combined oxidative phosphorylation deficiency 59

Combined oxidative phosphorylation deficiency 59 is a multisystem condition that affects energy production in cells, particularly impacting both the central nervous system and other organs. Variants in the MRPL39 gene, which encodes a mitochondrial ribosomal protein involved in protein synthesis, are responsible for this condition. It is inherited in an autosomal recessive manner, meaning that both parents must carry a variant even though they may show no symptoms themselves. Prevalence estimates are not well established, and affected individuals can present with a broad range of clinical features.

The clinical presentation of combined oxidative phosphorylation deficiency 59 involves a range of neurological and systemic features. Characteristic findings include consistently elevated brain lactate levels by MRS and decreased activities of mitochondrial complex IV and complex I, which point to an underlying impairment in cellular energy production. Affected children often exhibit neurodevelopmental challenges such as attention deficit hyperactivity disorder, global developmental delay, and cognitive or behavioral difficulties. After a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills, and many also face other challenges including feeding difficulties, vomiting, and migraine. In addition, variable features affecting other organ systems such as hypertrophic cardiomyopathy, congestive heart failure, retinal degeneration, and cholelithiasis may be observed. Not all individuals experience all features, and severity varies considerably.

Combined oxidative phosphorylation deficiency 59 is caused by pathogenic variants in the MRPL39 gene. MRPL39 plays a critical role in mitochondrial protein synthesis, and dysfunction in this protein disrupts the normal energy production process in cells. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual has received one altered copy of the gene from each carrier parent. Families are encouraged to seek genetic counseling to understand the implications of this inheritance pattern for future family planning.

Currently, management focuses on supportive care and symptom management, with treatment tailored to the needs of each individual. Because there are no FDA-approved treatments specifically linked to this condition, care is provided by a multidisciplinary team experienced in managing multisystem disorders. Regular surveillance is an essential part of long-term care, helping to identify potential complications early, whether they involve cardiac, neurological, or other organ systems. Genetic counseling is recommended to help families understand the condition and to discuss potential treatment strategies with their healthcare team.

The long-term outlook for combined oxidative phosphorylation deficiency 59 is highly variable, with outcomes depending on the severity of symptoms, age at diagnosis, and access to specialized care. With current standards of care, many individuals experience an initial phase of developmental regression followed by a period of relative stabilization, although some may face later complications. Outcomes described in medical literature continue to evolve as standards of care improve, and families are encouraged to connect with specialists experienced in managing multisystem and neurodevelopmental conditions. That severity and symptoms vary widely between individuals, and genetic counseling can offer additional guidance for family planning.