Clinical and molecular findings in children with complex I deficiency

Abstract

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.

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

“…Given the wide variability in the clinical manifestations of complex I deficiency, we investigated whether a correlation between the severity of the clinical phenotype and mutation-specific cellular features could exist. We used a cellular model consisting of primary human skin fibroblasts derived from a cohort of four individuals (Pat#1 (patient 2 in Corona et al 25 ), Pat#2 (patient 8 in Bugiani et al 26 ), Pat#3 (patient 4 in Bugiani et al 26 ), Pat#4 (patient 6 in Malfatti et al 27 )) bearing mutations in the ND5 gene and from three independent healthy individuals as controls (Ctrl#1, Ctrl#2 and Ctrl#3). Pat#1 and Pat#2 are two unrelated patients with the same 13514A4G mutation, displaying atypical MELAS and Leigh syndrome, respectively, Pat#3 is a Leigh patient with a different mutation (13513G4A) and Pat#4 has the 13063G4A mutation and is affected by typical MELAS.…”

“…In this work, we investigated autophagy and mitochondrial Ca 2+ signaling in human fibroblasts from control subjects and from a set of patients carrying mutations in the mtDNA-encoded ND5 subunit of the ETC complex I. [25][26][27] Despite the impaired complex I activity 25,26 and the increased ROS production (data not shown), these cells do not show any major defects in resting ΔΨ mt (Supplementary Figure S5c) or in organelle morphology (Figures 4d and e). However, we observed a marked increase of the autophagic flux in fibroblasts carrying the 13514A4G mutation (Figures 1a-d and Supplementary Figures S1a-d).…”

“…All the experiments were performed on primary skin fibroblasts derived from MELAS or Leigh syndrome patients carrying different point mutations in the ND5 subunit of complex I (Pat#1 (patient 2 in Corona et al 25 ), Pat#2 (patient 8 in Bugiani et al 26 ), Pat#3 (patient 4 in Bugiani et al 26 ), Pat#4 (patient 6 in Malfatti et al 27 )) and three independent control fibroblast cultures from healthy individuals (Ctrl#1, Ctrl#2 and Ctrl#3). Primary fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM), supplemented with 20% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100 μg/ml) and transfected with Lipofectamine 2000 (Life Technologies, Waltham, MA, USA), according to the manufacturer's instructions.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Complex I consists of 44 different structural subunits, one of which is found twice, for a total of 45 subunits. Pathogenic mutations have been identified in 21 CI subunit genes, including all seven of the mtDNA-encoded subunits [44,45] (Table 1).…”

The mitochondrial 13513G>A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff–Parkinson–White

“…The m.13514A4G mutation affects the same codon as the m.13513G4A transition and has been reported in four patients with a MELAS-or LS-like phenotype. 4,10,11 …”