{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatric Neurology, Centre for Neuromuscular Disorders, University Duisburg-Essen, 45147 Essen, Germany",
    "Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V ., 44227 Dortmund, Germany",
    "Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neuropathology, Berlin, Germany",
    "Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK",
    "Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany",
    "Department of Neuropathology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany",
    "Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany",
    "Department of Neurology, BG-University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany ; Heimer Institute for Muscle Research, BG-University Hospital Bergmannsheil, 44789 Bochum, Germany",
    "Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany",
    "Brain and Mind Research Institute, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Heike Kölbel"
    },
    {
      "affs": [
        1
      ],
      "name": "Andreas Hentschel"
    },
    {
      "affs": [
        2
      ],
      "name": "Corinna Preuße"
    },
    {
      "affs": [
        3
      ],
      "name": "May Tiet"
    },
    {
      "affs": [
        4
      ],
      "name": "Maike Dohrn"
    },
    {
      "affs": [
        0
      ],
      "name": "David Muhmann"
    },
    {
      "affs": [
        3
      ],
      "name": "Jelle van den Ameele"
    },
    {
      "affs": [
        0
      ],
      "name": "Lei Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Ulrike Schara-Schmidt"
    },
    {
      "affs": [
        5
      ],
      "name": "Joachim Weis"
    },
    {
      "affs": [
        3
      ],
      "name": "Rita Horvath"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Alexander Mensch"
    },
    {
      "affs": [
        0,
        7,
        8,
        9
      ],
      "name": "Andreas Roos"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4smm86ay1pm30.bib",
  "cited_by": 0,
  "doi": "10.1093/jnen/nlag057",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7619715/",
  "id": "4smm86ay1pm30",
  "issns": [
    "0022-3069",
    "1554-6578"
  ],
  "landing_url": "https://doi.org/10.1093/jnen/nlag057",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2804|Hereditary Neurological Disorders"
    ]
  ],
  "openalex": "W7203787984",
  "pdf_url": "https://www.repository.cam.ac.uk/bitstreams/1659cbdd-2fcb-48a3-8780-220bffade2cc/download",
  "pmcid": "PMC7619715",
  "pmid": "42616755",
  "published": "2026-08-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4smm86ay1pm30.ris",
  "sources": [
    {
      "first_seen": "2026-11-12T12:23:45Z",
      "native_id": "PMC7619715",
      "source": "pmc",
      "url": "https://doi.org/10.1093/jnen/nlag057"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Hereditary Neurological Disorders",
      "subfield": "neuroscience"
    }
  ],
  "title": "When Muscles Matter in SORD Neuropathy",
  "title_text": "When Muscles Matter in SORD Neuropathy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T12:24:54Z",
  "url": "https://research.draconitic.com/paper/4smm86ay1pm30",
  "venue": "Journal of neuropathology and experimental neurology",
  "versions": []
}