Alternative titles; symbols
SNOMEDCT: 129644003, 234433009; ORPHA: 2587;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q22 | Myeloperoxidase deficiency | 254600 | Autosomal recessive | 3 | MPO | 606989 |
A number sign (#) is used with this entry because of evidence that myeloperoxidase deficiency (MPOD) is caused by homozygous or compound heterozygous mutation in the myeloperoxidase gene (MPO; 606989) on chromosome 17q23.
Lehrer and Cline (1969) found no detectable activity of the lysosomal enzyme myeloperoxidase in neutrophils and monocytes of a patient with disseminated candidiasis. Other granule-associated enzymes were normal. Leukocytes from one of the proband's sisters also showed no MPO activity. Leukocytes from the proband's 4 sons showed about one-third normal levels. The proband and his relatives had not experienced frequent or unusual bacterial infections. The incidence of candidiasis may be increased in persons with myeloperoxidase deficiency, and the ability of the leukocytes of affected persons to resist Candida in vitro may be reduced.
Salmon et al. (1970) demonstrated immunologically the absence of MPO protein, or at least the absence of cross-reacting material, in homozygotes. Eosinophil peroxidase (EPX; 131399), which is chemically distinct from MPO, was normal. Kitahara et al. (1981) found partial deficiency in heterozygotes; only 2 of these had serious infections (recurrent streptococcal cellulitis and aseptic meningitis).
Variable expression in families makes it difficult to interpret the genetics of the disorder (Cech et al., 1979). In the 17 cases reported by Cramer et al. (1982), autosomal recessive inheritance was proved in 7 cases and was considered likely in at least 8 others because of the presence of 2 or 3 deficient persons in the family.
Eosinophil peroxidase contributes to the peroxidase activity of blood leukocytes. Because EPX expression is normal in MPO-deficient subjects, eosinophil contamination can significantly contribute to peroxidase activity in leukocytes from family members of an MPO-deficient subject and thereby undermine correct interpretation of the inheritance pattern. To avoid this potential problem, Nauseef et al. (1998) used cytochemical, immunochemical, and genetic techniques to assess the inheritance pattern of MPO deficiency in 16 individuals from 5 unrelated kindreds. Each kindred had an index case with MPO deficiency caused by the R569W missense mutation (606989.0001). The analysis demonstrated that MPO deficiency was not inherited as a simple autosomal recessive trait. Most subjects were compound heterozygotes with respect to the R569W mutation and demonstrated a spectrum of phenotypes. The data demonstrated the broad phenotypic impact of compound heterozygosity on the expression and function of a multimeric protein such as MPO.
The defective cellular immunity in this condition was restored to normal by transfusion of HLA identical leukocytes from a healthy brother (Valdimarsson et al., 1972). Immune responses remained normal after 17 months. Persistence of functionally competent grafted cells was considered the likely mechanism.
Although previously considered to be rare, MPO deficiency was found by Parry et al. (1981), using automated flow cytometry, to have a frequency of 1 in several thousand.
Cramer et al. (1982) found reports of 17 cases of apparently primary MPO deficiency and reported a high frequency in the Friuli-Venezia Giulia region of northeastern Italy. A screening method identified 45 suspected subjects.
Nauseef (1988) reviewed the studies on the frequency of myeloperoxidase deficiency in apparently healthy populations, pointing out that this information was an unexpected dividend of the technology for performing differential counts automatically. The prevalence in the U.S. is on the order of 1 in 2,000.
Marchetti et al. (2004) performed a population screening of approximately 40,000 Italians, and after 4 months identified 15 individuals with partial or complete MPOD, for a prevalence of 1/2,500 individuals, consistent with previous reports. None of the patients exhibited any MPOD-associated symptoms. Genetic analysis revealed homozygosity, compound heterozygosity, and heterozygosity for mutations in the MPO gene (see, e.g., 606989.0001 and 606989.0003-606989.0007); patients who were heterozygous showed partial MPOD whereas patients with biallelic mutations had complete MPOD.
