An algorithm of conditions to be considered in the differential diagnosis of elevated serum or urine methylmalonic acid detected either during the follow up of an increased propionylcarnitine (C3) on newborn screening or following a positive urine organic acid screen in a symptomatic individual. The algorithm includes disorders that can present after the newborn period.

AC = acylcarnitine profile; CBC = complete blood count; Cbl = cobalamin; MMA = methylmalonic acid; Mut = mutase; OA = organic acids; PA = propionic acid; TC-II = transcobalamin II

Footnotes:

1. Succinate ligase deficiency (caused by biallelic pathogenic variants in SUCLA2 or SUCLG1) presents with lactic acidosis; excess 2-methylcitric, 3-hydroxyproprionic acid, and 3-hydroxyisovaleric acid in the urine; and excess C3-propionylcarnitine and C4-dicarboxylic carnitine (C4DC) in the blood and/or urine.

2. CMAMMA presents with normal propionylcarnitine (C3) in the plasma acylcarnitine profile and elevated methylmalonic and malonic acid in the plasma or urine. CMAMMA can be caused by biallelic pathogenic variants in ACSF3 or ZBTB11.

3. Methylmalonyl-semialdehyde-dehydrogenase deficiency (MMASDH) and other ill-defined syndromes should be considered (see Differential Diagnosis).

4. B₁₂ deficiency syndromes include intrinsic factor deficiency, Imerslund-Gräsbeck syndrome, and others. cblF and cblJ can have low serum B₁₂ concentration due to abnormal gastrointestinal absorption.

5. In rare instances metabolites can be normal in affected individuals.