The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy
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Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme’s substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.
KeywordsNeuropathy Hereditary sensory autonomic neuropathy Serine palmitoyl-CoA transferase Sphingolipid
Distal motor latency
Hereditary sensory and autonomic neuropathy
Nerve conduction velocity
Quantitative sensory testing
Sequencing Initiative Suomi
Serine palmitoyl-CoA transferase
In memoriam to B.R. a dear colleague and friend who unexpectedly passed away too premature. We thank Riitta Lehtinen for technical assistance. The authors wish to thank the following funding sources for support: Hospital District of Helsinki and Uusimaa (for M.A. and E.Y.), Sigrid Jusélius Foundation (for H.T.), University of Helsinki (for H.T.), the Academy of Finland (for H.T. and E.Y.), The 7th Framework Program of the European Commission (“RESOLVE”, Project Number 305707) for S.S. Furthermore, T.H. and S.S are grateful to the Hurka Foundation, the Novartis Foundation, and the Rare Disease Initiative Zurich (“radiz”, Clinical Research Priority Program for Rare Diseases, University of Zurich).
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflict of interest.
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