MT-ATP6

Mitochondrial complex V deficiency is a shortage (deficiency) or loss of function in complex V of the electron transport chain that can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs.[12] Ataxia, microcephaly, developmental delay and intellectual disability have been observed in patients with a frameshift mutation in MT-ATP6. This causes a C insertion at position 8612 that results in a truncated protein only 36 amino acids long, and two T > C single-nucleotide polymorphisms at positions 8610 and 8614 that result in a homopolymeric cytosine stretch.[13]

Another common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of the cardiac muscle that can lead to heart failure.[12] The m.8528T>C mutation occurs in the overlapping region of the MT-ATP6 and MT-ATP8 genes and has been described in multiple patients with infantile cardiomyopathy. This mutation changes the initiation codon in MT-ATP6 to threonine as well as a change from tryptophan to arginine at position 55 of MT-ATP8.[14][15] Individuals with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslanting palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia).[12]

Pathogenic variants of the mitochondrial gene MT-ATP6 are known to cause mtDNA-associated Leigh syndrome, a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.[5] Other variants known to cause mtDNA-associated Leigh syndrome involve MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ATP6.[16] MT-ATP6 gene mutations associated with Leigh syndrome change one DNA building block (nucleotide) in the MT-ATP6 gene. The most common genetic change replaces the nucleotide thymine with guanine at position 8993 (written as T8993G). The mutations that cause Leigh syndrome impair the function or stability of the ATP synthase complex, inhibiting ATP production and impairing oxidative phosphorylation. Although the exact mechanism is unclear, researchers believe that impaired oxidative phosphorylation can lead to cell death because of decreased energy available in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles, and heart, seem especially sensitive to decreases in cellular energy. Cell death in the brain likely causes the characteristic changes in the brain seen in Leigh syndrome, which contribute to the signs and symptoms of the condition. Cell death in other sensitive tissues may also contribute to the features of Leigh syndrome. A heteroplasmic T→C MT-ATP6 mutation at position 9185 results in the substitution of a highly conserved leucine to proline at codon 220 and a heteroplasmic T→C missense mutation at position 9191 converted a highly conserved leucine to a proline at position 222 of the polypeptide, leading to a Leigh-type phenotype. The T9185C mutation resulted in a mild and reversible phenotype, with 97% of the patient's muscle and blood samples reflecting the mutation. The T9191C mutation presented a much more severe phenotype that resulted in the death of the patient at 2 years of age.[17]

Some of the mutations of the ATP6 gene that cause Leigh syndrome are also responsible for a similar, but less severe, condition called neuropathy, ataxia, and retinitis pigmentosa (NARP).[18] A small number of mutations in the MT-ATP6 gene have been identified in people with NARP. Each of these mutations changes one nucleotide in the MT-ATP6 gene. As in Leigh syndrome, the most common genetic change associated with NARP replaces the nucleotide thymine with guanine at position 8993 (written as T8993G). The mutations that cause NARP alter the structure or function of ATP synthase, reducing the ability of mitochondria to produce ATP. Although the precise effects of these mutations are unclear, researchers continue to investigate how changes in the MT-ATP6 gene interfere with ATP production and lead to muscle weakness, vision loss, and the other features of NARP.[5]

A condition called familial bilateral striatal necrosis, which is similar to Leigh syndrome, can also result from changes in the MT-ATP6 gene. In the few reported cases with these mutations, affected children have had delayed development, problems with movement and coordination, weak muscle tone (hypotonia), and an unusually small head size (microcephaly). Researchers have not determined why MT-ATP6 mutations result in this combination of signs and symptoms in children with bilateral striatal necrosis.[5]