Clinical, Radiological and Genetic Characteristics of Children With Ndufv1-Related Mitochondrial Complex 1 Deficiency

Introduction: Mitochondrial disorders are inherited disorders of energy metabolism due to dysfunction of mitochondrial respiratory chain or oxidative phosphorylation. Mitochondrial complex 1 deficiency, nuclear type 4 (MC1DN4) is an autosomal recessive disorder caused by mutations in the NADH-Ubiquinone Oxidoreductase Flavoprotein 1 (NDUFV1) gene. We aimed to further characterize this cohort. Methods: This prospective cohort study was conducted in the Pediatric Neurology unit of a tertiary care hospital. Children with clinico-radiological suspicion of mitochondrial encephalopathy were enrolled and evaluated. Next generation sequencing was performed by an in-house Ion Torrent next-generation sequencing technology to identify the genetic variations. Clinical, biochemical, radiological, and genetic data was recorded in a pre-structured proforma. Results: We enrolled 100 children with suspected mitochondrial encephalopathy. Of these, n=14 (14%) had variations in the NDUFV1 gene responsible for MC1DN4. Genetic analysis identified five different variants (p.Arg386Cys; p.Thr423Met; p.Phe373Ser; p.Asp127Gly; p.Val195Met), of these, p.Arg386Cys, c.1156C>T (78%) was the most common. The mean age at presentation was 2 years (range 0.4 - 6 years). The most common symptoms were developmental delay (100%), spasticity (57%), regression in milestones (50%), dystonia (50%), and seizures (28%). Brain MRI revealed predominant involvement of periventricular white matter with or without corpus callosum involvement. Conclusion: Mitochondrial NDUFV1-related disorders present in infancy with developmental delay and regression following trivial insults. Highly prevalent p.Arg386Cys variant of NDUFV1 gene can be a target for future diagnostic and therapeutic studies.