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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.