RESUMEN
We present clinical and laboratory data from 14 cases with an isolated deficiency of the mitochondrial ATP synthase (7-30% of control) caused by nuclear genetic defects. A quantitative decrease of the ATP synthase complex was documented by Blue-Native electrophoresis and Western blotting and was supported by the diminished activity of oligomycin/aurovertin-sensitive ATP hydrolysis in fibroblasts (10 cases), muscle (6 of 7 cases), and liver (one case). All patients had neonatal onset and elevated plasma lactate levels. In 12 patients investigated 3-methyl-glutaconic aciduria was detected. Seven patients died, mostly within the first weeks of life and surviving patients showed psychomotor and various degrees of mental retardation. Eleven patients had hypertrophic cardiomyopathy; other clinical signs included hypotonia, hepatomegaly, facial dysmorphism and microcephaly. This phenotype markedly differs from the severe central nervous system changes of ATP synthase disorders caused by mitochondrial DNA mutations of the ATP6 gene presenting mostly as NARP and MILS.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/enzimología , Encefalomiopatías Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/deficiencia , Adenosina Trifosfato/metabolismo , Adolescente , Edad de Inicio , Cardiomiopatía Hipertrófica Familiar/enzimología , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Hipertrófica Familiar/fisiopatología , Núcleo Celular/genética , Niño , Preescolar , Cara/anomalías , Femenino , Hepatomegalia/enzimología , Hepatomegalia/genética , Hepatomegalia/fisiopatología , Humanos , Lactante , Recién Nacido , Ácido Láctico/sangre , Masculino , Microcefalia/enzimología , Microcefalia/genética , Mitocondrias/enzimología , Mitocondrias/genética , Enfermedades Mitocondriales/fisiopatología , Encefalomiopatías Mitocondriales/fisiopatología , ATPasas de Translocación de Protón Mitocondriales/genética , SíndromeRESUMEN
Combined OXPHOS-system enzyme deficiencies are observed in approximately 25% of all OXPHOS-system disturbances. Of these, combined complex I and III deficiency is relatively scarce. So far, only mtDNA and thymidine phosphorylase (TP) mutations have been associated with combined OXPHOS-system disturbances. In this report we show, for the first time, that a nuclear gene mutation in a structural, nuclear encoded complex I gene is associated with combined complex I and III deficiency. After our initial report we describe mutations in the NDUFS4 gene of complex I in two additional patients. The first mutation is a deletion of G at position 289 or 290. Amino acid 96 changes from a tryptophan to a stop codon. The mutation was found homozygous in the patient; both parents are heterozygous for the mutation. The second mutation is a transition from C to T at cDNA position 316. Codon is changed from CGA (arginine) to TGA (stop). The patient is homozygous for the mutation; both parents are heterozygous. Both mutations in the NDUFS4 gene led to a premature stop in Leigh-like patients with an early lethal phenotype. We hypothesise that the structural integrity of the OXPHOS system, in mammal supermolecular structures, may be responsible for the observed biochemical features.