Functional characterization of the c. 462delA mutation in the NDUFS4 subunit gene of mitochondrial complex I

To the Editor : Isolated deficiency of complex I (CI) is the most commonly identified biochemical defect in childhoodonset mitochondrial diseases (1). Approximately 50% of CI-deficient individuals exhibit Leigh syndrome (LS) or Leigh-like syndrome, a devastating neurodegenerative disorder characterized by specific neuroradiological and neuropathological features. Although CI deficiency has been associated to distinct mutations in all its seven mitochondrial DNA (mtDNA) genes and in 12 of its 38 nuclear genes, the genetic cause of a large proportion of patients is still unknown. We describe the identification and functional characterization of c.462delA mutation of the CI subunit gene NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4 ) in two siblings with LS. Patient 1, the second child of a family with a highly possible history of consanguinity, displayed normal psychomotor developmental milestones until the age of 4–5 months when she began to show hyporeactivity, convergent strabismus and failure to thrive. Neurological examination revealed axial hypotonia with increased muscle tone at four limbs, absent head control, poor visual contact, dysphagia and rotatory nystagmus. Serum lactate levels, urinary organic acids, serum amino acids were normal. Brain magnetic resonance imaging (MRI) showed symmetric T2 hyperintensity involving the tegmentum of the brainstem bilaterally, along the course of the medial longitudinal fascicle. There was also bilateral hyperintensity of the substantia nigra and subthalamic nuclei. The muscle biopsy revealed increased fiber size variability, few type II hypotrophic fibers, no ragged red or cytochrome c oxidase (COX)-deficient fibers and 49% decrease of CI activity when normalized to citrate synthase and to complexes II and III (I + III/CS/II + III) (Table 1). Respiratory support became progressively necessary and the patient died in 9 months. Patient 2, the younger brother, born at term with normal birth parameters, presented rotatory nystagmus, poor visual contact, no head control, and axial hypotonia at 5 months. Brain MRI showed a similar picture as in Patient 1; magnetic resonance spectroscopy showed mild reduction of N-acetylaspartate and a pathological lactate Table 1. Biochemical assay of respiratory chain in total muscle lysates from Patient1a