JNNP: The significance of gene screening for amyotrophic lateral sclerosis system

Amyophic lateral sclerosis (ALS) is an adult neurodegenerative disease characterized by sexual damage and cell death of motor neurons up and down the motor cort, brain and spinal cord.
this leads to neuromuscular system failure, with most cases dying within 2-5 years of symptoms, usually from respiratory failure.
up to 50% of cases also show mild cognitive impairment, with about 5% progressing to clinically recognized frontal lobe dementia (FTD).
Although most ALS cases are considered exudable (sALS), 5% to 10% of ALS cases have been shown to be family-based, usually chromosomal explicit inheritance, and about 60%-70% of ALS patients are genetically related to familial amyotrophic lateral sclerosis (fALS).
most common genetic cause of amyotrophic lateral sclerosis is the amplification of the GGGGCC (G4C2) hexanucleotide repeat sequence in the first inclusion of the C9orf72 gene.
in the UK queue study, this rate of expansion in fALS and sALS cases was 43% and 7%, respectively, comparable to the 39.3% and 7.0% figures for fALS and sALS worldwide.
in patients with fALS and sALS, the next most common genetic cause of ALS, SOD1, TARDBP, and FUS gene mutations were also reported.
, obvious cases of transmission may also carry potentially pathogenic variants of known ALS genes.
in a recent study screening 17 ALS-related genes, 27.8% of apparent cases of transmission carried potentially pathogenic or rare variants of the known ALS gene.
Currently, at least in the UK, only cases with a family history of ALS, dementia or a younger age tend to routinely screen for genes in a clinical setting, and with the emergence of specific genetic forms of treatment for diseases associated with SOD1 or C9orf72 mutations, this raises the question of whether all ALS patients should be genetically screened.
"ALS Multi-Center Biomarker Research Strategy" (AMBRoSIA) is a longitudinal bioscopy program in which newly referred ALS patients are exposed to participate in the study.
agreed to be genetically screened on a research basis, taking blood, urine and cerebrospinal fluid samples vertically, and conducting skin biopsies for fibroblast culture.
results of prospective gene screening for patients with exudable ALS and familial ALS were reported in this paper.
targeted 44 genomes in a sequence of 100 prospective cases of ALS patients recruited from the Sports Neurone Disease Clinic in Sheffield, UK.
subjects were diagnosed with amyotrophic lateral sclerosis by a neurologist consultant.
7/100 patients had familial amyotrophy lateral sclerosis, but most had exudable amyotrophy lateral sclerosis.
21% of ALS patients had a confirmed or possible disease-caused mutation, and 93% of them had no ALS family history.
15% met the inclusion criteria for current ALS gene therapy trials.
5/21 pathogenic mutation has an additional uncertainty variant (VUS).
another 21% of ALS patients carry VUS in the ALS-related gene.
, 13 percent of patients carried more than one genetic variant (pathogenic or VUS).
patients with ALS carrying both variants had a significantly earlier onset age than those with a single variant (median age of 56 years vs 60 years, p -0.0074).
results show that screening for known ALS genes can produce clinically actionable results in about 21 percent of patients, and potentially clinical VUS can be found in about 21 percent of patients.
these percentages are likely to increase as the number of alS gene pathogens confirmed in future studies increases.
we have developed a VUS prioritization pipeline that uses genome-wide case control queues to predict clinical outcomes.
Although the study was conducted at a large three-level referral ALS center and needs to be further validated in other settings, the data in this paper suggest that all ALS patients should be genetically tested under careful consultation, especially given the new personalized medication being developed.
Shepheard SR, Parker MD, Cooper-Knock J, et al Value of screening screening of patients with amyotrophic lateral sclerosis Journal of Neurology, Neurosurgery and Psymty Publiced Online First: 14 February 2021. doi: 10.1136/jnnp-2020-325014MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Met Medical" or "Source: MedSci Original" are owned by Mets Medicine and are not authorized to reproduce any media, website or individual, "Source: Metz Medicine" shall be indicated at the time of authorization for reprint.
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