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The respiratory chain/oxidative phosphorylation system consists of five multisubunit complexes, four of which, complexes I, II, III, and IV, cooperate to generate a proton gradient across the mitochondrial inner membrane. Complex V (ATP synthase or ATPase) couples proton flow from the intermembrane space back to the matrix by the conversion of ADP and inorganic phosphate to ATP. ATP synthase comprises an integral membrane component F 0 and a peripheral moiety F1 . All five subunits of F1 (α, β, [GAMMA], δ, [straight epsilon]) and most F0 subunits of the mammalian ATP synthase are nuclear encoded. Only two F0 proteins (ATP6 and 8) are encoded by mitochondrial DNA. 1 Besides the nuclear genes coding for the subunits of the ATPase complex, several assembly genes have been studied in yeast and their human analogues have been described. 2, 3 Complete loss of the ATP synthase enzyme activity is probably not compatible with life. However, partial loss reflected by a lower amount of functional ATP synthase has been associated with human disease. 4 This was the case for mutations in MTATP6 , a mitochondrial encoded component, which causes ATP synthase deficiency. 5 No pathogenic mutations involving nuclear encoded subunits have yet been found. We studied two unrelated children with decreased complex V activity and report on a mutation in the ATP12 assembly gene in one patient.
PATIENTS
Patient 1 was a full-term baby girl, born with a birth weight of 2.550 kg and head circumference of 30.5 cm, the first child of healthy consanguineous parents of Moroccan origin. Family history was unremarkable.
The girl presented with dysmorphic features, including a large mouth, prominent nasal bridge, micrognathia, rocker bottom feet, and flexion contractures of the limbs associated with camptodactylia. She was hypertonic and did not suck well. The liver was enlarged. Initial investigation including karyotype and skeletal x ray was normal. The kidneys were hypoplastic. Clinically, the presentation resembled COFS (cerebro-oculofacioskeletal) syndrome (Pena-Shokeir type II), except for the absence of microphtalmia and cataracts. Metabolic screening showed increased urinary lactate, fumarate, methylglutaconic acid, and amino acids. In CSF, lactate was 2.9 mmol/l (normal <2), pyruvate was normal. In plasma, amino acids were normal but lactate fluctuated between 2.7 and 10 mmol/l (normal <2.2) and pyruvate...