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Intracellular metabolism of cobalamin. The intracellular cobalamin metabolism and related pathways – including the complementation groups and corresponding genes – are shown.
Endocytosis of cobalamin bound to its blood carrier transcobalamin (TC) occurs through the transcobalamin receptor (TCblR). Inside the lysosome, cobalamin is released from transcobalamin and then transported into the cytoplasm where it undergoes enzyme-mediated reduction (Cbl III to Cbl II) and then mitochondrial adenosylation to form adenosylcobalamin (AdoCbl) or cytosolic methylation to form methylcobalamin. 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 AdoCbl and MeCbl deficiencies causing elevations in MMA and homocysteine (purple).

Testing algorithm to confirm the diagnosis of a disorder of intracellular cobalamin metabolism in a proband
Footnotes:
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.

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.

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 5'-deoxyadenosylcobalamin, an activated form of vitamin B₁₂. The pathway of cellular processing of cobalamin (reduction from Cbl⁺³ to Cbl⁺²) and subsequently 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) methylmalonyl-CoA mutase or isolated AdoCbl deficiency and associated increase in serum methylmalonic acid [sMMA] (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 methylmalonic acidemia occurs: epimerase deficiency (MCEE) and succinate-CoA ligase deficiency (SUCLA2/SUCLG1), combined malonic and methylmalonic acidemia (ACSF3, ZBTB11), and methylmalonyl-semialdehyde dehydrogenase deficiency (ALDH6A1). The light purple striped box indicates cblX deficiency (HCFC1), the only X-linked disorder in this pathway and rare transcription factors (ZNF143, THAP11) or neighboring genes (PRDX1) associated with cblC deficiency or epi-cblC. See Disorders of Intracellular Cobalamin Metabolism.
MMA = methylmalonic acid; Cbl = cobalamin; Cbl⁺³ = oxidized cobalamin, Cbl⁺² = reduced cobalamin; AdoCbl = 5'-deoxyadenosylcobalamin; MeCbl = methylcobalamin; TC = transcobalamin; TCblR = transcobalamin receptor.
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-MMA)
MCEE
Isolated methylmalonic acidemia caused by mutation of SUCLA2 and SUCLG1 is discussed in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria and SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria, respectively.