2. Academic Validation
  3. Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration

Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration

  • Mitochondrion. 2025 Dec 16:87:102110. doi: 10.1016/j.mito.2025.102110.
Cunhui Pan 1,  Ruowei Zhu 2,  Xi Huang 1,  Haolin Duan 1,  Tenghui Wu 1,  Xiaole Wang 1,  Ying Ding 3,  Chen Chen 1,  Fang He 1,  Jing Peng 1,  Fei Yin 1,  Xiaoting Lou 4,  Li Yang 5
Affiliations

Affiliations

  • 1 Department of Pediatrics, Clinical Research Center of Children's Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 2 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Neonatology, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 4 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Laboratory Medicine Center, Department of Genetic and Genomic Medicine, Zheiiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Laboratory Medicine and Bioengineering, Hangzhou Medica College, Hnagzhou, China.
  • 5 Department of Pediatrics, Clinical Research Center of Children's Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: [email protected].
PMID: 41412221 DOI: 10.1016/j.mito.2025.102110
Abstract

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.

Keywords

Developmental and epileptic encephalopathy; FOXRED1; Mitochondrial dysfunction; Niacin; Ohtahara Syndrome.

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