A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C
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Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare, autosomal dominantly inherited, slowly progressive and length-dependent axonal peripheral neuropathy. HSAN1 is associated with several mutations in serine-palmitoyltransferase (SPT), the first enzyme in the de novo sphingolipid biosynthetic pathway. HSAN1 mutations alter the substrate specificity of SPT, which leads to the formation of 1-deoxysphingolipids, an atypical and neurotoxic subclass of sphingolipids. This study describes the clinical and neurophysiological phenotype of a German family with a novel SPTCL2 mutation (c.529A > G; N177D) associated with HSAN1 and the biochemical characterization of this mutation.) The mutaion was identified in five family members that segregated with the diesease. Patients were characterized genetically and clinically for neurophysiological function. Their plasma sphingolipid profiles were analyzed by LC–MS. The biochemical properties of the mutation were characterized in a cell-based activity assay. Affected family members showed elevated 1-deoxysphingolipid plasma levels. HEK293 cells expressing the N177D SPTLC2 mutant showed increased de novo 1-deoxysphingolipid formation, but also displayed elevated canonical SPT activity and increased C20 sphingoid base production. This study identifies the SPTLC2 N177D variant as a novel disease-causing mutation with increased 1-deoxySL formation and its association with a typical HSAN1 phenotype.
KeywordsHSAN1 Serine-palmitoyltransferase 1-deoxysphingolipids Neuropathy Mass spectrometry
The family is thanked for participating in this study. The study was supported by 7th Framework Program of the European Commission (“RESOLVE,” Project number 305707); the Swiss National Foundation-SNF (Project 31003A_153390/1); and the Rare Disease Initiative Zurich (“radiz,”), University of Zurich).
Compliance with Ethical Standards
Conflict of interest
The authors have no conflict of interest to declare.
The manuscript is a retrospective case report that does not require ethics committee approval at our institution.
Written informed consent was obtained from all participants involved in this study.
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