SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause

• Published in: Journal of neurogenetics 2024-04, Vol.38 (2), p.1-40
• Main Authors: Arlt, Annabelle, Akova-Öztürk, Esra, Schirmacher, Anja, Schlüter, Bernhard, Rust, Stephan, Meyer Zu Hörste, Gerd, Wiendl, Heinz, Wiethoff, Sarah
• Format: Article
• Language: English
• ISSN: 0167-7063; 1563-5260; 1563-5260
• DOI: 10.1080/01677063.2024.2374898

Pathogenic, biallelic variants in were identified in 2020 as a novel cause for autosomal-recessive Charcot-Marie-Tooth disease (CMT) type 2, an inherited neuropathy. codes for the enzyme sorbitol dehydrogenase. Loss of this enzyme's activity leads to an increase of sorbitol in serum. We retrospectively screened 166 patients with axonal neuropathy (predominantly CMT type 2, but including intermediate form of CMT and distal hereditary motor neuropathy (dHMN)) without identified genetic etiology for mutations at a single large German neuromuscular center. Clinical and electrophysiology exam findings were analyzed for genotype-phenotype correlation. Five patients of the total cohort of 166 patients harbored pathogenic variants in (3%). The homozygous frameshift variant c.757delG (p.Ala253Glnfs*27) was the most common (4/5). One additional case carried this variant on one allele only and an additional pathogenic missense variant c.458C > A (p.Ala153Asp) on the other allele. Age of onset ranged from early infancy to mid-twenties, and phenotypes comprised axonal CMT (4) and dHMN (1). Our findings strengthen the importance of screening for pathogenic variants in , especially in patients with genetically unconfirmed axonal neuropathy, especially CMT type 2 and dHMN.