Myeloperoxidase Deficiency Clinical Presentation

Updated: Oct 19, 2016
  • Author: Maureen M Petersen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Presentation

History

Recurrent infections

Most individuals with partial or total myeloperoxidase (MPO) deficiency have no increased frequency of infections, probably because MPO-independent mechanisms in the polymorphonuclear leukocytes (PMNs) can take over. In general, it is considered a relatively benign immunodeficiency and was removed from the Classification of Primary Immunodeficiency Disease by the Primary Immunodeficiency Disease Classification Committee of the International Union of the Immunologic Societies in 2005.

Severe infections are uncommon, occurring in fewer than 5% of patients with MPO deficiency. If infectious disease occurs, it is usually a fungal infection (particularly candidal, such as C albicans or C tropicalis) that occurs in a patient who also has diabetes mellitus. Patients without diabetes mellitus rarely have problems, although the reason for this is unknown. Possibly, MPO deficiency becomes clinically significant only in the presence of an additional defect in the host defense, or perhaps the MPO-independent system is defective in some patients with diabetes mellitus.

Physicians should entertain the diagnosis of MPO deficiency in cases of invasive fungal infection in a patient with no known predisposing immune defects (eg, chemotherapy, corticosteroid treatment) or in a patient with concomitant diabetes mellitus. Some consider peroxidase staining of the peripheral blood smear to be part of the complete evaluation of a patient with a suspected immunodeficiency.

Increased incidence of malignancy

A strong association between total MPO deficiency and malignancies has been reported by several independent investigators. In vitro, MPO-deficient neutrophils have decreased destruction of malignant cells demonstrating that the MPO system plays a central role in tumor surveillance. [8]

MPO is released from neutrophils in lung tissue in response to pulmonary insult including damage secondary to tobacco smoke exposure. MPO has been shown to convert the metabolites of benzo[a]pyrene from tobacco smoke into a highly reactive carcinogen. Researchers have demonstrated that decreased MPO can decrease lung cancer risk. [11]

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Causes

Hereditary cases can be caused by a number of mutations, including R569W, Y173C, M251T, G501S, and R499C.

  • R569W: This is the most common defect identified to date. Tryptophan is substituted for arginine at codon 569. Tryptophan cannot form electrostatic bonds. Most patients described have been compound heterozygotes, but one has been homozygous for this mutation. The mutation results in a maturational arrest at the stage of apopro-MPO that is unprocessed, enzymatically inactive, and undelivered to the azurophilic granules. [12]

  • Y173C: Cysteine is substituted for tyrosine at codon 173. This leads to an additional site for intramolecular disulfide bonds, which presumably leads to abnormal folding of the protein. Apopro-MPO is converted into pro-MPO, which is malfolded. This malfolded pro-MPO seems to be sequestered by calnexin (a molecular chaperone) and retained in the endoplasmic reticulum. The trapped precursor then undergoes degradation in the endoplasmic reticulum. Pro-MPO is prevented from entering the secretory pathway and cannot proceed to become mature MPO in the azurophilic granules. Therefore, MPO deficiency resulting from this mutation occurs because of an abnormality of protein folding. Interestingly, abnormalities in protein folding have also been described in cystic fibrosis and protein C deficiency.

  • M251T: In this defect, mature subunits are formed, but their enzymatic activity is markedly low.

  • G501S: This mutation is a missense mutation within part of the heme-binding pocket. It has been identified in a Japanese patient with complete MPO deficiency. [13]

  • R499C: This mutation is a nonsynonymous mutation that results in an arginine to cysteine substitution in the exon 9 coding region. The mutation was identified in a Japanese patient with complete MPO deficiency. Further genetic analysis revealed mRNA was transcribed into an appropriate peptide sequence, but no MPO protein was evident on Western blot findings. [14]

  • As time goes on and more cases are analyzed, more mutations are being identified. Some pretranslational defects have been described that could be caused by mutations in the regulatory portion of the MPO gene or by the presence of mutations in other genes involved in the regulation of the MPO gene.

  • Acquired MPO deficiency is less common than the hereditary form. This condition can be transient. The enzyme defect is corrected when the underlying condition has resolved. In most cases of acquired deficiency, the deficiency is partial and affects only a proportion of neutrophils (see Pathophysiology).

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