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Metabolic pathway. Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol. Deficiency of PCC results in propionic acidemia (PA) and accumulation of 3-OH propionate, methylcitrate, and glycine, among other metabolites. PCC, located inside the mitochondrion, is a heterododecamer (α6β6) comprising six α-subunits (orange) and six β-subunits (purple). Biotin (blue), bicarbonate, and ATP have binding sites in the α-subunit. The β-subunits form a central core.

Major pathway of the conversion of propionyl-CoA into succinyl-CoA. The biotin-dependent enzyme propionyl-CoA carboxylase converts propionyl-CoA into D-methylmalonyl-CoA, which is then racemized into L-methylmalonyl-CoA and isomerized into succinyl-CoA, a Krebs cycle intermediate. The L-methylmalonyl-CoA mutase reaction requires adenosylcobalamin, an activated form of vitamin B₁₂. The pathway of cellular processing of cobalamin (OH-Cbl) in the formation of adenosyl- (AdoCbl) and methylcobalamin (MeCbl) is depicted. Adenosyl-cobalamin is the cofactor of the methylmalonyl-CoA mutase reaction; methylcobalamin is the cofactor of the methionine synthase reaction.
The color-coded boxes around the cobalamin-processing enzymes indicate their role in causing: (1) isolated AdoCbl deficiency and associated increase in MMA (blue); (2) isolated MeCbl deficiency and hyperhomocysteinemia (green); (3) both cofactor deficiencies causing elevations in MMA and homocysteine (purple). Note: The light blue striped boxes indicate the enzymes (and the genes encoding them) that are deficient in different disorders in which isolated methylmalonic acidemia occurs: epimerase deficiency (MCEE) and succinate-CoA ligase deficiency (SUCLA2/SUCLG1), combined malonic and methylmalonic acidemia (ACSF3), and methylmalonyl-semialdehyde dehydrogenase deficiency (ALDH6A1). The light purple striped box indicates cblX deficiency (HCFC1), the only X-linked disorder in this pathway.
The genes (and the enzymatic subtypes) associated with isolated methylmalonic acidemia included in this GeneReview are:
MMUT (mut⁰, mut^–)
MMAA (cblA)
MMAB (cblB)
MMADHC (cblD variant 2)
MCEE
Isolated methylmalonic acidemia caused by mutation of SUCLA2 and SUCLG1 is discussed in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Mild Methylmalonic Aciduria and SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria, respectively.

Immediate management and testing algorithm to be pursued simultaneously after the clinical or laboratory suspicion of PA

Testing algorithm to confirm the diagnosis of a disorder of intracellular cobalamin metabolism in a proband
1. While diagnostic testing is being performed, contact genetics/metabolic team and initiate treatment immediately.
2. The following results on NBS could be due to a cobalamin disorder: ↑C3, ↑C3/C2, ↓Met.
3. The following biochemical testing should be performed: plasma total homocysteine, serum methylmalonic acid, plasma amino acids, plasma acylcarnitine profile, serum vitamin B₁₂, urine organic acids. B₁₂ deficiency must be ruled out; in babies positive on newborn screening, maternal serum vitamin B₁₂ levels should be measured to rule out maternal B₁₂ deficiency. Note: Individuals with cblF and cblJ can have B₁₂ deficiency as part of their condition. In rare cases, metabolites can normalize with vitamin B₁₂ therapy; molecular genetic testing should be used for diagnosis.
4. Methylmalonic acidemia
5. Homocystinuria
6. Variants in PRDX1 can be seen in individuals with only one MMACHC pathogenic variant [Guéant et al 2018].
7. Multigene panel should include ABCD4, HCFC1, LMBRD1, MMADHC, THAP11, and ZNF143.