Clinical Guidance

The phenotypes of isolated methylmalonic acidemia (MMA) described below that are associated with the enzymatic subtypes mut0, mut–, cblA, cblB, and cblD-MMA share clinical presentations and a natural history characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress . Each such decompensation can be life threatening. reviews the phenotypes, causative genes, enzymatic subtypes, and clinical correlations that will be discussed further in this section.

Diagnostic Criteria

For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

Management Guidelines

Consensus guidelines on the diagnosis, management, and follow-up for individuals with methylmalonic acidemia were published in 2014 (full text) and revised in 2021 (full text). Several additional expert reviews and publications detail management in acute crises and chronic monitoring, treatment of hyperammonemia, dietary practices, and other aspects of clinical care: , , , , , , , , and , among others. When isolated MMA is suspected during the diagnostic evaluation due to elevated propionylcarnitine (C3) on a newborn blood spot, metabolic treatment should be initiated immediately, while the suspected diagnosis is being confirmed. Once confirmed, development and evaluation of treatment plans, training and education of affected individuals and their families, and careful monitoring of dietary treatment (to avoid malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Surveillance Guidelines

During the first year of life, infants may need to be evaluated as frequently as every week and continued at intervals determined by the frequency of metabolic crises/admissions, growth patterns, and dietary needs. Attention to transition periods (e.g., after the first two years, in adolescence) with other stressors in the family are necessary for modification of dietary prescription. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the following are recommended. See .

Table 13.