1. De novo variants in the SPTLC1 gene among unrelated patients were associated with juvenile amyotrophic lateral sclerosis using exome sequencing.
2. Patients presenting with early onset of symptoms in keeping with amyotrophic lateral sclerosis clinical syndrome should be screened for variants in SPTLC1 gene.
Evidence Rating Level: 2 (Good)
Study Rundown: Juvenile amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterized by onset of symptoms prior to 25 years and progressive paralysis and eventual death from respiratory failure. This family-based genetic study sought to identify genetic variants associated with juvenile ALS among unrelated patients using whole-exome sequencing. The main endpoint of the analysis was de novo variants observed in the index case and not among unaffected family members. In 3 patients diagnosed with juvenile ALS and failure to thrive, exome sequencing was able to identify de novo variants in the SPTLC1 gene (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Through various structural and functional assays, SPTLC1 genetic variants have been shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy (type 1A) through disruption of an essential enzyme complex in the sphingolipid synthesis pathway. Thus, these findings helped expand the known phenotypes associated with SPTLC1 genetic variants in patients with juvenile ALS. The results suggested sphingolipid metabolism as a pathway in motor neuron disease where abnormal plasma metabolites may be used as a marker of disease and therapy. Lastly, patients presenting with early onset of symptoms in keeping with ALS clinical syndrome should be screened for variants in SPTLC1 gene. A limitation of this study was the lack of DNA available for analysis from the parents of patient 4 and thus, it was not possible to determine whether phenotypic variations were a result of spontaneous mutation.
In-Depth [prospective cohort]: This multicenter family-based genetic study enrolled 66 patients with juvenile ALS and 6,258 adult patients with ALS at various academic hospitals and a government research facility between March 2016 and March 2020, with observation until October 2020. Among this case series of unrelated patients with juvenile ALS and severe growth retardation, whole-exome sequencing was performed to identify the disease-associated gene. Exclusion criteria included patients with a family history of neurological disorders, where de novo variants may serve as the underlying genetic mechanism. In total, trio whole-exome sequencing was performed in 3 patients with juvenile ALS along with their parents and a further 63 patients with juvenile ALS and 6,258 adult patients with ALS were subsequently screened for SPTLC1 genetic variants. De novo variants were identified in 3 unrelated patients with juvenile ALS and failure to thrive including 2 patients with p.Ala20Ser and another with p.Ser331Tyr as well as p.Leu39del in a patient with juvenile ALS where parental DNA was unavailable.
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