the LHC

Event-shape observables measured using charged particles in inclusive $Z$-boson events are presented, using the electron and muon decay modes of the $Z$ bosons. The measurements are based on an integrated luminosity of $1.1 {\rm fb}^{-1}$ of proton--proton collisions recorded by the ATLAS detector at the LHC at a centre-of-mass energy $\sqrt{s}=7$ TeV. Charged-particle distributions, excluding the lepton--antilepton pair from the $Z$-boson decay, are measured in different ranges of transverse momentum of the $Z$ boson. Distributions include multiplicity, scalar sum of transverse momenta, beam thrust, transverse thrust, spherocity, and $\mathcal{F}$-parameter, which are in particular sensitive to properties of the underlying event at small values of the $Z$-boson transverse momentum. The Sherpa event generator shows larger deviations from the measured observables than Pythia8 and Herwig7. Typically, all three Monte Carlo generators provide predictions that are in better agreement with the data at high $Z$-boson transverse momenta than at low $Z$-boson transverse momenta and for the observables that are less sensitive to the number of charged particles in the event.Comment: 36 pages plus author list + cover page (54 pages total), 14 figures, 4 tables, submitted to EPJC, All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2014-0

Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Supplementary Material for: Global Epidemiology of Amyotrophic Lateral Sclerosis: A Systematic Review of the Published Literature

<b><i>Background:</i></b> Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources. <b><i>Objective:</i></b> To provide a comprehensive and critical review of the epidemiological literature on ALS. <b><i>Methods:</i></b> MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates. <b><i>Results:</i></b> In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases. <b><i>Conclusions:</i></b> Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS

Supplementary Material for: Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration

<b><i>Background:</i></b> The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the <i>C9ORF72</i> gene. The frequency of the <i>C9ORF72</i> expansion in Finland is among the highest in the world. <b><i>Methods:</i></b> We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded <i>C9ORF72</i>. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E <i>(APOE)</i> genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier. <b><i>Results:</i></b> The <i>C9ORF72</i> expansion was present in 20 of 70 (29%) probands. Significant associations with the <i>C9ORF72</i> expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The <i>APOE</i> ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers. <b><i>Conclusion:</i></b> In line with the suggested <i>C9ORF72</i> core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to <i>C9ORF72</i>-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis