Journal article
Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD
Brain (London, England : 1878), Vol.148(10), pp.3737-3747
10/03/2025
DOI: 10.1093/brain/awaf021
PMCID: PMC12493047
PMID: 39938083
Abstract
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>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.
Details
- Title: Subtitle
- Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD
- Creators
- Andrea Cortese - National Hospital for Neurology and NeurosurgeryMaike F Dohrn - University of MiamiRiccardo Curro - National Hospital for Neurology and NeurosurgerySara Negri - Istituti Clinici Scientifici MaugeriPetra Lassuthova - University Hospital in MotolChiara Pisciotta - Fondazione IRCCS Istituto Neurologico Carlo BestaStefano Tozza - University of Naples Federico IIAbdullah Al-Ajmi - Jahra HospitalChangyoung Feng - University of RochesterPedro J Tomaselli - Universidade de São PauloGorka Fernandez-Eulate - Pitié-Salpêtrière HospitalSaif Haddad - National Hospital for Neurology and NeurosurgeryMatilde Laurà - National Hospital for Neurology and NeurosurgeryAlexander M Rossor - National Hospital for Neurology and NeurosurgeryElisa Vegezzi - IRCCS Mondino Foundation, 27100 Pavia, ItalyStefano Facchini - National Hospital for Neurology and NeurosurgeryJames N Sleigh - University College LondonAdriana Rebelo - University of MiamiDanique Beijer - Dr. John T. Macdonald FoundationJacquelyn Raposo - Dr. John T. Macdonald FoundationMario Saporta - University of MiamiBarbora Lauerova - University Hospital in MotolHelena F Pernice - Humboldt-Universität zu BerlinPascal Achenbach - RWTH Aachen UniversityUlrike Schöne - RWTH Aachen UniversityTayir Alon - Rabin Medical CenterMarcus Deschauer - Klinikum rechts der IsarIsabell Cordts - Klinikum rechts der IsarCarolin D Obermaier - Praxis für Humangenetik TübingenNatalie Winter - University of TübingenPeter D Creigh - University of RochesterJanet E Sowden - University of RochesterTyler Rehbein - University of RochesterStefania Magri - Fondazione IRCCS Istituto Neurologico Carlo BestaAlessandro Bertini - Fondazione IRCCS Istituto Neurologico Carlo BestaPaola Saveri - Fondazione IRCCS Istituto Neurologico Carlo BestaPaolo Ripellino - Ospedale regionale di LuganoJingyu Huang - Dr. John T. Macdonald FoundationAleksandra Nadaj-Pakleza - Hôpitaux Universitaires de StrasbourgAlison Ross - NHS GrampianJames K L Holt - Walton CentreKathryn M Brennan - Queen Elizabeth University HospitalRivka Sukenik-Halevy - Tel Aviv UniversityVaroona Bizaoui - Centre Hospitalier Universitaire de Caen NormandieYesim Parman - Istanbul UniversityEsra Battaloglu - Boğaziçi UniversityArman Cakar - Istanbul UniversityHadil Alrohaif - Al-Sabah HospitalSimon Hammans - University Hospital Southampton NHS Foundation TrustKishore R Kumar - Garvan Institute of Medical ResearchMarina L Kennerson - Anzac Research InstituteHülya Kayserili - Koç UniversityDefne A Amado - University of PennsylvaniaKatrin Hahn - Humboldt-Universität zu BerlinPaola Valentino - Magna Graecia UniversityFrancesca Cavalcanti - Institute for Biomedical Research and InnovationCarlo Gaetano - Istituti Clinici Scientifici MaugeriFranco Taroni - Fondazione IRCCS Istituto Neurologico Carlo BestaGeir J Braathen - Telemark HospitalHenry Houlden - National Hospital for Neurology and NeurosurgeryTanya Stojkovic - Pitié-Salpêtrière HospitalStojan Peric - University of BelgradeAlessandra Bolino - Vita-Salute San Raffaele UniversityStefano C Previtali - IRCCS Ospedale San RaffaeleYi-Chung Lee - National Yang Ming Chiao Tung UniversityAyşe N Başak - Koç UniversitySherifa A Hamed - Assiut UniversityRicardo Rojas-Garcia - Centre for Biomedical Network Research on Rare DiseasesKristl G Claeys - KU LeuvenWilson Marques - Clinics Hospital of Ribeirão PretoTeresa Sevilla - Instituto de Investigación Sanitaria La FeBeate Schlotter-Weigel - Ludwig-Maximilians-Universität MünchenFiore Manganelli - University of Naples Federico IIRuxu Zhang - Third Xiangya HospitalDavid N Herrmann - University of RochesterSteven S Scherer - University of PennsylvaniaPavel Seeman - University Hospital in MotolDavide Pareyson - Fondazione IRCCS Istituto Neurologico Carlo BestaMary M Reilly - National Hospital for Neurology and NeurosurgeryMichael E Shy - University of IowaStephan Züchner - University of Miami
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.148(10), pp.3737-3747
- DOI
- 10.1093/brain/awaf021
- PMID
- 39938083
- PMCID
- PMC12493047
- NLM abbreviation
- Brain
- ISSN
- 1460-2156
- eISSN
- 1460-2156
- Language
- English
- Electronic publication date
- 02/13/2025
- Date published
- 10/03/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984790971302771
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