SORD neuropathy 2

Pons N, Fernández-Eulate G, Pegat A, Théaudin M, Guieu R, Ripellino P, Devedjian M, Mace P, Masingue M, Léonard-Louis S, Petiot P, Roche P, Bernard E, Bouhour F, Good JM, Verschueren A, Grapperon AM, Salort E, Grosset A, Chanson JB, Nadaj-Pakleza A, Bédat-Millet AL, Choumert A, Barnier A, Hamdi G, Lesca G, Prieur F, Bruneel A, Latour P, Stojkovic T, Attarian S, Bonello-Palot N. SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages. Eur J Neurol. 2023 Jul;30(7):2001-2011. doi: 10.1111/ene.15793. Epub 2023 Apr 4. PMID: 36943151.

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.

Laššuthová P, Mazanec R, Staněk D, Sedláčková L, Plevová B, Haberlová J, Seeman P. Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients. Sci Rep. 2021 Apr 19;11(1):8443. doi: 10.1038/s41598-021-86857-0. PMID: 33875678; PMCID: PMC8055917.

Abstract

Recently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients). The prevalent c.757del variant was tested with fragment analysis (931 patients). Sanger sequencing in additional 70 patients was done. PCR primers were designed to amplify the SORD gene with the exclusion of the pseudogene SORD2P. Sequence differences between gene and pseudogene were identified and frequencies of SNPs were calculated. Eighteen patients from 16 unrelated families with biallelic variants in the SORD gene were found and the c.757del was present in all patients on at least one allele. Three novel, probably pathogenic, variants were detected, always in a heterozygous state in combination with the c.757del on the second allele. Patients presented with a slowly progressive axonal HN. Almost all patients had moderate pes cavus deformity. SORD neuropathy is frequent in Czech patients and the third most common cause of autosomal recessive HN. The c.757del is highly prevalent. Specific amplification of the SORD gene with the exclusion of the pseudogene is essential for a precise molecular diagnostics.