combined oxidative phosphorylation defect type 26

Combined oxidative phosphorylation defect type 26 is a multisystem disorder caused by pathogenic variants in the TRMT5 gene that impair mitochondrial function. Individuals with this condition typically exhibit a range of features including muscle weakness, lactic acidosis, and liver cirrhosis. It is inherited in an autosomal recessive pattern, which means that a person must inherit two copies of the mutated gene to be affected. This condition is very rare, affecting fewer than 1 in 1,000,000 people, and early signs such as exercise intolerance and spasticity may develop in infancy or early childhood.

The clinical presentation of combined oxidative phosphorylation defect type 26 involves several characteristic features. Nearly all affected individuals show increased circulating lactate, lactic acidosis, cirrhosis, spasticity, exertional dyspnea, muscle weakness, and exercise intolerance. Neurological involvement is also noted, with many individuals experiencing poor speech and global developmental delay, along with brain atrophy seen in some cases. Other variable manifestations include renal tubular dysfunction, hypertonia, difficulty standing, malabsorption, feeding difficulties, narrow mouth, blue sclerae, and 2-3 toe syndactyly. Not all individuals experience all features, and severity varies considerably.

Combined oxidative phosphorylation defect type 26 is caused by pathogenic variants in the TRMT5 gene, which is critical for proper mitochondrial function. The condition follows an autosomal recessive inheritance pattern, meaning that affected individuals inherit a mutated copy of TRMT5 from each parent. It is more common when parents share a common ancestor, as this increases the likelihood that both carry the same rare genetic variant. Genetic counseling is recommended for families to understand recurrence risks and explore family planning options.

Currently, management focuses on supportive care and symptom control, as there are no treatments specifically approved for combined oxidative phosphorylation defect type 26. Care is typically provided by a multidisciplinary team that addresses respiratory difficulties, muscle weakness, feeding challenges, and liver dysfunction. Regular surveillance is an essential part of long-term care and helps to identify emerging complications at an early stage. Patients should discuss treatment options with their healthcare team and consider genetic counseling to help guide care decisions.

The outlook for individuals with combined oxidative phosphorylation defect type 26 is highly variable, and the severity and range of symptoms differ widely between affected individuals. With current standards of care, many patients are able to manage their symptoms, although complications involving multiple organ systems may influence long-term health. Outcomes described in medical literature continue to evolve as standards of care improve. Families are encouraged to connect with specialists familiar with this condition and to seek genetic counseling for further guidance and support.