| Functional step | Complementation group / phenotype label | Gene(s) | Typical biochemical hallmarks | Notes / ontology suggestions | Evidence |
|---|---|---|---|---|---|
| Blood transport / cellular uptake | Transport defects (not classic complementation label in gathered evidence) | **TCN2**, **CD320/TCblR** | Can present with cobalamin deficiency biochemistry; newborn screening reports may flag methylmalonic aciduria and/or homocysteine abnormalities depending on downstream impact | Transport proteins specifically noted as causes of inborn errors of cobalamin transport; useful differential when biochemical pattern suggests acquired-like or transport-level B12 dysfunction. **CHEBI:** cobalamin **CHEBI:30411** | (pqac-00000001, pqac-00000007) |
| Lysosomal export / intracellular trafficking | **cblF** | **LMBRD1** | Typically part of **combined MMA + homocystinuria** spectrum in intracellular cobalamin disorders | LMBD1 is required for lysosomal handling/export and mediates ABCD4 lysosomal translocation; grouped among combined MMA/homocystinuria disorders. **GO:** cobalamin metabolic process **GO:0009235** | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Lysosomal export / intracellular trafficking | ABCD4-related intracellular transport defect | **ABCD4** | Combined or cobalamin-defect pattern; interpreted with MMA and tHcy in NBS algorithms | ABCD4 identified as lysosomal cobalamin exporter/handling protein relevant to intracellular cobalamin deficiency; included in cobalamin-defect differential diagnosis. **GO:** cobalamin metabolic process **GO:0009235** | (pqac-00000001, pqac-00000019) |
| Intracellular processing before cofactor synthesis | **cblC** | **MMACHC** | **Combined**: **↑MMA + ↑tHcy**, often **↓Met** | Canonical combined methylmalonic acidemia and homocystinuria phenotype; MMACHC acts after uptake and before synthesis of methylcobalamin and adenosylcobalamin. **HPO:** Elevated urine methylmalonate **HP:0012120**; Homocystinuria **HP:0003235**; **GO:** cobalamin metabolic process **GO:0009235**; methionine biosynthetic process **GO:0009086** | (pqac-00000002, pqac-00000004, pqac-00000006) |
| Intracellular sorting of cobalamin toward cytosolic/mitochondrial pathways | **cblD-MMA** | **MMADHC** | **Isolated MMA**: **↑MMA** without homocysteinemia | MMADHC-related cblD may be phenotype-specific; cblD-MMA is one recognized presentation. | (pqac-00000002, pqac-00000004, pqac-00000005) |
| Intracellular sorting of cobalamin toward cytosolic/mitochondrial pathways | **cblD-HC** | **MMADHC** | **Isolated remethylation defect**: **↑tHcy + ↓Met**, without MMA elevation | cblD-HC is the homocystinuria-predominant MMADHC phenotype. **HPO:** Homocystinuria **HP:0003235**; Low methionine not explicitly mapped in gathered evidence. | (pqac-00000005) |
| Intracellular sorting of cobalamin toward cytosolic/mitochondrial pathways | **cblD-MMA/HC** | **MMADHC** | **Combined**: **↑MMA + ↑tHcy**, often **↓Met** | MMADHC can cause isolated MMA, isolated homocystinuria, or combined disease depending on variant/location effect. | (pqac-00000002, pqac-00000004, pqac-00000005) |
| Remethylation cofactor regeneration / methionine synthase reductase pathway | **cblE** | **MTRR** | **↑tHcy + homocystinuria + ↓Met**; not an MMA-predominant disorder | cblE is a methylcobalamin/remethylation defect distinct from cblG; grouped with disorders causing homocysteinemia and hypomethioninemia. **GO:** methionine biosynthetic process **GO:0009086** | (pqac-00000005) |
| Downstream cytosolic remethylation enzyme | **cblG** | **MTR** | **↑tHcy + homocystinuria + ↓Met**; generally without isolated MMA predominance | cblG corresponds to methionine synthase deficiency; directly affects vitamin B12-dependent methyl transfer to remethylate homocysteine to methionine. | (pqac-00000002, pqac-00000005, pqac-00000006) |
| Mitochondrial adenosylcobalamin pathway / mutase chaperone | **cblA** | **MMAA** | **Isolated MMA**: **↑MMA** without homocysteinemia | cblA affects mitochondrial AdoCbl-dependent mutase pathway; part of isolated methylmalonic aciduria group. | (pqac-00000000, pqac-00000005) |
| Mitochondrial adenosylcobalamin pathway / adenosyltransferase | **cblB** | **MMAB** | **Isolated MMA**: **↑MMA** without homocysteinemia | cblB affects cofactor synthesis for methylmalonyl-CoA mutase and is grouped with isolated MMA disorders. | (pqac-00000000, pqac-00000005) |
| Downstream mitochondrial enzyme | mut / isolated MMA | **MMUT** | **Isolated MMA**: **↑MMA** without homocysteinemia | Included because differential diagnosis of cobalamin-pathway disease often separates mutase defects from intracellular cobalamin defects; mut− and mut0 subgroups noted. | (pqac-00000003, pqac-00000005) |
| Disease-level biomarker ontology row | Applies across combined cobalamin disorders | — | **↑MMA**, **↑tHcy**, and often **↓Met** are the key hallmarks that distinguish combined intracellular cobalamin defects from isolated MMA or isolated remethylation defects | Suggested ontology set for knowledge-base annotation: **CHEBI:30411** (cobalamin); **HP:0012120** (Elevated urine methylmalonate); **HP:0003235** (Homocystinuria); **GO:0009235** (cobalamin metabolic process); **GO:0009086** (methionine biosynthetic process). | (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000006) |


*Table: This table summarizes the main inborn errors of cobalamin metabolism and transport relevant to methylmalonic acidemia and homocystinuria, organized by functional step, gene, and characteristic biochemical pattern. It is useful for distinguishing combined intracellular cobalamin defects from isolated MMA and isolated remethylation disorders.*