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The neuropathology of <jats:italic>NDUFV1<\/jats:italic>-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the <jats:italic>NDUFV1<\/jats:italic> gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the <jats:italic>NDUFV1<\/jats:italic> gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one <jats:italic>NDUFV1<\/jats:italic> variant (c.565\u00a0T\u2009&gt;\u2009C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).<\/jats:p>","DOI":"10.1186\/s40478-022-01445-1","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T09:08:02Z","timestamp":1664183282000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The neuropathologic findings in a case of progressive cavitating leukoencephalopathy due to NDUFV1 pathogenic variants"],"prefix":"10.1186","volume":"10","author":[{"given":"Nicole","family":"Becker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gosse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Kubat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3888-5583","authenticated-orcid":false,"given":"Kyle S.","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"1445_CR1","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.msard.2018.01.003","volume":"20","author":"PS Bindu","year":"2018","unstructured":"Bindu PS, Sonam K, Chiplunkar S, Govindaraj P, Nagappa M, Vekhande CC, Aravinda HR, Ponmalar JJ, Mahadevan A, Gayathri N et al (2018) Mitochondrial leukoencephalopathies: a border zone between acquired and inherited white matter disorders in children? 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