Mitochondrial Complex V (Atp Synthase) Deficiency, Nuclear Type 4


A number sign (#) is used with this entry because of evidence that mitochondrial complex V deficiency nuclear type 4 (MC5DN4) is caused by mutation in the ATP5A1 gene (ATP5F1A; 164360) on chromosome 18q. One such family has been reported.

Mutation in the ATP5A1 gene can also cause COXPD22 (616045), which shows some overlapping clinical features.

For a general phenotypic description of the nuclear type of mitochondrial complex V deficiency and a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see MC5DN1 (604273).

Clinical Features

Jonckheere et al. (2013) reported 2 sibs, born of unrelated Dutch parents, with fatal infantile encephalopathy. After birth, the infants were irritable with a high-pitched cry and showed horizontal and vertical nystagmus, abnormal primitive reflexes, and tonus dysregulation. Both died in the first weeks of life due to a severe encephalopathy characterized by intractable seizures manifest as apneic spells. Brain MRI of one of the sibs showed a progressive and severe encephalopathy characterized by hyperdense thalami and subcortical densities. Postmortem examination showed extensive cerebral damage, small cerebellum, damaged pons and brainstem, and cystic degeneration of the white matter. Other findings included hypoplastic lungs, small renal cysts, and small lipid droplets in skeletal muscle, all suggestive of a mitochondrial disease. Brain MRI of the younger sib showed progressive damage to the frontal and parietooccipital regions, the pyramidal tract, basal ganglia, cerebellum, and pons. Metabolic screening showed no abnormalities in either case. Patient fibroblasts showed decreased oxygen consumption rate, isolated complex V deficiency, and decreased complex V assembly.


The transmission pattern of MC5DN4 in the family reported by Jonckheere et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs with fatal infantile mitochondrial encephalopathy, Jonckheere et al. (2013) identified a heterozygous missense mutation in the ATP5A1 gene (R329C; 164360.0001) inherited from the unaffected father. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in 1,200 control exomes. The sibs expressed only the mutant allele, the father expressed both the mutant and wildtype allele, and the mother expressed only the wildtype allele. Although no mutations were identified in the mother's ATP5A1 gene, there was no evidence for a splicing defect, and MLPA excluded gene rearrangements; the mother had only about 60% ATP5A1 mRNA, consistent with a gene expression defect. SNP analysis indicated that both patients inherited the same maternal allele. Complementation of patient fibroblasts with wildtype ATP5A1 completely normalized complex V amount and activity. The findings indicated that the ATP5A1 defect found in these patients was disease-causing, even though the exact nature of the mutation inherited from the mother remained unknown.