Mitochondrial Complex V (Atp Synthase) Deficiency, Nuclear Type 5

A number sign (#) is used with this entry because of evidence that mitochondrial complex V (ATP synthase) deficiency nuclear type 5 (MC5DN5) is caused by homozygous mutation in the ATP5F1D gene (603150) on chromosome 19p13.

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 604273.

Clinical Features

Olahova et al. (2018) reported 2 unrelated children, both born of consanguineous parents, with a similar metabolic disorder resulting from mitochondrial dysfunction. The first patient presented on the second day of life with an episode of lethargy associated with lactic acidosis, hypoglycemia, hyperammonemia, and 3-methylglutaconic aciduria. She later developed dilated cardiomyopathy with subsequent normalization of resting systolic function. At 9 years of age, she had mild developmental delay, short stature, gait imbalance, ankle contractures, and reduced reflexes. She had recurrent episodic metabolic decompensation associated with lactic acidosis, muscle breakdown, and increased serum creatine kinase. She was treated with several oral supplements resulting in subjective improvement. The second child had delayed speech in early childhood, but did not present until age 4 years with fever and metabolic decompensation manifest as lethargy, seizures, lactic acidosis, ketoacidosis, and hyperammonemia. Serial neuroimaging showed transient edema within the brain, which resolved completely. At age 6 years, he attended a normal school (IQ of 81) and had mildly impaired exercise intolerance, pes planus, pes adductus, gait dyspraxia, amblyopia, and episodic emesis and lethargy associated with illness. He had no cardiac abnormalities. Organic acid analysis showed persistently increased 3-methylglutaconic and 3-methylglutaric acid excretion. Fibroblast and skeletal muscle cells derived from both patients showed decreased complex V activity (5% and 16% of controls, respectively) and reduced amounts of complex V, whereas other OXPHOS enzymes were normal. Mitochondria derived from 1 patient's cells showed a decrease in the number of cristae and impaired maximal respiration in response to palmitate compared to controls. Plasma analysis of metabolites and lipids in this 1 patient was consistent with impaired mitochondrial fatty acid oxidation and accumulation of citric acid cycle intermediates.

Inheritance

The transmission pattern of MC5DN5 in the families reported by Olahova et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated children, both born of consanguineous parents, with MC5DN5, Olahova et al. (2018) identified homozygous missense mutations in the ATP5F1D gene (P82L, 603150.0001 and V106G, 603150.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient fibroblasts had normal amounts of the mutant ATP5F1D protein, but significantly decreased levels of other complex V subunits, indicating reduced assembly of complex V. Expression of each mutation in Drosophila with RNAi-mediated knockdown of the ATP5F1D homolog was unable to fully rescue abnormal phenotypes (see ANIMAL MODEL), suggesting that the mutations resulted in a partial loss of function.

Animal Model

Olahova et al. (2018) found that RNAi-mediated knockdown of the homologous ATP5F1D gene in Drosophila was lethal. Targeted knockdown of the gene in the eye, antenna, and brain caused pupal lethality and a nearly complete loss of the head. This lethality and the development of eye, antenna, and brain could be rescued by expression of wildtype human ATP5F1D. Expression of the human mutations P82L (603150.0001) and V106G (603150.0002) rescued the lethality, but the mutant animals still had eye and antenna abnormalities, with the V106G mutation having a more severe effect. The eye defects were characterized as glassy eyes, small eyes, and bar eyes.