combined malonic and methylmalonic acidemia

Combined malonic and methylmalonic acidemia is an inborn error of metabolism that leads to the accumulation of malonic acid and methylmalonic acid in body fluids, with higher levels of methylmalonic acid. This condition is linked to pathogenic variants in the ACSF3 gene and is inherited in an autosomal recessive pattern. It can present in childhood with metabolic acidosis, developmental delay, dystonia, and failure to thrive or later in life with seizures, memory loss, and cognitive decline. Prevalence estimates are not well established, and the condition displays marked variability in clinical presentation.

Individuals affected by combined malonic and methylmalonic acidemia often exhibit a range of metabolic and neurological features. In early life, children may present with metabolic acidosis, developmental delay, and dystonia along with failure to thrive, which can prompt further evaluation for metabolic disorders. As some patients age, seizures including generalized clonic and focal impaired awareness seizures may develop, and there can be issues with memory impairment, atypical behavior, and delayed speech and language development. Not all individuals experience every feature, and severity varies considerably, reflecting the diverse nature of the condition.

The underlying cause of combined malonic and methylmalonic acidemia is due to pathogenic variants in the ACSF3 gene, which encodes a protein involved in mitochondrial metabolism. Disruption of this protein can impair normal fatty acid processing and energy production. The condition is inherited in an autosomal recessive manner, meaning that both parents carry one altered copy of the gene; therefore, each child has a 25% chance of being affected. Genetic counseling is recommended to help families understand the inheritance and implications for future family planning.

Currently, management focuses on supportive care and symptom management, as there are no treatments specifically approved for combined malonic and methylmalonic acidemia. Treatment is tailored to the individual and typically involves a multidisciplinary team that coordinates regular surveillance to detect potential complications early. Patients should discuss their options with healthcare professionals, and genetic counseling is recommended to provide further guidance on long-term care and family planning.

The clinical course of combined malonic and methylmalonic acidemia is highly variable, with outcomes ranging from significant developmental challenges early in life to later onset of seizures and cognitive difficulties. Many individuals experience an initial presentation followed by a period where symptoms may stabilize, although some may later encounter further neurological issues. Outcomes described in medical literature continue to evolve as standards of care improve, and families often find it helpful to connect with specialists experienced in metabolic and developmental disorders to support ongoing management.