Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5-related disorders

NDUFAF5 encodes a Complex I assembly factor which is critical to the modification of a core subunit, NDUFS7, in early Complex I factor assembly. Mutations in NDUFAF5 have been previously shown to cause Complex I deficiency leading to mitochondrial respiratory chain impairment. More than 15 individuals affected by variants in NDUFAF5 have been described; however, there is phenotypic heterogeneity within this cohort. Some individuals display features of classical Leigh syndrome with early onset neurodegeneration whereas others live into early adulthood with progressive neurological deficits. Here, we present a clinical report of a 17-year-old African American individual with compound heterozygous mutations in NDUFAF5. The individual presented with childhood onset bilateral optic atrophy and developed progressive neuromuscular decline with relatively preserved cognition over time.