Novel Missense Variation in NDUFA9 Gene in an Iranian Patient with Fatal Leigh Syndrome

: Mitochondrial diseases are caused by disturbances in the oxidative phosphorylation (OXPHOS) system. Leigh syndrome encompasses a spectrum of mitochondrial diseases characterized by necrotizing encephalopathy. Thus far, two cases carrying a variant in NDUFA9 with a diagnosis of Leigh syndrome have been reported. NDUFA9 is a subunit involved in the assembly and stability of the mitochondrial respiratory complex I. We present a lethal phenotype of Leigh syndrome in a four-month-old boy born to a consanguineous (first cousins) Iranian couple. The patient’s clinical course was notable for episodes of cyanosis, seizures, lactic acidosis, nystagmus, spastic paraplegia, apnea, and respiratory arrest. Due to high branched-chain amino acids, an initial diagnosis of maple syrup urine disease was considered; however, the patient did not respond to treatment. Via exome sequencing, we identified a novel homozygous missense variation in NDUFA9 (c.1069C>G, p.Arg357Gly), and a posthumous diagnosis of Leigh syndrome was made. This report highlights the potential differential diagnosis of Leigh syndrome and further describes the phenotypic spectrum of NDUFA9 defects.