👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Hereditary MPO deficiency is classically autosomal recessive; family studies show that many completely deficient subjects are compound heterozygotes and that heterozygous relatives often have partial deficiency, so the phenotype is a quantitative spectrum rather than a simple two-state trait.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:29262241 SUPPORT Other

"Myeloperoxidase deficiency, first described in 1954, is an autosomal recessive disorder caused by mutations in the MPO gene on chromosome 17."

StatPearls review states autosomal recessive inheritance of MPO gene variants.

PMID:6296995 SUPPORT Human Clinical

"MPO deficiency was found to follow autosomal recessive inheritance and only rarely to have clinical effects."

Two-generation family studies of 12 cases supporting recessive inheritance.

PMID:9468285 REFUTE Human Clinical

"Our 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."

Kindred study showing the inheritance departs from a simple recessive pattern because of compound heterozygosity and partial phenotypes.

⚙

Pathophysiology

8

MPO Pathogenic Variants

Biallelic or compound heterozygous variants in MPO cause the disease. The most frequent allele in Western populations is the exon 10 missense variant R569W; other missense, frameshift, splice-site and small-deletion alleles (Y173C, M251T, the exon 9 14-base deletion, and several Italian and Japanese alleles) have been described. Several genotypes produce the same biochemical phenotype.

MPO hgnc:7218

Downstream

Defective MPO Precursor Maturation Missense MPO variants produce a precursor protein that is not processed into the mature heavy and light subunits.

Show evidence (2 references)

PMID:7904599 SUPPORT Human Clinical

"At the amino acid level this mutation would replace arginine at codon 569 with tryptophan. Six of seven patients with complete MPO deficiency had this mutation."

Identifies R569W as the predominant causal MPO variant in completely deficient patients.

PMID:15108282 SUPPORT Human Clinical

"The genetic characterization of the subjects showed the presence of three already-known mutations (c.752T>C, c.1705C>T, and c.1566_1579del14) and six novel mutations"

Population screening shows allelic heterogeneity of MPO variants in MPO-deficient subjects.

Defective MPO Precursor Maturation

Mutant MPO precursors are glycosylated and acquire heme but are retained in the endoplasmic reticulum in prolonged association with calreticulin and calnexin, are not proteolytically processed to mature subunits, and are degraded by the proteasome through endoplasmic reticulum quality control. Neutrophils therefore carry a 90-kDa precursor but no mature enzyme.

ER-associated degradation of mutant MPO precursor GO:0036503 ↑ INCREASED MPO precursor proteolytic maturation GO:0051604 ↓ DECREASED

Downstream

Loss of Neutrophil and Monocyte Myeloperoxidase Activity

Show evidence (2 references)

PMID:9637725 SUPPORT In Vitro

"it was neither proteolytically processed to mature MPO subunits nor secreted. After prolonged association with calreticulin and calnexin in the endoplasmic reticulum, MPOY173C was degraded."

Transfection study showing that the Y173C precursor is retained in the ER and degraded instead of being matured.

PMID:7904599 SUPPORT Human Clinical

"neutrophils from individuals with MPO deficiency lack enzymatic and immunochemical evidence for mature MPO but have a 90-kDa precursor protein"

Patient neutrophils contain unprocessed precursor but no mature MPO.

Loss of Neutrophil and Monocyte Myeloperoxidase Activity

Peroxidase activity is absent (complete deficiency) or reduced (partial deficiency) in neutrophils and monocytes, while eosinophil peroxidase, encoded by a separate gene, is preserved.

neutrophil CL:0000775 monocyte CL:0000576

myeloperoxidase peroxidase activity GO:0004601 ↓ DECREASED

azurophil granule GO:0042582

Downstream

Impaired Hypochlorous Acid Generation

Impaired Neutrophil Extracellular Trap Formation

Compensatory Enhancement of the Respiratory Burst

Reduced neutrophil myeloperoxidase activity

Show evidence (2 references)

PMID:217268 SUPPORT Human Clinical

"Peroxidase activity is completely absent from the neutrophils and monocytes although it is present in the eosinophils."

Case documenting absent neutrophil and monocyte peroxidase with preserved eosinophil peroxidase.

