MedGen

Mitochondrial complex V deficiency nuclear type 4A (MC5DN4A) is an autosomal dominant metabolic disorder characterized by poor feeding and failure to thrive in early infancy. Laboratory studies show increased serum lactate, alanine, and ammonia, suggesting mitochondrial dysfunction. Some affected individuals show spontaneous resolution of these symptoms in early childhood and have subsequent normal growth and development, whereas others show developmental delay with impaired intellectual development and movement abnormalities, including dystonia, ataxia, or spasticity; these neurologic deficits are persistent (Lines et al., 2021, Zech et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, nuclear types, see MC5DN1 (604273). [from OMIM]

Mitochondrial complex V deficiency is a shortage (deficiency) of a protein complex called complex V or a loss of its function. Complex V is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Complex V is the last of five mitochondrial complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.

Mitochondrial complex V deficiency 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.

Another common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of the heart (cardiac) muscle that can lead to heart failure. People 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).

Some people with mitochondrial complex V deficiency have groups of signs and symptoms that are classified as a specific syndrome. For example, mitochondrial complex V deficiency can cause a condition called neuropathy, ataxia, and retinitis pigmentosa (NARP). NARP causes a variety of signs and symptoms chiefly affecting the nervous system. Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have cognitive impairment and an eye disorder called retinitis pigmentosa that causes vision loss.

A condition called Leigh syndrome can also be caused by mitochondrial complex V deficiency. Leigh syndrome is characterized by progressive loss of mental and movement abilities (developmental or psychomotor regression) and typically results in death within 2 to 3 years after the onset of symptoms. Both NARP and Leigh syndrome can also have other causes. [from MedlinePlus Genetics]