Multi-generational mitochondrial complex V deficiency due to the recurrent ATP5F1A c.620G>A (p.Arg207His) pathogenic variant: A novel family and a review of the literature.

ATP5F1A encodes part of the catalytic core of mitochondrial complex V, which is responsible for the majority of ATP production. Mitochondrial complex V deficiency, nuclear type 4A (MC5DN4A; MIM#620358) is due to monoallelic pathogenic variants in ATP5F1A. MC5DN4A is a neonatal-onset disorder with features including growth faltering, developmental delay, epilepsy, and a biochemical phenotype indicative of urea cycle dysfunction. Interestingly, patients who have MC5DN4A due to the recurrent pathogenic ATP5F1A c.620G>A (p.Arg207His) variant appear to demonstrate clinical resolution before 18 months of age. All reported cases of MC5DN4A due to the ATP5F1A c.620G>A (p.Arg207His) variant have been de novo. Here we present a mother and her three children with MC5DN4A harboring the ATP5F1A c.620G>A (p.Arg207His) variant. The oldest child has growth faltering, seizures, autism spectrum disorder, global developmental delay, urea cycle dysfunction, and elevated plasma lactate without full clinical resolution. The two younger children have similar biochemical findings with a more severe clinical phenotype including congenital heart disease, growth faltering, sideroblastic anemia, and hypogammaglobulinemia, however both children are showing signs of spontaneous clinical resolution. Additionally, both younger children have a deletion of the entire coding sequence of NDUFA12, which may be contributing to the more severe presentation. The mother is reportedly asymptomatic. In summary, we present the first known instance of transgenerational transmission of the pathogenic ATP5F1A c.620G>A (p.Arg207His) variant. The presence of congenital heart disease, sideroblastic anemia, and hypogammaglobulinemia in two cases may indicate a phenotypic expansion of MC5DN4A or may suggest a modifying effect of the NDUFA12 deletion on the phenotype.