Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family
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Le résumé fourni par la source
Abstract Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluate five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo , in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 2-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family
- Date Crossref
- 26/09/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Institute of Neurological Disorders and Stroke pays non établi dans la noticeStructure de recherche
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Columbia University Irving Medical Center Department of Neurology pays non établi dans la noticeÉtablissement de santé
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University of Pennsylvania Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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National Institutes of Health pays non établi dans la noticeOrganisme public
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National Institute on Aging Neuromuscular Diseases Research Section pays non établi dans la noticeStructure de recherche
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Institute of Aging pays non établi dans la noticeStructure de recherche
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National Institutes of Health Clinical Center Rehabilitation Medicine Department pays non établi dans la noticeÉtablissement de santé
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National Institute of Allergy and Infectious Diseases pays non établi dans la noticeStructure de recherche
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Laboratory of Clinical Immunology and Microbiology Neuroimmunological Diseases Section pays non établi dans la noticeStructure de recherche
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National Institute of Allergy and Immunology pays non établi dans la noticeStructure de recherche
National Institute of Neurological Disorders and Stroke, Department of Neurology — Columbia University Irving Medical Center et Department of Neurology — University of Pennsylvania, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.