The molecular basis of an enzymopathy is in the mutation(s) in the respective gene. Most enzymopathies are autosomal recessive disorders. Therefore, the patient has a mutation in each of the 2 allelic genes encoding the respective enzyme: the mutation may be the same in both alleles (homozygosity), or there may be 2 different mutations (compound heterozygosity or biallelic mutations). In most cases the mutation causes instability of the protein: since mature red blood cells cannot make proteins, the enzyme activity with which a reticulocyte is endowed will decay as the red blood cell ages in circulation.

Since we are dealing with ubiquitously expressed genes, the presence of such manifestations is not surprising. Whether they are present or not, and to what extent, depends mainly on 3 factors: (1) nonerythroid cells may express alternative forms of a particular enzyme, from the same gene or from other genes; (2) if the main mechanism of deficiency is enzyme instability, cells other than erythrocytes may compensate by increased biosynthesis; (3) if the main mechanism of deficiency is a qualitative change (eg, in the active site), all cells expressing the gene will be affected. The last 2 factors may explain why extraerythrocytic manifestations may vary even within the same enzymopathy.

G6PD deficiency is widespread in malaria-endemic areas, consequent on malaria having been the selective agent for this polymorphism.⁴²  In areas endemic for Plasmodium vivax malaria, a test for G6PD deficiency should be carried out before giving primaquine or tafenoquine, the only drugs that prevent relapse. This has been a strong stimulus for the development of quantitative point-of-care tests for G6PD deficiency.⁴³