PMID:15108282 SUPPORT Human Clinical

"Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity."

Defines the disease by the lack of neutrophil peroxidase activity.

Impaired Hypochlorous Acid Generation

Without MPO, hydrogen peroxide produced by the NADPH oxidase respiratory burst is not converted with chloride into hypochlorous acid and its downstream chlorinating oxidants inside the phagosome.

neutrophil CL:0000775

Downstream

Impaired Neutrophil Candidacidal Activity

Show evidence (3 references)

PMID:15689384 SUPPORT Other

"The initial product of the MPO-H2O2-chloride system is hypochlorous acid"

Review establishing hypochlorous acid as the product of the MPO-H2O2-chloride system that is lost when MPO is absent.

PMID:17592500 SUPPORT Other

"A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent."

Review stating that chloride-dependent HOCl generation is the activity unique to MPO, and hence the one no other peroxidase replaces.

PMID:8960464 SUPPORT Human Clinical

"This was demonstrated by comparing myeloperoxidase mass concentration measured with an enzyme immunoassay, lack of HOCl production"

Totally MPO-deficient neutrophils produced no HOCl.

Impaired Neutrophil Extracellular Trap Formation

Completely MPO-deficient neutrophils fail to form neutrophil extracellular traps, whereas partially deficient neutrophils form them; MPO acts cell-autonomously in NET formation.

neutrophil CL:0000775

neutrophil extracellular trap formation GO:0140645 ↓ DECREASED

Downstream

Impaired Neutrophil Candidacidal Activity

Show evidence (1 reference)

PMID:20974672 SUPPORT In Vitro

"In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation."

Shows the NET defect depends on complete loss of MPO.

Compensatory Enhancement of the Respiratory Burst

MPO-deficient neutrophils show increased phagocytic activity and increased superoxide production (enhanced lucigenin chemiluminescence), which is thought to compensate for the missing MPO system and to explain why most affected individuals do not suffer severe bacterial infection.

neutrophil CL:0000775

respiratory burst GO:0045730 ↑ INCREASED

Show evidence (3 references)

PMID:8960464 SUPPORT Human Clinical

"The lack of myeloperoxidase activity is compensated for by an increased phagocytic activity, an increased production of superoxide anion (lucigenin-chemiluminescence)"

Ex vivo study of MPO-deficient granulocytes showing enhanced superoxide production and phagocytosis.

PMID:17384005 SUPPORT Human Clinical

"Lucigenin-enhanced chemiluminescence (LCL) is increased in neutrophils from MPO-deficient patients, whereas neutrophils from patients with CGD show a decreased response."

Confirms increased NADPH-oxidase-derived superoxide signal in MPO-deficient neutrophils.

PMID:2831185 SUPPORT Other

"In the absence of MPO, auxiliary mechanisms protect most MPO-deficient hosts from clinically significant sequelae"

Review attributing the usual clinical silence of MPO deficiency to MPO-independent auxiliary microbicidal mechanisms.

Impaired Neutrophil Candidacidal Activity

Killing of Candida albicans by MPO-deficient neutrophils is markedly impaired, while killing of Staphylococcus aureus is only minimally affected, so the clinical susceptibility that does occur is dominated by Candida.

neutrophil CL:0000775

neutrophil-mediated killing of fungus GO:0070947 ↓ DECREASED

Downstream

Severe Candida infection The candidacidal defect predisposes to invasive candidiasis, but only a minority of MPO-deficient individuals develop it, usually with a second risk factor such as diabetes mellitus.

Hepatic candidiasis

Fungal meningitis

Unusual fungal osteomyelitis

Candida esophagitis

Unusual fungal skin infection

Show evidence (3 references)

PMID:6267975 SUPPORT Human Clinical

"In assays of leukocyte function only minor defects in killing of Staphylococcus aureus by MPO-deficient cells were noted whereas killing of Candida albicans was much more impaired."

Patient neutrophils show a selective, marked defect in Candida killing.

PMID:216438 SUPPORT Human Clinical

"The microbicidal activity of the granulocytes was partially diminished with regard to Staphylococcus aureus and was almost nil with regard to Candida albicans."

