Biallelic Variants in the <scp> <i>DARS2</i> </scp> Gene as a Novel Cause of Axonal Charcot–Marie–Tooth Disease
Our findings expand the DARS2-related disease spectrum, establishing a novel association with axonal CMT. Hypomorphic variants, such as p.Ser238Phe, when paired with more deleterious variants, result in isolated axonal CMT, whereas more severe combinations-although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation-result in axonal CMT with central nervous system involvement, albeit without leukoencephalopathy. These observations raise the possibility that DARS2-associated diseases form a continuum rather than representing strictly distinct central or peripheral nervous system disorders. ANN NEUROL 2025;98:1335-1351.
Authors
- Laura Carrera‐García (ORCID: https://orcid.org/0000-0003-4762-7591)
- Siiri Sarv (ORCID: https://orcid.org/0009-0000-0935-7055)
- Santiago Ramón‐Maiques (ORCID: https://orcid.org/0000-0001-9674-8088)
- Lara Cantarero (ORCID: https://orcid.org/0000-0002-5196-5262)
- Janet Hoenicka (ORCID: https://orcid.org/0000-0002-6790-6988)
- Ülle Murumets
- Katrin Õunap (ORCID: https://orcid.org/0000-0002-4594-6364)
- J. Expósito (ORCID: https://orcid.org/0000-0002-6233-823X)
- Gajja Sophi Salomons (ORCID: https://orcid.org/0000-0003-2509-3648)
- Dèlia Yubero (ORCID: https://orcid.org/0000-0001-7742-0589)
- Eve Õiglane‐Shlik
- C. Ortez (ORCID: https://orcid.org/0000-0001-8187-8103)
- Berta Estévez‐Arias (ORCID: https://orcid.org/0000-0002-1711-7489)
- Émilien Delmont (ORCID: https://orcid.org/0000-0002-5591-2774)
- Carsten G. Bönnemann (ORCID: https://orcid.org/0000-0002-5930-2324)
- A. Nascimento (ORCID: https://orcid.org/0000-0003-4952-5732)
- Jordi Muchart (ORCID: https://orcid.org/0000-0003-4702-5072)
- Sanna Puusepp (ORCID: https://orcid.org/0000-0001-8465-5634)
- Daniel Natera‐de Benito (ORCID: https://orcid.org/0000-0001-7764-2085)
- Nathalie Bonello‐Palot (ORCID: https://orcid.org/0000-0002-8657-1271)
- Francesc Palau (ORCID: https://orcid.org/0000-0002-8635-5421)
- Liis Väli (ORCID: https://orcid.org/0000-0002-5727-8404)
- Bjarne Udd
- Teele Meren
Institutions
- National Institutes of Health (US)
- Hospital Sant Joan de Déu Barcelona (ES)
- University of Helsinki (FI)
- Inserm (FR)
- Aix-Marseille Université (FR)
- Instituto de Salud Carlos III (ES)
- Tartu University Hospital (EE)
- Assistance Publique Hôpitaux de Marseille (FR)
- Amsterdam Neuroscience (NL)
- National Institute of Neurological Disorders and Stroke (US)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Equilibrium Research (GB)
- Tampere University Hospital (FI)
- Tampere University (FI)
- Instituto de Biomedicina de Valencia (ES)
- Hôpital de la Timone (FR)
- Centro de Investigacion Principe Felipe (ES)
- Folkhälsans Forskningscentrum (FI)
- Institut de Recerca Sant Joan de Déu
- University of Tartu (EE)
- Universitat de Barcelona (ES)
- University of Amsterdam (NL)
Publication Details
- Journal
- Annals of Neurology
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1002/ana.78005
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Eesti Teadusagentuur
- Generalitat de Catalunya
- HORIZON EUROPE Framework Programme
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación