Myeloperoxidase Deficiency: Associated Conditions and Genetic Basis
Myeloperoxidase (MPO) deficiency is primarily caused by mutations in the MPO gene located on chromosome 17q, with most patients being compound heterozygotes carrying different mutations on each allele. 1, 2
Gene Involved
The MPO gene (chromosome 17q) is the sole gene responsible for hereditary myeloperoxidase deficiency. 1 Specific mutations identified include:
- R569W (c.1705C>T) - associated with increased neutrophil counts in population studies 1, 3
- Y173C
- M251T (c.752T>C) - located in the heme pocket region, strongly associated with increased neutrophil abundance (p < 10⁻¹⁰) 1, 2, 3
- 14-base deletion in exon 9 - leads to aberrant mRNA splicing 1, 2
- c.2031-2A>C - splice-site mutation associated with pustular skin disease and increased neutrophil counts (p = 5.1 × 10⁻⁶) 3
- A332V (c.995C>T) - population association with neutrophil counts (p < 10⁻¹⁰) 3
Most patients are compound heterozygotes rather than having identical mutations on both alleles. 1, 2
Associated Diseases and Conditions
Primary Clinical Manifestations
Infectious Complications:
- Candida infections - occur predominantly in MPO-deficient patients who also have diabetes mellitus, though affecting <5% of MPO-deficient individuals 4, 5
- Chronic bacterial and fungal infections, particularly in childhood 5
- Recurrent infections despite normal white blood cell counts 5
Pustular Skin Diseases:
- Generalized pustular psoriasis (GPP) - potentially life-threatening with cutaneous and systemic neutrophilia 3
- Acral pustular psoriasis 3
- Acute generalized exanthematous pustulosis (AGEP) 3
Malignancy:
- Evidence suggests individuals with total MPO deficiency show high incidence of malignant tumors, as MPO-deficient neutrophils exhibit depressed lytic action against malignant cells in vitro 4
Hematologic Associations
Acquired MPO Deficiency in Myeloproliferative Neoplasms:
- Myelofibrosis (MF) - 7.4% (6/81) of patients demonstrate MPO deficiency 6
- Strongly associated with homozygous CALR mutations in myelofibrosis patients 6
- Also causes eosinophilic peroxidase (EPX) deficiency when associated with homozygous CALR mutations 6
- Not observed in polycythemia vera or essential thrombocythemia 6
The mechanism involves CALR (calreticulin) serving as a chaperone for MPO glycoprotein in the endoplasmic reticulum; without functional CALR, immature MPO protein precursors are degraded in the proteasome. 6
Laboratory Manifestations
Pseudoneutropenia:
- Automated analyzers (ADVIA 2120i) may incorrectly count neutrophils as monocytes due to absent MPO staining 7
- Results in falsely elevated monocyte counts with low mean peroxidase index (MPXI <-20) 7
- Manual differential count reveals normal neutrophil numbers 7
Increased Neutrophil Counts:
- MPO loss-of-function mutations paradoxically associated with increased neutrophil abundance in population studies 3
- MPO inhibition delays neutrophil apoptosis and increases cell viability 3
ANCA-Associated Vasculitis Connection
While MPO is the target antigen in anti-MPO ANCA-positive vasculitis (including microscopic polyangiitis and some cases of EGPA), this represents autoimmunity against MPO rather than MPO deficiency. 8, 9, 10 The -463G>A polymorphism in the MPO gene promoter reduces MPO expression but is studied in the context of cancer risk, not primary deficiency. 11
Clinical Pitfalls
Critical caveat: Most MPO-deficient individuals remain asymptomatic throughout life because MPO-independent microbicidal mechanisms compensate for the deficiency. 4 Serious infections occur primarily when MPO deficiency coexists with diabetes mellitus or other immunocompromising conditions. 4
Diagnostic error: Automated hematology analyzers can produce misleading results showing severe neutropenia with monocytosis; always verify with manual differential count when MPXI is markedly low. 7