Granulocytes of an MPO-deficient patient had almost no candidacidal activity.

PMID:15507755 SUPPORT Model Organism

"MPO-KO mice showed severely reduced cytotoxicity to various microorganisms such as Candida albicans, Aspergillus fumigatus, and Klebsiella pneumoniae"

Mpo-knockout mice reproduce the reduced antifungal killing seen in human MPO deficiency.

Hyperglycemia-Impaired Granulocyte Fungicidal Activity

Coexisting diabetes mellitus is the main clinical modifier. Hyperglycemia itself impairs the fungicidal activity of normal granulocytes, adding a second hit to the MPO-dependent candidacidal defect; most reported cases of serious Candida infection in MPO deficiency occurred in diabetic patients.

neutrophil CL:0000775

neutrophil-mediated killing of fungus GO:0070947 ↓ DECREASED

Downstream

Impaired Neutrophil Candidacidal Activity

Show evidence (3 references)

PMID:216438 SUPPORT In Vitro

"Fungicidal activity of normal granulocytes was shown to be impaired during the in vitro artificial hyperglycemic condition."

In vitro hyperglycemia impairs granulocyte fungicidal activity, the proposed mechanism for the diabetes interaction.

PMID:9766845 SUPPORT Other

"Infectious diseases, especially with species of Candida, have been observed predominantly in MPO-deficient patients who also have diabetes mellitus"

Review noting that Candida infections cluster in diabetic MPO-deficient patients.

PMID:2831185 SUPPORT Other

"except for some persons with diabetes mellitus who suffer severe candidal disease"

Review identifying diabetes mellitus as the setting in which MPO deficiency produces severe candidal disease.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Digestive 2

Hepatic candidiasis HP:5210167

Show evidence (1 reference)

PMID:217268 SUPPORT Human Clinical

"Reported here is a case of hereditary myeloperoxidase deficinecy in a diabetic patient suffering from a Candida albicans liver abscess."

Case report of Candida liver abscess in MPO deficiency.

Candida esophagitis HP:0033351

Show evidence (1 reference)

PMID:17614858 SUPPORT Human Clinical

"Toxemia with disseminated intravascular coagulation (DIC) and acute renal failure had masked the symptoms of invasive candida esophagitis and disseminated candidiasis in both lungs."

Autopsy case with invasive Candida esophagitis in MPO deficiency.

Immune 4

Severe Candida infection VERY_RARE HP:6001283

Show evidence (2 references)

PMID:9766845 SUPPORT Other

"but the frequency of such cases is very low, less than 5% of reported MPO-deficient subjects"

Review estimating the frequency of Candida and other infections among reported MPO-deficient subjects.

PMID:17614858 SUPPORT Human Clinical

"Candida sepsis was discovered as the cause of death at postmortem examination. Myeloperoxidase (MPO) deficiency was identified as having supported the invasive candida infection."

Case of fatal disseminated candidiasis in an MPO-deficient patient.

Fungal meningitis HP:0032159

Show evidence (1 reference)

PMID:27301573 SUPPORT Human Clinical

"A patient with Candida meningitis and low dihydrorhodamine oxidation signal was diagnosed with chronic granulomatous disease but actually had compound heterozygous myeloperoxidase deficiency."

Case report of Candida meningitis in compound heterozygous MPO deficiency.

Unusual fungal osteomyelitis HP:5210206

Show evidence (2 references)

PMID:2825109 SUPPORT Human Clinical

"A CT scan of the mastoids showed extensive bone destruction of the base of the skull and C-1."

Documents skull-base bone destruction in the index case.

PMID:2825109 SUPPORT Human Clinical

"histopathologic findings were suggestive of mycotic infection and cultures were positive for Candida albicans"

Establishes Candida albicans as the cause of the osteomyelitis.

Unusual fungal skin infection HP:5210236

Show evidence (1 reference)

PMID:9114158 SUPPORT Human Clinical

"We present a case of myeloperoxidase deficiency manifesting as disseminated pustular candidal dermatitis in a nondiabetic male."

Case report of cutaneous candidiasis as the presenting manifestation of MPO deficiency.

Metabolism 1

Reduced neutrophil myeloperoxidase activity OBLIGATE HP:6000375

Show evidence (2 references)

PMID:9766844 SUPPORT Human Clinical

"Peroxidase deficiencies are manifested by the irregular location of these clusters. This makes it possible to identify persons totally or partially lacking myeloperoxidase."

Describes detection of total or partial MPO deficiency on peroxidase-based analyzers.

PMID:6267975 SUPPORT Human Clinical

"Partial (13 patients) or complete (13 patients) MPO deficiency was confirmed by examination of cytochemical stains in 26"

Screening cohort confirming partial and complete neutrophil MPO deficiency by cytochemistry.

🧬

Genetic Associations

1

MPO (Causative)

Gene: MPO hgnc:7218 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:29262241 SUPPORT Other

"is an autosomal recessive disorder caused by mutations in the MPO gene on chromosome 17"

Identifies MPO as the causal gene.

PMID:9637725 SUPPORT Human Clinical

"We identified a novel missense mutation in the MPO gene at codon 173 whereby tyrosine is replaced with cysteine (Y173C) that is associated with MPO deficiency"

Reports a further causal MPO missense allele.

💊

Medical Actions

1

Antifungal therapy for invasive candidiasis

Action: systemic antifungal therapy Ontology label: Antifungal Therapy NCIT:C15704

Agent: amphotericin B CHEBI:2682

Platform: Small molecule

There is no disease-specific therapy and asymptomatic individuals need no treatment. Invasive Candida infections are treated with systemic antifungal agents; amphotericin B cured extensive candidal skull-base osteomyelitis in a child with MPO deficiency.

Target Phenotypes: Candida osteomyelitis HP:5210206

Show evidence (1 reference)

PMID:2825109 SUPPORT Human Clinical

"The child was treated successfully with amphotericin B."

Case report of successful amphotericin B treatment of Candida osteomyelitis in MPO deficiency.

🔬

Diagnosis

2

Peroxidase-based automated leukocyte differential

Hematology analyzers that separate leukocytes by peroxidase staining and volume (Technicon/Bayer H series, Siemens ADVIA) flag MPO deficiency through displaced neutrophil clusters and a low mean peroxidase index. Neutrophils may be misclassified as monocytes, giving a spurious neutropenia with monocytosis; a manual differential count is normal.

flow cytochemistry NCIT:C16585

Results: Low mean peroxidase index; neutrophils misplaced into the monocyte region

Show evidence (2 references)

PMID:9766844 SUPPORT Human Clinical

"The deficiency is quantified by the myeloperoxidase index, which is expressed for every routine analysis and for which normal values were determined."

Describes the analyzer-derived MPO index used to detect and grade deficiency.

PMID:31622460 SUPPORT Human Clinical

"When MPO deficiency is present, neutrophils may be incorrectly counted as monocytes with lower MPXI values."

Describes the pseudoneutropenia artefact that brings MPO deficiency to attention.

Molecular genetic testing of MPO

Sequencing of MPO identifies the causal alleles and distinguishes hereditary from acquired deficiency.

MPO gene sequencing NCIT:C19770

Results: Biallelic or compound heterozygous pathogenic MPO variants

Show evidence (1 reference)

PMID:15108282 SUPPORT Human Clinical

"a population screening was carried out to detect mutations in the MPO gene"

MPO gene analysis was used to characterize screen-detected MPO-deficient subjects.

📊

Prevalence

2

General population (hospital hematology screening, United States)

Point Prevalence 37.5 per 100,000 (25.0–50.0) 1–9 per 10,000

Hereditary MPO deficiency (complete plus partial) occurs in 1 in 2,000 to 1 in 4,000 individuals, as ascertained by automated peroxidase-based leukocyte differential counting.

Show evidence (1 reference)

PMID:9468285 SUPPORT Human Clinical

"Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population"

States the population frequency of hereditary MPO deficiency.

Japan (clinical hematology laboratories), complete deficiency

Point Prevalence 1.75 per 100,000 1–9 per 100,000

Complete MPO deficiency 1 in 57,135 and partial deficiency 1 in 17,501 in a Japanese survey using Technicon H series analyzers; complete deficiency is considerably rarer in Japan than in European and North American series.

Show evidence (1 reference)

PMID:12953846 SUPPORT Human Clinical

"We identified 26 cases of complete MPO deficiency, prevalence 1 in 57,135, and 129 cases of partial deficiency, prevalence 1 in 17,501."

Population-based laboratory survey reporting prevalence of complete and partial MPO deficiency in Japan.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Myeloperoxidase Deficiency:

Chronic granulomatous disease MONDO:0018305

Overlapping Features Complete MPO deficiency produces a strongly reduced dihydrorhodamine 123 oxidation signal, the standard screening test for chronic granulomatous disease, and can be misdiagnosed as CGD. MPO deficiency is distinguished by normal eosinophil DHR signal (eosinophil peroxidase is preserved), rescue of the DHR signal by added recombinant MPO, and increased rather than decreased lucigenin chemiluminescence.

Show evidence (2 references)

PMID:17384005 SUPPORT Human Clinical

"Eosinophils from MPO-deficient individuals retain eosinophilic peroxidase and therefore generate a normal DHR signal."

Gives a laboratory feature that separates MPO deficiency from CGD.

PMID:27301573 SUPPORT Human Clinical

"Myeloperoxidase deficiency is the most common inherited phagocyte disorder (1:2000) and causes an abnormal dihydrorhodamine oxidation test, which also is seen in chronic granulomatous disease."

States the DHR overlap that makes CGD the key differential.

Acquired myeloperoxidase deficiency

Overlapping Features Secondary MPO deficiency occurs with other hematological or nonhematological diseases and must be separated from the primary hereditary form.

Show evidence (1 reference)

PMID:9766845 SUPPORT Other

"an acquired abnormality associated with other hematological or nonhematological diseases has been occasionally described, but the primary deficiency is the form more commonly reported"

Distinguishes acquired from primary MPO deficiency.

