MPO deficiency is the most common inherited disorder of phagocytes but is almost always asymptomatic.18 MPO is present in azurophilic granules of neutrophils and monocytes and catalyzes the production of a potent antimicrobial agent, HOCl, from chloride and hydrogen peroxide (see Fig. 1., reaction 4). HOCl in turn reacts with a variety of primary and secondary amines to form chloramines, some of which can be toxic. Moreover, HOCl is capable of activating latent metalloproteinases (e.g., collagenase) and inactivating antiproteinases.
Fig1. REACTIONS OF RESPIRATORY BURST PATHWAY. GSH, Glutathione; GSSG, oxidized glutathione; HOCl, hypochlorous acid; NADPH, nicotinamide adenine dinucleotide phosphate.
Complete MPO deficiency is seen in approximately 1 in 4000 individuals, and partial deficiency is even more common (1 in 2000 persons). The key features of MPO deficiency are summarized in Table 1. The disorder is inherited in an AR manner. In the few cases reported, several different mutations have been identified, which generally appear to affect the posttranslational processing of a precursor polypeptide for MPO. Acquired forms of MPO deficiency are also seen. The gene that encodes for MPO is located on chromosome 17 at q22–q23 near the breakpoint for the 15-to-17 translocation of promyelocytic leukemia. Subpopulations of MPO-deficient cells can be seen not only in the M3 (promyelocytic) form of acute myeloid leukemia but also in the M2 and M4 forms. MPO-deficient cells are also seen in approximately 25% of patients with chronic myeloid leukemia and myelodysplastic syndromes.
Table1. Summary of Myeloperoxidase Deficiency
One of the most curious features of MPO deficiency is the remarkable lack of clinical symptoms in affected persons, given the prediction that severe MPO deficiency would cripple important antimicrobial reactions catalyzed by hypochlorous acid (HOCl). In vitro an impressive defect in killing Candida albicans and hyphal forms of Aspergillus fumigatus is observed. Bacterial killing in vitro is also abnormal in being somewhat slower than normal, but eventually it is complete. MPO-deficient mice also exhibit abnormalities in host defense against Candida and Klebsiella spp. However, excessive or unusual infections in MPO-deficient patients are uncommon, except for rare individuals who also have diabetes mellitus.18 In these individuals, disseminated fungal infections (usually candidiasis) are seen.
The discrepancy between the in vitro and in vivo manifestations of MPO deficiency in most patients can be explained in several ways. First, the respiratory burst in MPO-deficient neutrophils is substantially augmented, presumably from the absence of HOCl-mediated toxic effects on the NADPH oxidase. Second, other products of the respiratory burst, together with the oxygen-independent antibacterial proteins, appear to have sufficient potency to compensate for the loss of MPO-dependent reactions. Finally, residual amounts of MPO coupled with the normal levels of eosinophil peroxidase may provide at least some degree of peroxidative activity at the sites of infection.
Treatment is usually not required for MPO deficiency except in those individuals with fungal infections. In these patients, aggressive use of antifungal antibiotics is indicated. The prognosis is excellent in the majority of patients with MPO deficiency.