By immunoautoradiography and other methods, Nauseef et al. (1983) found that partial MPO deficiency is characterized by the presence of electrophoretically and immunologically normal MPO in amounts about half that seen in PMNs of normal subjects. Completely MPO-deficient PMNs lacked MPO peptides; no CRM was found in the 5 unrelated subjects studied. Purified MPO is composed of 2 peptide subunits of 60,000 and 12,000 Da. Nauseef et al. (1983) concluded that since deficiency is associated with the absence of more than 1 peptide, the genetic defect may involve (a) failure to synthesize a single precursor peptide; (b) defective regulation of the synthesis of 2 separate peptides; or (c) an aberration in postsynthetic processing or packaging into azurophilic granules.
Stendahl et al. (1984) pointed out that patients lacking myeloperoxidase usually do not show any increased susceptibility to infection or altered inflammatory response. In a patient with generalized pustular psoriasis and complete MPO deficiency, they found that MPO-deficient neutrophils showed enhanced phagocytosis and exaggerated superoxide production on stimulation in vitro. They suggested that apart from being a potent antimicrobial system, the oxidizing activity of the MPO-H2O2-halide system may modulate the inflammatory response which otherwise could elicit inflammatory reactions and tissue injury.
Using a cDNA probe for MPO in studies of 3 completely and 2 partially MPO-deficient persons, Nauseef (1989) found no evidence of major deletion or rearrangement of the MPO gene. Myeloid precursors in 1 patient contained normal amounts of an mRNA that was the same size as that for MPO in normal persons. Two different endonuclease digestion patterns were found in MPO-deficient subjects who were biochemically and phenotypically identical.
In 6 of 7 patients with myeloperoxidase deficiency, Nauseef et al. (1994) identified an arg569-to-trp mutation in the myeloperoxidase gene (R569W; 606989.0001). The mutation was found in homozygosity in 1 patient and in heterozygosity in the others.
In 4 affected individuals over 3 generations of a family with myeloperoxidase deficiency, DeLeo et al. (1998) identified heterozygosity for a missense mutation in the MPO gene (Y173C; 606989.0002).
Romano et al. (1997) studied a family with MPOD in which the father was compound heterozygous for a missense mutation (M251T; 606989.0003) and a 14-bp deletion (606989.0004) in the MPO gene. His affected 5-year-old daughter was heterozygous for the 14-bp deletion; his wife, who also had reduced myeloperoxidase activity, did not carry either mutation. The authors suggested that the defect in the wife might be a regulatory mutation.
In a Japanese patient with MPOD, Ohashi et al. (2004) identified homozygosity for a missense mutation in the MPO gene (G501S; 606989.0009). In another Japanese patient with MPOD, Persad et al. (2006) identified a nearby substitution in MPO (R499C; 606989.0010). Both patients were asymptomatic and identified by automated flow hematocytochemistry screening.
Cech, P., Stalder, H. S., Widmann, J. J., Rohrer, A., Miescher, P. A. Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess. Am. J. Med. 66: 149-153, 1979. [PubMed: 217268] [Full Text: https://doi.org/10.1016/0002-9343(79)90507-2]
Cramer, R., Soranzo, M. R., Dri, P., Rottini, G. D., Bramezza, M., Cirielli, S., Patriarca, P. Incidence of myeloperoxidase deficiency in an area of northern Italy: histochemical, biochemical and functional studies. Brit. J. Haemat. 51: 81-87, 1982. [PubMed: 6280744] [Full Text: https://doi.org/10.1111/j.1365-2141.1982.tb07292.x]
DeLeo, F. R., Goedken, M., McCormick, S. J., Nauseef, W. M. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J. Clin. Invest. 101: 2900-2909, 1998. [PubMed: 9637725] [Full Text: https://doi.org/10.1172/JCI2649]
Kitahara, M., Eyre, H. J., Simonian, Y., Atkin, C. L., Hasstedt, S. J. Hereditary myeloperoxidase deficiency. Blood 57: 888-893, 1981. [PubMed: 6260268]
Klebanoff, S. J., Pincus, S. H. Hydrogen peroxide utilization in myeloperoxidase-deficient leukocytes: a possible microbicidal control mechanism. J. Clin. Invest. 50: 2226-2229, 1971. [PubMed: 5116211] [Full Text: https://doi.org/10.1172/JCI106718]
Lehrer, R. I., Cline, M. J. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J. Clin. Invest. 48: 1478-1488, 1969. [PubMed: 5796360] [Full Text: https://doi.org/10.1172/JCI106114]
Marchetti, C., Patriarca, P., Solero, G. P., Baralle, F. E., Romano, M. Genetic characterization of myeloperoxidase deficiency in Italy. Hum. Mutat. 23: 496-505, 2004. [PubMed: 15108282] [Full Text: https://doi.org/10.1002/humu.20027]
Nauseef, W. M., Brigham, S., Cogley, M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J. Biol. Chem. 269: 1212-1216, 1994. [PubMed: 7904599]
Nauseef, W. M., Cogley, M., Bock, S., Petrides, P. E. Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation. J. Leukoc. Biol. 63: 264-269, 1998. [PubMed: 9468285] [Full Text: https://doi.org/10.1002/jlb.63.2.264]
Nauseef, W. M., Root, R. K., Malech, H. L. Biochemical and immunologic analysis of hereditary myeloperoxidase deficiency. J. Clin. Invest. 71: 1297-1307, 1983. [PubMed: 6189859] [Full Text: https://doi.org/10.1172/jci110880]
Nauseef, W. M. Myeloperoxidase deficiency. Hemat. Oncol. Clin. North Am. 2: 135-158, 1988. [PubMed: 2831185]
Nauseef, W. M. Aberrant restriction endonuclease digests of DNA from subjects with hereditary myeloperoxidase deficiency. Blood 73: 290-295, 1989. [PubMed: 2462938]
Ohashi, Y. Y., Kameoka, Y., Persad, A. S., Koi, F., Yamagoe, S., Hashimoto, K., Suzuki, K. Novel missense mutation found in a Japanese patient with myeloperoxidase deficiency. Gene 327: 195-200, 2004. [PubMed: 14980716] [Full Text: https://doi.org/10.1016/j.gene.2003.11.023]
Parry, M. F., Root, R. K., Metcalf, J. A., Delaney, K. K., Kaplow, L. S., Richar, W. J. Myeloperoxidase deficiency: prevalence and clinical significance. Ann. Intern. Med. 95: 293-301, 1981. [PubMed: 6267975] [Full Text: https://doi.org/10.7326/0003-4819-95-3-293]
Persad, A. S., Kameoka, Y., Kanda, S., Niho, Y., Suzuki, K. Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency. Gene Expr. 13: 67-71, 2006. [PubMed: 17017121] [Full Text: https://doi.org/10.3727/000000006783991863]
Romano, M., Dri, P., Da Dalt, L., Patriarca, P., Baralle, F. E. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood 90: 4126-4134, 1997. Note: Erratum: Blood 121: 5104 only, 2013. [PubMed: 9354683]
Ross, D. W., Kaplow, L. S. Myeloperoxidase deficiency: increased sensitivity for immunocytochemical compared to cytochemical detection of enzyme. Arch. Path. Lab. Med. 109: 1005-1006, 1985. [PubMed: 2996459]
Salmon, S. E., Cline, M. J., Schultz, J., Lehrer, R. I. Myeloperoxidase deficiency: immunologic study of a genetic leukocyte defect. New Eng. J. Med. 282: 250-253, 1970. [PubMed: 4983030] [Full Text: https://doi.org/10.1056/NEJM197001292820505]
Stendahl, O., Coble, B.-I., Dahlgren, C., Hed, J., Molin, L. Myeloperoxidase modulates the phagocytic activity of polymorphonuclear neutrophil leukocytes: studies with cells from a myeloperoxidase-deficient patient. J. Clin. Invest. 73: 366-373, 1984. [PubMed: 6321554] [Full Text: https://doi.org/10.1172/JCI111221]
Valdimarsson, H., Moss, P. D., Holt, P. J. L., Hobbs, J. R. Treatment of chronic mucocutaneous candidiasis with leukocytes from HL-A compatible sibling. Lancet 299: 469-472, 1972. Note: Originally Volume I. [PubMed: 4109818] [Full Text: https://doi.org/10.1016/s0140-6736(72)90123-7]