Clinical and molecular findings in children with complex I deficiency

• Published in: Biochimica et biophysica acta Vol. 1659; no. 2; pp. 136 - 147
• Main Authors: Bugiani, M., Invernizzi, F., Alberio, S., Briem, E., Lamantea, E., Carrara, F., Moroni, I., Farina, L., Spada, M., Donati, M.A., Uziel, G., Zeviani, M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 06-12-2004
• Subjects: Acidosis, Lactic - etiology; Acidosis, Lactic - genetics; Cardiomyopathies - etiology; Cardiomyopathies - genetics; Child; Children; Complex I deficiency; DNA, Mitochondrial; Electron Transport Complex I - deficiency; Electron Transport Complex I - genetics; Humans; Infant; Iron-Sulfur Proteins - genetics; Leigh Disease - etiology; Leigh Disease - genetics; Leukoencephalopathy, Progressive Multifocal - etiology; Leukoencephalopathy, Progressive Multifocal - genetics; Metabolism, Inborn Errors - etiology; Metabolism, Inborn Errors - genetics; Mitochondrial disorder; Mitochondrial Proteins - genetics; mtDNA mutation; Mutation; NAD(P)H Dehydrogenase (Quinone) - genetics; NADH Dehydrogenase - genetics; Nuclear DNA mutation; Proteins - genetics; mtDNA mutation; Children; Nuclear DNA mutation; Mitochondrial disorder; Complex I deficiency
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2004.09.006

Isolated complex I deficiency, the most frequent OXPHOS disorder in infants and children, is genetically heterogeneous. Mutations have been found in seven mitochondrial DNA (mtDNA) and eight nuclear DNA encoded subunits, respectively, but in most of the cases the genetic basis of the biochemical defect is unknown. We analyzed the entire mtDNA and 11 nuclear encoded complex I subunits in 23 isolated complex I-deficient children, classified into five clinical groups: Leigh syndrome, progressive leukoencephalopathy, neonatal cardiomyopathy, severe infantile lactic acidosis, and a miscellaneous group of unspecified encephalomyopathies. A genetic definition was reached in eight patients (35%). Mutations in mtDNA were found in six out of eight children with Leigh syndrome, indicating a prevalent association between this phenotype and abnormalities in ND genes. In two patients with leukoencephalopathy, homozygous mutations were detected in two different nuclear-encoded complex I genes, including a novel transition in NDUFS1 subunit. In addition to these, a child affected by mitochondrial encephalomyopathy had heterozygous mutations in NDUFA8 and NDUFS2 genes, while another child with neonatal cardiomyopathy had a complex rearrangement in a single NDUFS7 allele. The latter cases suggest the possibility of unconventional patterns of inheritance in complex I defects.