methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency is a rare metabolic disorder characterized by a persistent elevation of methylmalonic acid in plasma, urine, and cerebrospinal fluid. It arises from pathogenic variants in the MCEE gene that disrupt normal metabolic processing. The condition is typically recognized in infancy, with affected individuals presenting with acute metabolic episodes and nonspecific neurological symptoms, though some may be asymptomatic. It is very rare, affecting fewer than 1 in 1,000,000 people.

Patients with this condition commonly exhibit a consistent set of clinical features, including ketonuria, dehydration, spasticity, failure to thrive, methylmalonic aciduria, gastroesophageal reflux, motor delay, an elevated concentration of circulating palmitoleylcarnitine, and metabolic acidosis. These findings may precipitate episodes marked by vomiting, dehydration, confusion, and even hallucinations during periods of acute metabolic decompensation. That not all individuals experience every feature, and severity can vary considerably. Early signs often lead to targeted metabolic evaluations while additional symptoms can evolve over time.

This condition is caused by pathogenic variants in the MCEE gene, which plays a critical role in the metabolism of methylmalonyl-CoA. It is inherited in an autosomal recessive manner, meaning that an affected individual has received one altered copy of the gene from each parent. This condition is more common when parents share a common ancestor, as there is an increased likelihood that both carry the same rare variant. Genetic counseling is recommended to help families understand recurrence risks and to discuss options for future family planning.

Currently, management focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency. Treatment is tailored to the individual and generally involves a multidisciplinary team to address issues such as metabolic acidosis, dehydration, and nutritional needs. Regular monitoring and proactive management are essential to mitigate metabolic crises. Patients should discuss all treatment options with their healthcare team and consider genetic counseling for further guidance.

Outcomes vary widely depending on the severity of symptoms, the age at diagnosis, and access to specialized care. With current standards of care, many individuals experience stabilization following episodes of metabolic decompensation, although the overall clinical course can differ markedly between individuals. Outcomes described in medical literature continue to evolve as standards of care improve, and it is important to recognize that severity and symptoms can vary considerably. Connecting with a genetic counselor and support groups can offer valuable guidance and resources for affected families.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.