Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis

• DOI: 10.1007/s00415-024-12776-5
• Publication Date: 2024-12-12T12:22:00Z
• Authors: So Okubo; Hiroya Naruse; Hiroyuki Ishiura; Atsushi Sudo; Kayoko Esaki; Jun Mitsui; Takashi Matsukawa; Wataru Satake; Peter Greimel; Nanoka Shingai; Yasushi Oya; Takeo Yoshikawa; Shoji Tsuji; Tatsushi Toda
• Keywords: Sphingolipid; Proband

Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1 , encoding subunit serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), have recently been associated with juvenile ALS. ALS elevated levels sphinganines ceramides. Reports on remain limited. This study aimed to investigate frequency relevant clinical characteristics. Methods We analyzed whole-exome whole-genome sequence data from 40 probands familial 413 patients sporadic without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis droplet digital PCR (ddPCR) were used assess splicing mosaicism, respectively. Plasma sphingolipid quantified analyze biochemical consequences. Results The heterozygous c.58G>A, p.Ala20Thr variant was 21-year-old Japanese female patient presenting symmetric weakness which slowly progressed over 15 years. RT-PCR showed no splice defects. significantly increased compared her asymptomatic parents. ddPCR revealed that father harbored mosaic 17% relative mutant allele abundance peripheral blood leukocytes. Conclusions pathogenic ALS, likely inherited an parent mosaicism. Lipid results are consistent previous findings -associated Further studies necessary determine effect .