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Several aminoacyl\u2010tRNA synthetases have been linked to CMT.\n                      <jats:italic>DARS2<\/jats:italic>\n                      , encoding the mitochondrial aspartyl\u2010tRNA synthetase, has been typically associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. This study aimed to investigate the association between biallelic\n                      <jats:italic>DARS2<\/jats:italic>\n                      variants and axonal CMT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated 5 individuals from 3 unrelated families with axonal CMT and biallelic\n                      <jats:italic>DARS2<\/jats:italic>\n                      variants. Functional studies in fibroblasts assessed their effects on DARS2 expression, localization, and mitochondrial function. Enzymatic activity was evaluated in HEK293 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The 5 individuals, including 4 adults, presented with childhood\u2010onset progressive axonal CMT. None had leukoencephalopathy, but one showed central nervous system involvement, with intellectual disability and epilepsy. Genetic analysis identified compound heterozygous\n                      <jats:italic>DARS2<\/jats:italic>\n                      variants: family A, p.Ser238Phe and p.Arg336Cys; family B, p.Ser238Phe and p.Ile25Thrfs*38; family C, c.492+2T&gt;C and p.Pro503Leu. Functional studies revealed reduced DARS2 protein levels, mitochondrial network abnormalities, and impaired mitochondrial function. p.Ser238Phe behaves as a hypomorphic allele, whereas p.Pro503Leu reduced DARS2 enzymatic activity by 75%.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Our findings expand the\n                      <jats:italic>DARS2<\/jats:italic>\n                      \u2010related 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\u2014although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation\u2014result in axonal CMT with central nervous system involvement, albeit without leukoencephalopathy. These observations raise the possibility that\n                      <jats:italic>DARS2<\/jats:italic>\n                      \u2010associated diseases form a continuum rather than representing strictly distinct central or peripheral nervous system disorders. ANN NEUROL 2025;98:1335\u20131351\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78005","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T08:29:05Z","timestamp":1755246545000},"page":"1335-1351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Biallelic Variants in the\n                    <scp>\n                      <i>DARS2<\/i>\n                    <\/scp>\n                    Gene as a Novel Cause of Axonal Charcot\u2013Marie\u2013Tooth Disease"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-7489","authenticated-orcid":false,"given":"Berta","family":"Est\u00e9vez\u2010Arias","sequence":"first","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology Hospital Sant Joan de D\u00e9u  Barcelona Spain"},{"name":"Laboratory of Neurogenetics and Molecular Medicine, Center for Genomic 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