This study provides compelling genetic and biochemical data that mutations in SPTLC1 are the cause of disease in two cases of juvenile-onset ALS. Researchers found two different mutations leading to an Ala20Ser amino acid change in two affected individuals with similar motor neuron phenotypes. One affected individual carried a de novo variant that was not found in her healthy parents or siblings. In contrast, the second affected individual likely inherited their p.Ala20Ser variant in an autosomal dominant manner from her father, in whom was found low-level mosaicism. Neither mutation was present in the control dataset or online databases of human polymorphisms, indicating they are rare variants in ethnically diverse populations. Mutations in this gene are already known to be involved in hereditary sensory autonomic neuropathy, type 1A, which also involves nerve abnormalities.
Mass spectrometry analysis of plasma obtained from the affected index patient confirmed the presence of abnormal sphingolipid metabolites indicating that the observed mutation disrupts the function of the encoded enzyme. Researchers used an in vitro biochemical assay to confirm that the p.Ala20Ser mutation shifts substrate specificity leading to increased use of non-canonical glycine and alanine and no discernible change in serine utilization. They used immunohistochemistry to demonstrate that SPTLC1 is abundantly expressed within the motor neurons of healthy spinal cord tissue. Although SPTLC1 mutations are more commonly linked to the hereditary sensory autonomic neuropathy, type 1A sensory and autonomic neurological phenotype; these new findings broaden the phenotypic implications of SPTLC1 mutations and suggest that nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1.
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