<scp><i>SORD</i></scp>‐related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages
Nicolas Pons, Gorka Fernández‐Eulate, Antoine Pégat, Marie Théaudin, Régis Guieu, Paolo Ripellino, Manon Devedjian, Patrick Mace, Marion Masingue, Sarah Léonard‐Louis, P. Petiot, Pauline Roché, E Bernard, Françoise Bouhour, Jean‐Marc Good, Annie Verschueren, Aude‐Marie Grapperon, Emmanuelle Salort, Anaïs Grosset, Jean‐Baptiste Chanson, Aleksandra Nadaj‐Pakleza, Anne‐Laure Bédat‐Millet, Ariane Choumert, Anne Barnier, G. Hamdi, Gaëtan Lesca, Fabienne Prieur, Arnaud Bruneel, Philippe Latour, Tanya Stojkovic, Shahram Attarian, Nathalie Bonello‐Palot
Abstract
BACKGROUND AND PURPOSE: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. METHODS: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. RESULTS: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. CONCLUSIONS: This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.