Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD
Authors: Cortese Andrea , Dohrn Maike F , Curro Riccardo , Negri Sara , Lassuthova Petra , Pisciotta Chiara , Tozza Stefano , Al-Ajmi Abdullah , Feng Changyoung , Tomaselli Pedro J , Fernandez-Eulate Gorka , Haddad Saif , Laurà Matilde , Rossor Alexander M , Vegezzi Elisa , Facchini Stefano , Sleigh James N , Rebelo Adriana , Beijer Danique , Raposo Jacquelyn , Saporta Mario , Lauerova Barbora , Pernice Helena F , Achenbach Pascal , Schöne Ulrike , Alon Tayir , Deschauer Marcus , Cordts Isabell , Obermaier Carolin D , Winter Natalie , Creigh Peter D , Sowden Janet E , Rehbein Tyler , Magri Stefania , Bertini Alessandro , Saveri Paola , Ripellino Paolo , Huang Jingyu , Nadaj-Pakleza Aleksandra , Ross Alison , Holt James K L , Brennan Kathryn M , Sukenik-Halevy Rivka , Bizaoui Varoona , Parman Yesim , Battaloglu Esra , Cakar Arman , Alrohaif Hadil , Hammans Simon , Kumar Kishore R , Kennerson Marina L , Kayserili Hülya , Amado Defne A , Hahn Katrin , Valentino Paola , Cavalcanti Francesca , Gaetano Carlo , Taroni Franco , Braathen Geir J , Houlden Henry , Stojkovic Tanya , Peric Stojan , Bolino Alessandra , Previtali Stefano C , Lee Yi-Chung , Başak Ayşe N , Hamed Sherifa A , Rojas-Garcia Ricardo , Claeys Kristl G , Marques Wilson , Sevilla Teresa , Schlotter-Weigel Beate , Manganelli Fiore , Zhang Ruxu , Herrmann David N , Scherer Steven S , Seeman Pavel , Pareyson Davide , Reilly Mary M , Shy Michael E , Züchner Stephan 
Published: January 2025

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available.

In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern, and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C&gt;A (p.Ala153Asp), while other variants were identified mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex, or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy (dHMN). Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies (NCS) were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in one fourth of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion).

In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.