Mitochondrial complex V deficiency

Mitochondrial complex V deficiency is a disorder caused by a shortage or loss of function in a protein complex essential for cellular energy production, often leading to severe neurological and cardiac complications.

Overview

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

Symptoms

The disorder can cause a wide variety of signs and symptoms affecting many organs, particularly the nervous system and the heart. It can be life-threatening in infancy or early childhood. Common features include:

• Feeding problems and slow growth
• Low muscle tone (hypotonia)
• Extreme fatigue (lethargy) and developmental delay
• Elevated levels of lactic acid in the blood (lactic acidosis), causing nausea, vomiting, weakness, and rapid breathing
• High levels of ammonia in the blood (hyperammonemia), which can lead to abnormal brain function (encephalopathy)
• Hypertrophic cardiomyopathy (thickening of the heart muscle that can lead to heart failure)
• Characteristic facial features, including a high forehead, curved eyebrows, downward-slanting eyes, a prominent nasal bridge, low-set ears, thin lips, and a small chin

Specific Syndromes

• NARP (Neuropathy, ataxia, and retinitis pigmentosa): Affects the nervous system, causing numbness, tingling, or pain in the arms and legs (sensory neuropathy), muscle weakness, balance and coordination problems (ataxia), cognitive impairment, and vision loss.
• Leigh syndrome: Characterized by progressive loss of mental and movement abilities (developmental or psychomotor regression), typically resulting in death within 2 to 3 years of symptom onset.

Causes & Risk Factors

The condition is caused by mutations in several genes that provide instructions for making components of complex V or proteins that help assemble it. These mutations impair the formation or function of complex V, reducing oxidative phosphorylation and potentially leading to cell death in high-energy tissues like the nervous system, heart, liver, kidneys, and skeletal muscles.

• Nuclear DNA: The TMEM70 gene is the most commonly mutated nuclear gene; it helps assemble and stabilize complex V.
• Mitochondrial DNA (mtDNA): Mutations in mtDNA can be present in all (homoplasmy) or some (heteroplasmy) of the mitochondria, with higher percentages of mutated mtDNA typically leading to more severe disease.

Inheritance

• Autosomal Recessive: When caused by nuclear DNA mutations, both copies of the gene in each cell must have mutations. Parents are typically unaffected carriers.
• Maternal Inheritance: When caused by mtDNA mutations, the condition is passed only from mothers to their children, as egg cells contribute mitochondria to the developing embryo.