Additional Notes

Methylmalonic acidemia and homocystinuria (MMA_HC) is a group of biochemically related but genetically heterogenous disorders characterized by increased levels of organic acids and/or homocysteine in the blood. The clinical course of MMA_HC is metabolic decompensation that manifests variably with regards to phenotype and age of onset depending on which step in the metabolic pathway is affected, and the severity of the deficit that ensues. The phenotypic features include intrauterine growth restriction, poor feeding, microcephaly, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, hypotonia, seizures, neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. The disorder is often detected via newborn screening based on elevated C3 propionylcarnitine or decreased methionine

This group of disorders includes:

1. Combined methylmalonic acidemia and homocystinuria due to disorders of intracellular cobalamin metabolism (AdoCbl and MeCbl deficiency; cblC and cblD-combined type),
2. Isolated methylmalonic acidemia due to complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase, and
3. Isolated homocystinuria due to methionine synthase reductase deficiency (cblE), methionine synthase deficiency (cblG), and cblD-homocystinuria