Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial...

Biallelic NDUFA9 variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of NDUFA9-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of NDUFA9-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic NDUFA9 variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new NDUFA9 variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic NDUFA9 variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.