combined oxidative phosphorylation deficiency 47

Combined oxidative phosphorylation deficiency 47 (COXPD47) is a multisystem disorder that affects energy production and development. The condition is caused by pathogenic variants in the MRPS28 gene, which encodes a mitochondrial ribosomal protein essential for efficient oxidative phosphorylation. Affected individuals typically present with problems evident from birth, such as intrauterine growth retardation and failure to thrive, accompanied by a constellation of dysmorphic and metabolic features. Given the absence of precise prevalence data, this disorder is understood to be very uncommon, and ongoing research is needed to further delineate its frequency and natural history.

The clinical presentation of COXPD47 involves multiple organ systems and is characterized by a consistent pattern of features. Neurologically, affected individuals manifest generalized hypotonia and microcephaly, which can impact early development. Craniofacial dysmorphisms are prominent, including ptosis, posteriorly rotated ears, low-set ears, a long philtrum, and a round face, lending a recognizable appearance. Metabolic disturbances are evident with features such as failure to thrive, dehydration, hypoglycemia, metabolic acidosis, and increased circulating lactate levels, reflecting compromised mitochondrial energy production. Musculoskeletal signs include short palm, short neck, toe syndactyly, and cone-shaped epiphyses of the distal phalanges. Additional systemic features include sensorineural hearing impairment, dysphagia, cataract formation, hepatomegaly with elevated hepatic transaminase concentrations, and, in males, cryptorchidism. Not all individuals experience every feature, and severity varies considerably.

Combined oxidative phosphorylation deficiency 47 results from pathogenic variants in the MRPS28 gene, which is crucial for the function of mitochondrial ribosomes. Disruption of MRPS28 leads to impaired protein synthesis within mitochondria, thereby affecting the cell’s energy production. The condition is inherited in an autosomal recessive manner, meaning that an affected individual has inherited two altered copies of the MRPS28 gene—one from each parent. As a result, parents typically do not show overt symptoms but carry one copy of the altered gene. This inheritance pattern implies that there is a 25% chance of recurrence with each pregnancy. Genetic counseling is recommended for families to better understand the implications and to explore reproductive options.

At present, there are no FDA-approved treatments specifically targeting combined oxidative phosphorylation deficiency 47. Consequently, management focuses on supportive care and addressing the symptoms as they present. Treatment is tailored to each individual and typically involves a multidisciplinary team that may include metabolic specialists, hepatologists, neurologists, and genetic counselors. Key aspects of care include nutritional support to combat failure to thrive, metabolic management to address hypoglycemia and acidosis, and physical therapy to aid in muscle strength and motor skills. Regular surveillance is an essential part of long-term management, with ongoing monitoring to detect complications early and to adjust care strategies as needed. Families are encouraged to discuss treatment options with their healthcare team to ensure that the most appropriate and effective strategies are implemented.

Combined oxidative phosphorylation deficiency 47 is a lifelong condition with a highly variable clinical course. Although many affected individuals experience significant challenges early in life, the trajectory of the disease can range from periods of stabilization to later complications affecting multiple organ systems. Outcomes described in medical literature continue to evolve as standards of care improve, and modern supportive measures have the potential to positively impact quality of life. It is important to recognize that severity and symptoms vary widely between individuals, making it difficult to predict the exact course of the condition. Families often find it helpful to connect with specialists familiar with this condition, and genetic counseling can provide valuable guidance in navigating future healthcare decisions.