{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:17:16Z","timestamp":1770895036044,"version":"3.50.1"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"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:p><jats:bold>Background:<\/jats:bold> As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Two Chinese patients with mitochondrial encephalopathy due to mutations in <jats:italic>FOXRED1<\/jats:italic> were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with <jats:italic>FOXRED1<\/jats:italic>-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C&amp;gt;T (p.R352W) variant. At the same time, the other carried a novel c.352C&amp;gt;T (p.Q118X) variant and a reported c.1054C&amp;gt;T (p.R352W) variant. To date, nine patients have been reported with <jats:italic>FOXRED1<\/jats:italic> defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C&amp;gt;T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold><jats:italic>FOXRED1<\/jats:italic>-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of <jats:italic>FOXRED1<\/jats:italic> defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C&amp;gt;T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.<\/jats:p>","DOI":"10.3389\/fneur.2021.633397","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T06:30:15Z","timestamp":1612333815000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the 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