{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T17:43:59Z","timestamp":1758044639785,"version":"3.44.0"},"reference-count":5,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Although <jats:italic>MICU1<\/jats:italic>-related myopathy with extrapyramidal signs (MPXPS) has been reported globally, its genotypic and phenotypic spectrum in Chinese populations remains poorly characterized. Here we investigate two unrelated Chinese pedigrees with MPXPS caused by novel compound heterozygous <jats:italic>MICU1<\/jats:italic> mutations, addressing this critical knowledge gap.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively analyzed the clinical features of four children from two unrelated families with MPXPS caused by compound heterozygous mutations in the <jats:italic>MICU1<\/jats:italic> gene. Whole exome sequencing (WES) was performed on the probands and their parents. Sanger sequencing was used to validate the candidate gene variants. A literature review and summary of cases with bi-allelic mutations in <jats:italic>MICU1<\/jats:italic> leading to MPXPS were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four children from two unrelated families presented with elevated muscle enzymes and liver function abnormalities. In Family 1, the proband (older brother, 8\u202fyears) exhibited typical MPXPS symptoms including motor dysfunction and cognitive impairment, while his younger brother (4\u202fyears) remained asymptomatic though with elevated muscle enzymes. WES identified compound heterozygous variants c.156G\u202f&amp;gt;\u202fA and c.235G\u202f&amp;gt;\u202fT in the two siblings. In Family 2, the proband (older sister, 3\u202fyears 4\u202fmonths) manifested early signs including pes planus and attention deficits, whereas her younger sister (1\u202fyear 6\u202fmonths) showed no clinical manifestations despite biochemical abnormalities. WES identified compound heterozygous variants EXON4-8 heterozygous deletion and c.1,372C\u202f&amp;gt;\u202fT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The phenotypic variations between the sibling pairs across both pedigrees may indicate age-dependent disease progression. The four children in this study with MPXPS due to compound heterozygous mutations in the <jats:italic>MICU1<\/jats:italic> gene showed phenotypic differences compared to previously reported MPXPS cases, indicating a positive correlation between <jats:italic>MICU1<\/jats:italic> loss of function and the severity of the phenotype, demonstrating a clear genotype\u2013phenotype correlation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2025.1624830","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T14:09:40Z","timestamp":1757686180000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees"],"prefix":"10.3389","volume":"16","author":[{"given":"Jieling","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoming","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuexu","family":"Ou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanhui","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1126\/science.1242993","article-title":"EMRE is an essential component of the mitochondrial calcium uniporter complex","volume":"342","author":"Sancak","year":"2013","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/ng.2851","article-title":"Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling","volume":"46","author":"Logan","year":"2014","journal-title":"Nat Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/jmd2.12114","article-title":"Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1","volume":"53","author":"Wilton","year":"2020","journal-title":"JIMD Rep"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/8904_2018_107","article-title":"A middle eastern founder mutation expands the genotypic and phenotypic Spectrum of mitochondrial MICU1 deficiency: a report of 13 patients","volume":"43","author":"Musa","year":"2019","journal-title":"JIMD Rep"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1111\/nan.12694","article-title":"Molecular pathophysiology of human MICU1 deficiency","volume":"47","author":"Kohlschmidt","year":"2021","journal-title":"Neuropathol Appl Neurobiol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1624830\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T14:09:41Z","timestamp":1757686181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1624830\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":5,"alternative-id":["10.3389\/fneur.2025.1624830"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1624830","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]},"article-number":"1624830"}}