combined oxidative phosphorylation defect type 8

Combined oxidative phosphorylation defect type 8 is a mitochondrial disorder that impairs the production of essential energy in cardiac, skeletal muscle and brain cells. This condition is caused by pathogenic variants in the AARS2 gene, which disrupt mitochondrial protein synthesis and lead to deficiencies in respiratory chain complexes I, III, and IV. Affected individuals typically present in infancy with severe cardiac and neurological involvement, including hypertrophic cardiomyopathy and pulmonary hypoplasia. Although it is extremely rare, affecting fewer than 1 in a million people, modern supportive care continues to evolve and improve outcomes.

Individuals with combined oxidative phosphorylation defect type 8 present with a distinct clinical picture involving multiple organ systems. Characteristic findings include a marked decrease in the activity of mitochondrial complexes I and IV, pulmonary hypoplasia, hypertrophic cardiomyopathy, EEG abnormalities, reduced left ventricular ejection fraction, and failure to thrive, all of which are invariably observed. In addition, many patients may experience congestive heart failure, generalized muscle weakness, motor delay, feeding difficulties, and biochemical abnormalities such as metabolic and lactic acidosis. Not all individuals experience all features, and severity varies considerably.

The underlying cause of combined oxidative phosphorylation defect type 8 is a mutation in the AARS2 gene. This gene encodes a mitochondrial enzyme that is essential for protein synthesis within the mitochondria, and its disruption leads to impaired formation of respiratory chain complexes necessary for energy production. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual inherits one mutated copy of AARS2 from each parent. This disorder is more common when parents share a common ancestor, since both are more likely to carry the same rare genetic variant. Genetic counseling is recommended for families to understand inheritance risks and options for family planning.

Currently, management of combined oxidative phosphorylation defect type 8 focuses on supportive care and symptomatic treatment rather than curative therapy. Without any specific foundational or targeted therapies available, treatment is tailored to the individual and typically involves a multidisciplinary team to address the various systems affected. Regular surveillance is an essential part of long-term care, with ongoing monitoring of cardiac function, neurological development, and metabolic status to detect emerging complications early. Patients should discuss treatment options with their healthcare team, and genetic counseling is recommended for affected families to assist with informed decision-making.

The long-term outlook for individuals with combined oxidative phosphorylation defect type 8 is highly variable and depends on the severity of multisystem involvement, such as cardiac, muscular, and neurological features. With current standards of care and regular surveillance, some individuals may experience periods of stabilization despite the challenges posed by severe hypertrophic cardiomyopathy, pulmonary hypoplasia, and metabolic disturbances. Outcomes described in medical literature continue to evolve as standards of care improve, and access to specialized care can influence long-term quality of life. Families are encouraged to connect with genetic counselors, specialist teams, and patient support networks to discuss management strategies and future planning.