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 multicentre 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. 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 were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter 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.

Brain Research Center National Yang Ming Chiao Tung University Taipei 112304 Taiwan

Center for Genomics and Transcriptomics Tübingen and Zentrum für Humangenetik Tübingen Tübingen 72076 Germany

Center for Networked Biomedical Research into Rare Diseases Madrid 28029 Spain

Charité University Medicine Berlin Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin Department of Neurology and Experimental Neurology Berlin 10117 Germany

Clinical Genetics NHS Grampian Aberdeen AB15 6RE UK

Clinical Hospital of Ribeirão Preto Department of Neurosciences and Behaviour Sciences University of São Paulo Ribeirão Preto 14015 010 Brazil

Department of Biostatistics and Computational Biology University of Rochester Rochester NY 14642 USA

Department of Brain and Behavioral Sciences University of Pavia Pavia 27100 Italy

Department of Medical and Surgical Sciences Institute of Neurology University Magna Graecia Catanzaro 88100 Italy

Department of Medical Genetics Koc University School of Medicine Istanbul 34010 Turkey

Department of Medical Genetics Telemark Hospital Trust Skien 3710 Norway

Department of Molecular Biology and Genetics Center for Life Sciences and Technologies Bogazici University Istanbul 34342 Turkey

Department of Neurology 3rd Xiangya Hospital Central South University Changsha 410013 China

Department of Neurology and Hertie Institute for Clinical Brain Research University of Tübingen Tübingen 72076 Germany

Department of Neurology and Psychiatry Assiut University Hospital Assiut 71515 Egypt

Department of Neurology Beilinson Hospital Rabin Medical Center Petah Tikva 4941492 Israel

Department of Neurology Carver College of Medicine University of Iowa Iowa City IA 52242 USA

Department of Neurology Maria Hilf Hospital Mönchengladbach Mönchengladbach 41063 Germany

Department of Neurology Medical Faculty RWTH Aachen University Aachen 52074 Germany

Department of Neurology Neurocenter of Southern Switzerland EOC Ospedale Regionale di Lugano Lugano 6900 Switzerland

Department of Neurology Neuromuscular Diseases Unit Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona 08193 Spain

Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan

Department of Neurology The Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA

Department of Neurology The Walton Centre Liverpool L9 7LJ UK

Department of Neurology University Hospital rechts der Isar School of Medicine and Health Technical University Munich München 81675 Germany

Department of Neurology University Hospitals Leuven Leuven 3000 Belgium

Department of Neurology University of Rochester Rochester NY 14642 USA

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London WC1N 3BG UK

Department of Neurosciences Reproductive Sciences and Odontostomatology University of Naples Federico 2 Naples 80131 Italy

Department of Paediatric Neurology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Praha 150 06 Czechia

Division of Neurology Department of Medicine Al Jahra Hospital Al Jahra 00020 Kuwait

Dr John T Macdonald Foundation John P Hussman Institute for Human Genomics University of Miami Miami FL 33136 USA

Faculty of Biomedical Sciences Università della Svizzera Italiana Lugano 6900 Switzerland

Friedrich Baur Institute at the Department of Neurology LMU University Hospital LMU Munich München 80336 Germany

Human Inherited Neuropathies Unit Division of Neuroscience Institute of Experimental Neurology IRCCS Ospedale San Raffaele Milan 20132 Italy

Institute for Biomedical Research and Innovation 87050 Italy

Institute of Neurological Sciences Queen Elizabeth University Hospital Glasgow G51 4TF UK

Institute of Neuropathology Medical Faculty RWTH Aachen University Aachen 52074 Germany

IRCCS Mondino Foundation Pavia 27100 Italy

Koç University School of Medicine Suna and İnan Kıraç Foundation Neurodegeneration Research Laboratory Research Center for Translational Medicine Istanbul 34010 Turkey

Kuwait Medical Genetics Centre Sabah Hospital Kuwait City Kuwait

Laboratorio di Epigenetica Dipartimento Medicina Riabilitativa NeuroMotoria MeRiNM Istituti Clinici Scientifici Maugeri IRCCS Pavia 27100 Italy

Laboratory for Muscle Diseases and Neuropathies Department of Neurosciences KU Leuven and Leuven Brain Institute Leuven 3000 Belgium

Molecular Medicine Laboratory and Department of Neurology Concord Repatriation General Hospital Concord Clinical School The University of Sydney Concord NSW 2006 Australia

Neurology Clinic University Clinical Center of Serbia Faculty of Medicine University of Belgrade Belgrade 11000 Serbia

Neurology Department La Fe Health Research Institute Neuromuscular Research Unit Valencia 46026 Spain

Neuromuscular Repair Unit Division of Neuroscience IRCCS Ospedale San Raffaele Milan 20132 Italy

Neuromuscular Unit Department of Neurology Istanbul University Istanbul Faculty of Medicine Istanbul 1827 Turkey

Neuromuscular Unit Neurology Department Istanbul Faculty of Medicine Istanbul University Istanbul 34093 Turkey

Nord Est Ile de France Neuromuscular Diseases Reference Center Pitié Salpêtrière Hospital APHP Paris 75013 France

Northcott Neuroscience Laboratory ANZAC Research Institute Sydney Local Health District Concord and School of Medical Sciences Faculty of Medicine and Health University of Sydney Sydney NSW 2050 Australia

Raphael Recanati Genetic Institute Rabin Medical Center Beilinson Hospital Petah Tikva 4941492 Israel

School of Medicine Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv 6997801 Israel

Service de Génétique Centre Hospitalier Universitaire Caen Normandie Caen 14000 France

Service de neurologie Centre de référence des maladies neuromusculaires Hôpitaux Universitaires de Strasbourg Strasbourg 67091 France

St Vincent's Healthcare Clinical Campus UNSW Medicine and Health UNSW Sydney Kensington NSW 2052 Australia

Translational Genomics of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen 72076 Germany

Translational Neurogenomics Group Genomic and Inherited Disease Program Garvan Institute of Medical Research Sydney NSW 2010 Australia

UK Dementia Research Institute University College London London WC1E 6BT UK

Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 20133 Italy

Unit of Rare Neurological Diseases Department of Clinical Neurosciences Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 20133 Italy

Vita Salute San Raffaele University Milan 20132 Italy

Wessex Neurological Centre University Hospital Southampton NHS Foundation Trust Southampton SO16 6YD UK

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