{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:47:45Z","timestamp":1792583265132,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["ZIA AG000933"],"award-info":[{"award-number":["ZIA AG000933"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI001242-07"],"award-info":[{"award-number":["AI001242-07"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Familial forms of amyotrophic lateral sclerosis (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 familial ALS (fALS) caused by the heterozygous p.R15L missense mutation in the gene CHCHD10.<\/jats:p>\n                  <jats:p>Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68%\u201381%) 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\u2013Bernhardt 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 versus 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 induced pluripotent stem cells and a knock-in 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 favour 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 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and peripherin (PRPH).<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awag115","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T17:49:16Z","timestamp":1774892956000},"source":"Crossref","is-referenced-by-count":2,"title":["Clinical and biochemical characterization of amyotrophic lateral sclerosis in a\n                    <i>CHCHD10<\/i>\n                    R15L family"],"prefix":"10.1093","author":[{"given":"Justin Y","family":"Kwan","sequence":"first","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian I","family":"Lantz","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad A","family":"Korobeynikov","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Huang","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taryn","family":"Haselhuhn","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine N","family":"Dore","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Madruga","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Danielian","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice B","family":"Schindler","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Chia","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Memoona","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody","family":"Crook","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcell","family":"Szabo","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makayla","family":"Portley","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M","family":"Sherer","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique C","family":"King","sequence":"additional","affiliation":[{"name":"Rehabilitation Medicine Department, Clinical Center, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1826-4309","authenticated-orcid":false,"given":"Tzu-Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kosa","sequence":"additional","affiliation":[{"name":"Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana","family":"Bielekova","sequence":"additional","affiliation":[{"name":"Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Ward","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Grunseich","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A","family":"Shneider","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan J","family":"Traynor","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-9108","authenticated-orcid":false,"given":"Derek P","family":"Narendra","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"2026102107371240200_awag115-B1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"2026102107371240200_awag115-B2","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200105313442207","article-title":"Amyotrophic lateral sclerosis","volume":"344","author":"Rowland","year":"2001","journal-title":"N Engl J 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