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Although classically associated with the NARP syndrome, recent evidence highlights an important role of\n                      <jats:italic>MT-ATP6<\/jats:italic>\n                      pathogenic variants in complicated adult-onset ataxias.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients\u2019 primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In both patients, we identified the same novel m.8777\u00a0T\u2009&gt;\u2009C variant in\n                      <jats:italic>MT-ATP6<\/jats:italic>\n                      with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in\n                      <jats:italic>MT-ATP6<\/jats:italic>\n                      ,\u00a0m.8879G\u2009&gt;\u2009T, in the patients with the most severe phenotype.\u00a0A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777\u00a0T\u2009&gt;\u2009C variant, while no functional defect was detected in m.8879G\u2009&gt;\u2009T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777\u00a0T\u2009&gt;\u2009C variant showed hyperpolarization of mitochondrial membranes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We describe a novel pathogenic mtDNA variant in\n                      <jats:italic>MT-ATP6<\/jats:italic>\n                      associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-024-03212-y","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T09:02:02Z","timestamp":1715850122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies"],"prefix":"10.1186","volume":"19","author":[{"given":"Daniele","family":"Sala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marchet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Nanetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Legati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Lamantea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Catania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-2253","authenticated-orcid":false,"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,16]]},"reference":[{"issue":"2\u20133","key":"3212_CR1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.bbabio.2004.09.006","volume":"1659","author":"M Bugiani","year":"2004","unstructured":"Bugiani M, Invernizzi F, Alberio S, Briem E, Lamantea E, Carrara F, Moroni I, et al. 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