Premium
The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment
Author(s) -
Fiorillo Chiara,
Capodivento Giovanna,
Geroldi Alessandro,
Tozza Stefano,
Moroni Isabella,
Mohassel Payam,
Cataldi Matteo,
Campana Chiara,
Morando Simone,
Panicucci Chiara,
Pedemonte Marina,
Brolatti Noemi,
Siliquini Sabrina,
Traverso Monica,
Baratto Serena,
Debellis Doriana,
Magri Stefania,
Prada Valeria,
Bellone Emilia,
Salpietro Vincenzo,
Donkervoort Sandra,
Gable Kenneth,
Gupta Sita D.,
Dunn Teresa M.,
Bönnemann Carsten G.,
Taroni Franco,
Bruno Claudio,
Sche Angelo,
Mandich Paola,
Nobbio Lucilla,
Nolano Maria
Publication year - 2022
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12842
Subject(s) - motor neuron , disease , medicine , sensory neuropathy , sensory system , neuroscience , pathology , biology
Aims SPTLC1 ‐related disorder is a late onset sensory‐autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl‐CoA transferase (SPT) substrate, l ‐serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l ‐serine in this specific genotype. Methods We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l ‐serine supplementation in skin fibroblasts of patients with p.S331 mutations. Results In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy‐sphingolipids with an excess of canonical products of the SPT enzyme. l ‐serine supplementation in patient fibroblasts reduced production of toxic 1‐deoxysphingolipids but further increased the overproduction of sphingolipids. Conclusions Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1 ‐related disorders. l ‐serine supplementation in these patients may be detrimental.