Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria

Mosaic structural variation in children with developmental disorders

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders

C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis.

INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset. METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance. RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96). CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration

Targeting Several CAG Expansion Diseases by a Single Antisense Oligonucleotide

To date there are 9 known diseases caused by an expanded polyglutamine repeat, with the most prevalent being Huntington's disease. Huntington's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available. It is caused by a CAG repeat expansion in the HTT gene, which results in an expansion of a glutamine stretch at the N-terminal end of the huntingtin protein. This polyglutamine expansion plays a central role in the disease and results in the accumulation of cytoplasmic and nuclear aggregates. Here, we make use of modified 2′-O-methyl phosphorothioate (CUG)n triplet-repeat antisense oligonucleotides to effectively reduce mutant huntingtin transcript and protein levels in patient-derived Huntington's disease fibroblasts and lymphoblasts. The most effective antisense oligonucleotide, (CUG)7, also reduced mutant ataxin-1 and ataxin-3 mRNA levels in spinocerebellar ataxia 1 and 3, respectively, and atrophin-1 in dentatorubral-pallidoluysian atrophy patient derived fibroblasts. This antisense oligonucleotide is not only a promising therapeutic tool to reduce mutant huntingtin levels in Huntington's disease but our results in spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy cells suggest that this could also be applicable to other polyglutamine expansion disorders as well

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

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed