Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5

Abstract Background Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 ( NDUFAF5 ) are linked to Leigh syndrome. Objective We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. Methods Patients with biallelic NDUFAF5 mutations were recruited from multi‐centers in Taiwan. Clinical, laboratory, radiological, and follow‐up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. Results Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early‐onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late‐onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late‐onset homozygous p.Met279Arg were older at onset ( P = 0.008), had less developmental delay ( P = 0.01), less hyponatremia ( P = 0.01), and better prognosis with preserved ambulatory function into early adulthood ( P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early‐onset patients ( P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early—versus late‐onset p.Met279Arg homozygous cases ( P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early‐onset case than a late‐onset patient. Conclusions The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.