Mitochondrial Complex V (Atp Synthase) Deficiency, Nuclear Type 1


A number sign (#) is used with this entry because of evidence that mitochondrial complex V (ATP synthase) deficiency nuclear type 1 (MC5DN1) is caused by homozygous mutation in the ATPAF2 gene (608918) on chromosome 17p11. One such patient has been reported.


A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010).

Genetic Heterogeneity of Mitochondrial Complex V Deficiency

Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (ATP5F1E; 606153) on chromosome 20q13; MC5DN4 (615228), caused by mutation in the ATP5A1 gene (ATP5FA1; 164360) on chromosome 18q; and MC5DN5 (618120), caused by mutation in the ATP5D gene (ATP5F1D; 603150) on chromosome 19p13.

Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 500015).

Clinical Features

Houstek et al. (1999) reported a male patient with ATPase deficiency who was born of healthy first-cousin parents. He was born at term with oligohydramnios, birth weight less than the 5th percentile, and length of 45 cm. Dysmorphic features included frontal bossing, short philtrum, micrognathia, low-set ears, and hypospadias. He had progressive hypotonia, severe lactic acidosis, cardiomegaly, and hepatomegaly, and died from heart failure on day 2. The mother had been pregnant 8 times, with 1 miscarriage. Three boys were healthy, but 2 girls died in the first week of life, probably due to severe metabolic acidosis. One boy with a congenital heart defect died at the age of 3 years due to failure to thrive and progressive psychomotor retardation. Three children of the mother's sister died within the first week of life without any metabolic investigations. Analysis of mtDNA in studies of the proband's fibroblasts and derived transmitochondrial cybrids revealed the nuclear origin of the defect. Because of the selectivity of the defect, Houstek et al. (1999) suggested that some assembly factor for ATPase biosynthesis might be missing.

De Meirleir et al. (2004) reported a girl, born of consanguineous Moroccan parents, with mitochondrial ATPase deficiency. She had a birth weight of 2.55 kg and head circumference of 30.5 cm, and presented with dysmorphic features, including a large mouth, prominent nasal bridge, micrognathia, rocker-bottom feet, and flexion contractures of the limbs associated with camptodactyly. She was hypertonic and had an enlarged liver and hypoplastic kidneys. Urinary, plasma, and CSF lactate levels were elevated, and she had increased urinary 3-methylglutaconic acid, a marker of inner mitochondrial membrane dysfunction. Cerebral MRI revealed marked cortical-subcortical atrophy, dysgenesis of the corpus callosum with absent anterior genu and rostrum, and hypoplasia of white matter. She had severe developmental delay with seizures and failure to thrive, and died at 14 months of age from intercurrent infection.

De Meirleir et al. (2004) reported a second unrelated male infant with complex V deficiency. At birth, he had an enlarged liver, respiratory insufficiency, and lactic acidosis. He had multiple cardiac arrests, and died from cardiac arrest on day 3.

Sperl et al. (2006) reported 14 patients with an isolated deficiency of mitochondrial ATP synthase (7 to 30% of control) presumably caused by nuclear genetic defects. Seven patients had previously been reported (e.g., Houstek et al., 1999; De Meirleir et al., 2004). Only 1 of the 14 patients, a female reported by De Meirleir et al. (2004), had been found to have a mutation (see MOLECULAR GENETICS). All patients had neonatal onset of lactic acidemia, variable failure to thrive, hypotonia, and respiratory insufficiency. Many had dysmorphic features, including microcephaly, low-set ears, retrognathia, and prominent nasal bridge. Eleven patients had hypertrophic cardiomyopathy, and all had psychomotor retardation. Laboratory studies showed intermittent 3-methylglutaconic aciduria, which appeared to be a marker for deranged mitochondrial energy metabolism. Seven patients died in infancy.

Wortmann et al. (2009) reported 3 females from a large Roma family with neonatal cardiomyopathy. The first girl presented with severe failure to thrive, hypertension, cardiomyopathy, and Wolf-Parkinson-White syndrome at age 3 years. A maternal cousin had hypertrophic cardiomyopathy with aortic and pulmonary valve stenosis. The third girl had feeding problems, hypertrophic cardiomyopathy, and aortic stenosis. Two patients had occasional extrasystoles. None had hypotonia, and all showed nearly normal psychomotor development at ages 3, 5, and 9 years. Laboratory studies showed very low ATP production, severe complex V deficiency, and moderate 3-methylglutaconic aciduria.

Molecular Genetics

In a female infant with decreased complex V activity, De Meirleir et al. (2004) identified homozygosity for a missense mutation in the ATPAF2 gene (W94R; 608918.0001). The consanguineous Moroccan parents and a healthy sib were heterozygous for the mutation, which was not found in 50 healthy Moroccan controls.

In a male infant with complex V deficiency, De Meirleir et al. (2004) screened for mutations in genes coding for ATP synthase subunits alpha (ATP5A; 164360), beta (ATP5B; 102910), and gamma (ATP5C; 108729) of F1 and assembly genes ATPAF1 (608917) and ATPAF2 but did not identify any mutations.