Update on genetics of amyotrophic lateral sclerosis

Brenner, Dávid; Freischmidt, Axel

doi:10.1097/wco.0000000000001093

Cited by 45 publications

(36 citation statements)

References 48 publications

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“…The familial forms of ALS have been linked to a myriad of distinct genes. Indeed, since the discovery in 1993 of the first causative gene, the one coding for Cu/Zn superoxide dismutase ( SOD1 ) (Rosen et al, 1993), more than 50 others associated with disease pathogenesis and susceptibility have been identified (Al-Chalabi et al, 2017; Brenner and Weishaupt, 2019), and research continues to uncover at an incredibly rapid pace novel monogenic disease genes, genetic risk factors, as well as disease-modifying genes. Due to the extremely heterogeneous and complex genetic architecture of ALS, the distinction between fALS and sALS is often blurred, the etiology of the disease not yet clearly defined for most patients and, as a consequence, effective treatments remain elusive (Morello et al, 2020).…”

Section: Introduction: Amyotrophic Lateral Sclerosis and Vapbmentioning

confidence: 99%

Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Borgese

Navone

Nukina

et al. 2021

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Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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Section: Introduction: Amyotrophic Lateral Sclerosis and Vapbmentioning

confidence: 99%

Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Borgese

Navone

Nukina

et al. 2021

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“…At the end of the study period, all recruiting hospitals were asked to report the number of available ALS patients during the recruitment period, the number of patients who were offered participation but declined, and the number of patients who were not offered participation. [18], UniProtKB [48] and recent published literature [1,6,[19][20][21]. AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal recessive; FTD, frontotemporal dementia; HSAN, hereditary sensory and autonomic neuropathy; HSP, hereditary spastic paraplegia; NA, not available; PLS, primary lateral sclerosis; SCA, spinocerebellar ataxia; SMA, spinal muscular atrophy; XLD, X-linked dominant.…”

Section: Study Populationmentioning

confidence: 99%

“…During bioinformatic filtering, 30 genes relevant to ALS were included and analyzed (Table 1). The selected genes were chosen based on information from OMIM [18] and recently published literature [1,6,[19][20][21]. The identified variants were filtered based on dominant and recessive inheritance models, using gnomAD (https://gnomad.broadinstitute.org/) minor allele frequencies of 0.1% and 2.0%, respectively.…”

Section: Genetic Analysesmentioning

confidence: 99%

Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study

et al. 2022

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Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40–70% of familial ALS patients and approximately in 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. Methods: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected with ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. Conclusion: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.

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“…The field of genetic ALS continues to develop rapidly with multiple disease gene discoveries per year (128), with the autosomal dominant inheritance of a hexanucleotide expansion in the first intron of the C9orf72 gene being the most common cause of familial ALS in people of Northern European ancestry, also as a major contributor to frontotemporal pathology in ALS. DTI studies in patients with C9orf72 expansion in crosssectional and longitudinal design demonstrated alterations in motor tracts (129)(130)(131); in addition, further white matter areas were found to be affected, e.g., in the frontal white matter (132) and segmentally in the corpus callosum (133).…”

Section: Mr Findings With Respect To Genetic Phenotypementioning

confidence: 99%

Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease—A clinico-radiological and neuroscientific perspective

et al. 2022

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Neuroimaging assessment of motor neuron disease has turned into a cornerstone of its clinical workup. Amyotrophic lateral sclerosis (ALS), as a paradigmatic motor neuron disease, has been extensively studied by advanced neuroimaging methods, including molecular imaging by MRI and PET, furthering finer and more specific details of the cascade of ALS neurodegeneration and symptoms, facilitated by multicentric studies implementing novel methodologies. With an increase in multimodal neuroimaging data on ALS and an exponential improvement in neuroimaging technology, the need for harmonization of protocols and integration of their respective findings into a consistent model becomes mandatory. Integration of multimodal data into a model of a continuing cascade of functional loss also calls for the best attempt to correlate the different molecular imaging measurements as performed at the shortest inter-modality time intervals possible. As outlined in this perspective article, simultaneous PET/MRI, nowadays available at many neuroimaging research sites, offers the perspective of a one-stop shop for reproducible imaging biomarkers on neuronal damage and has the potential to become the new gold standard for characterizing motor neuron disease from the clinico-radiological and neuroscientific perspectives.

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Update on genetics of amyotrophic lateral sclerosis

Cited by 45 publications

References 48 publications

Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study

Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease—A clinico-radiological and neuroscientific perspective

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