When Muscles Matter in SORD Neuropathy
10 affiliations
- 1Department of Pediatric Neurology, Centre for Neuromuscular Disorders, University Duisburg-Essen, 45147 Essen, Germany
- 2Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V ., 44227 Dortmund, Germany
- 3Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neuropathology, Berlin, Germany
- 4Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
- 5Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- 6Department of Neuropathology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- 7Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
- 8Department of Neurology, BG-University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany ; Heimer Institute for Muscle Research, BG-University Hospital Bergmannsheil, 44789 Bochum, Germany
- 9Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
- 10Brain and Mind Research Institute, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Abstract
Biallelic pathogenic variants in SORD, encoding sorbitol dehydrogenase, have recently been identified as a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease (CMT2). While the primary pathology is attributed to peripheral nerve degeneration, recent evidence suggests direct involvement of skeletal muscle. In this study, we investigated muscle biopsies from four genetically confirmed CMT-SORD patients (one presented with marked CK elevation of 13,000 after physical exercise) using an integrative approach combining histopathology, electron microscopy, proteomics, quantitative PCR, and biomarker analyses. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, with central nuclei representing a non-specific finding in neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum. Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle compared to controls, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs due to pathogenic GAN- and GDAP1 variants. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement (C2, C5, C9) and immunomodulatory (CD4, CD8, CD68, CD169) factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodelling. Despite mitochondrial vulnerability, results from the serum studies indicate that GDF-15 and FGF-21 do not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as contributors to disease pathology. The combined neurogenic and intrinsic myopathic features of SORD-related CMT2 underscore the need for therapeutic strategies targeting both neuronal and muscular compartments.
Related
- Eco-evolutionary Dynamics of Colonization: When Does Source Selection Matter?
- When Does Depth Matter For In-Context Learning? Adaptive Inference in Deep Transformers
- When do book–tax differences matter for earnings persistence? The role of sales decline
- Test-Retest Reliability of Motor Evoked Potentials Across Eight Bilateral Lower-Limb Muscles
- Probabilistic inference of homonymous and heteronymous recurrent inhibition in human muscles from large-scale motor neuron recordings
BibTeX
@article{kolbel2026when,
title = {{When Muscles Matter in SORD Neuropathy}},
author = {Heike Kölbel and Andreas Hentschel and Corinna Preuße and May Tiet and Maike Dohrn and David Muhmann and Jelle van den Ameele and Lei Chen and Ulrike Schara-Schmidt and Joachim Weis and Rita Horvath and Alexander Mensch and Andreas Roos},
journal = {Journal of neuropathology and experimental neurology},
year = {2026},
month = aug,
doi = {10.1093/jnen/nlag057},
url = {https://doi.org/10.1093/jnen/nlag057},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - When Muscles Matter in SORD Neuropathy
AU - Heike Kölbel
AU - Andreas Hentschel
AU - Corinna Preuße
AU - May Tiet
AU - Maike Dohrn
AU - David Muhmann
AU - Jelle van den Ameele
AU - Lei Chen
AU - Ulrike Schara-Schmidt
AU - Joachim Weis
AU - Rita Horvath
AU - Alexander Mensch
AU - Andreas Roos
PY - 2026
DA - 2026/08/19
JO - Journal of neuropathology and experimental neurology
DO - 10.1093/jnen/nlag057
UR - https://doi.org/10.1093/jnen/nlag057
AB - Biallelic pathogenic variants in SORD, encoding sorbitol dehydrogenase, have recently been identified as a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease (CMT2). While the primary pathology is attributed to peripheral nerve degeneration, recent evidence suggests direct involvement of skeletal muscle. In this study, we investigated muscle biopsies from four genetically confirmed CMT-SORD patients (one presented with marked CK elevation of 13,000 after physical exercise) using an integrative approach combining histopathology, electron microscopy, proteomics, quantitative PCR, and biomarker analyses. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, with central nuclei representing a non-specific finding in neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum. Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle compared to controls, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs due to pathogenic GAN- and GDAP1 variants. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement (C2, C5, C9) and immunomodulatory (CD4, CD8, CD68, CD169) factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodelling. Despite mitochondrial vulnerability, results from the serum studies indicate that GDF-15 and FGF-21 do not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as contributors to disease pathology. The combined neurogenic and intrinsic myopathic features of SORD-related CMT2 underscore the need for therapeutic strategies targeting both neuronal and muscular compartments.
SN - 0022-3069
SN - 1554-6578
ER -