{"doi":"10.1101/2025.09.22.25335938","title":"Clinical, neuropathological, and biochemical characterization of ALS in a large CHCHD10 R15L family","abstract":"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.","journal":"medRxiv","year":2025,"id":559153,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1460938,"name":"Christian I. Lantz","orcid":null,"position":1,"is_corresponding":false},{"id":821574,"name":"Vladislav A. Korobeynikov","orcid":"0000-0002-9127-292X","position":2,"is_corresponding":false},{"id":767935,"name":"Allison Snyder","orcid":"0000-0002-1857-928X","position":3,"is_corresponding":false},{"id":299700,"name":"Xiaoping Huang","orcid":"0000-0002-6826-0322","position":4,"is_corresponding":false},{"id":781082,"name":"Taryn Haselhuhn","orcid":null,"position":5,"is_corresponding":false},{"id":1460939,"name":"Katherine N Dore","orcid":null,"position":6,"is_corresponding":false},{"id":1065056,"name":"Angelo Madruga","orcid":null,"position":7,"is_corresponding":false},{"id":512633,"name":"Laura E. Danielian","orcid":null,"position":8,"is_corresponding":false},{"id":472282,"name":"Alice B. Schindler","orcid":null,"position":9,"is_corresponding":false},{"id":240476,"name":"Ruth Chia","orcid":"0000-0002-4709-7423","position":10,"is_corresponding":false},{"id":1043299,"name":"Memoona Rasheed","orcid":null,"position":11,"is_corresponding":false},{"id":1460940,"name":"Jody Crook","orcid":null,"position":12,"is_corresponding":false},{"id":250240,"name":"Marcell Szabo","orcid":"0000-0002-1336-1951","position":13,"is_corresponding":false},{"id":295305,"name":"Makayla Portley","orcid":"0000-0003-2866-9198","position":14,"is_corresponding":false},{"id":1460941,"name":"Carolyn M. Sherer","orcid":null,"position":15,"is_corresponding":false},{"id":338086,"name":"Monique C. King","orcid":null,"position":16,"is_corresponding":false},{"id":1061028,"name":"Tzu-Hsiang Huang","orcid":null,"position":17,"is_corresponding":false},{"id":1460942,"name":"Peter Kosa","orcid":null,"position":18,"is_corresponding":false},{"id":347281,"name":"Bibiana Bielekova","orcid":"0000-0002-0959-9430","position":19,"is_corresponding":false},{"id":225567,"name":"Michael E. Ward","orcid":"0000-0002-5296-8051","position":20,"is_corresponding":false},{"id":1449627,"name":"Chris Grunseich","orcid":null,"position":21,"is_corresponding":false},{"id":550624,"name":"Neil A. Shneider","orcid":"0000-0002-3223-7366","position":22,"is_corresponding":false},{"id":401518,"name":"Bryan Traynor","orcid":"0000-0002-3010-8851","position":23,"is_corresponding":false},{"id":299707,"name":"Derek P. Narendra","orcid":"0000-0002-8696-9108","position":24,"is_corresponding":false},{"id":374709,"name":"Justin Kwan","orcid":"0000-0003-1558-4451","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41040684","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}