{ }

Source YAML

click to show

name: Myeloperoxidase Deficiency
creation_date: "2026-09-23T19:09:54Z"
category: Mendelian
description: >-
  Myeloperoxidase deficiency is an inherited defect of the neutrophil and
  monocyte azurophil-granule enzyme myeloperoxidase (MPO), caused by
  biallelic or compound heterozygous variants in MPO on chromosome 17. Most
  pathogenic missense alleles yield a precursor that is not processed into
  mature enzyme, so affected neutrophils lack peroxidase activity and cannot
  convert respiratory-burst hydrogen peroxide and chloride into hypochlorous
  acid; completely deficient neutrophils also fail to form neutrophil
  extracellular traps. It is the most common inherited phagocyte defect,
  usually detected incidentally by automated hematology analyzers that
  classify leukocytes by peroxidase staining. Most affected individuals are
  asymptomatic because MPO-independent microbicidal systems compensate, but
  candidacidal activity is markedly impaired and a small minority, mostly
  those with coexisting diabetes mellitus, develop severe or disseminated
  Candida infection.
synonyms:
- MPO deficiency
- MPOD
disease_term:
  preferred_term: myeloperoxidase deficiency
  term:
    id: MONDO:0009694
    label: myeloperoxidase deficiency
parents:
- functional neutrophil defect
notes: >-
  No GeneReviews chapter exists for this disease (just check-genereviews
  --online returned NO_CHAPTER); the StatPearls chapter PMID:29262241 is cited
  for orientation only. Acquired MPO deficiency secondary to myeloid
  neoplasms or other conditions is out of scope for this entry, which covers
  the hereditary MPO-gene disorder.
prevalence:
- population: General population (hospital hematology screening, United States)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 37.5
  rate_low: 25.0
  rate_high: 50.0
  notes: >-
    Hereditary MPO deficiency (complete plus partial) occurs in 1 in 2,000 to
    1 in 4,000 individuals, as ascertained by automated peroxidase-based
    leukocyte differential counting.
  evidence:
  - reference: PMID:9468285
    reference_title: "Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population"
    explanation: States the population frequency of hereditary MPO deficiency.
- population: Japan (clinical hematology laboratories), complete deficiency
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.75
  notes: >-
    Complete MPO deficiency 1 in 57,135 and partial deficiency 1 in 17,501 in a
    Japanese survey using Technicon H series analyzers; complete deficiency is
    considerably rarer in Japan than in European and North American series.
  evidence:
  - reference: PMID:12953846
    reference_title: "Prevalence of inherited myeloperoxidase deficiency in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 26 cases of complete MPO deficiency, prevalence 1 in 57,135, and 129 cases of partial deficiency, prevalence 1 in 17,501."
    explanation: Population-based laboratory survey reporting prevalence of complete and partial MPO deficiency in Japan.
pathophysiology:
- name: MPO Pathogenic Variants
  description: >-
    Biallelic or compound heterozygous variants in MPO cause the disease. The
    most frequent allele in Western populations is the exon 10 missense
    variant R569W; other missense, frameshift, splice-site and small-deletion
    alleles (Y173C, M251T, the exon 9 14-base deletion, and several Italian
    and Japanese alleles) have been described. Several genotypes produce the
    same biochemical phenotype.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MPO
    term:
      id: hgnc:7218
      label: MPO
  evidence:
  - reference: PMID:7904599
    reference_title: "Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the amino acid level this mutation would replace arginine at codon 569 with tryptophan. Six of seven patients with complete MPO deficiency had this mutation."
    explanation: Identifies R569W as the predominant causal MPO variant in completely deficient patients.
  - reference: PMID:15108282
    reference_title: "Genetic characterization of myeloperoxidase deficiency in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The genetic characterization of the subjects showed the presence of three already-known mutations (c.752T>C, c.1705C>T, and c.1566_1579del14) and six novel mutations"
    explanation: Population screening shows allelic heterogeneity of MPO variants in MPO-deficient subjects.
  downstream:
  - target: Defective MPO Precursor Maturation
    causal_link_type: DIRECT
    description: >-
      Missense MPO variants produce a precursor protein that is not processed
      into the mature heavy and light subunits.
    evidence:
    - reference: PMID:7904599
      reference_title: "Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have thus hypothesized that hereditary MPO deficiency reflects a defect in processing of a mutated primary translation product."
      explanation: Links the mutated MPO primary translation product to a processing defect.
- name: Defective MPO Precursor Maturation
  description: >-
    Mutant MPO precursors are glycosylated and acquire heme but are retained
    in the endoplasmic reticulum in prolonged association with calreticulin
    and calnexin, are not proteolytically processed to mature subunits, and
    are degraded by the proteasome through endoplasmic reticulum quality
    control. Neutrophils therefore carry a 90-kDa precursor but no mature
    enzyme.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: ER-associated degradation of mutant MPO precursor
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: INCREASED
  - preferred_term: MPO precursor proteolytic maturation
    term:
      id: GO:0051604
      label: protein maturation
    modifier: DECREASED
  evidence:
  - reference: PMID:9637725
    reference_title: "A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "it was neither proteolytically processed to mature MPO subunits nor secreted. After prolonged association with calreticulin and calnexin in the endoplasmic reticulum, MPOY173C was degraded."
    explanation: Transfection study showing that the Y173C precursor is retained in the ER and degraded instead of being matured.
  - reference: PMID:7904599
    reference_title: "Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neutrophils from individuals with MPO deficiency lack enzymatic and immunochemical evidence for mature MPO but have a 90-kDa precursor protein"
    explanation: Patient neutrophils contain unprocessed precursor but no mature MPO.
  downstream:
  - target: Loss of Neutrophil and Monocyte Myeloperoxidase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10482305
      reference_title: "Quality control in the endoplasmic reticulum: lessons from hereditary myeloperoxidase deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the quality control system operating in the endoplasmic reticulum retrieves malfolded MPO precursors from the biosynthetic pathway and creates the biochemical phenotype of MPO deficiency"
      explanation: Review stating that ER retrieval of misfolded precursors produces the loss of enzyme that defines the disease.
- name: Loss of Neutrophil and Monocyte Myeloperoxidase Activity
  description: >-
    Peroxidase activity is absent (complete deficiency) or reduced (partial
    deficiency) in neutrophils and monocytes, while eosinophil peroxidase,
    encoded by a separate gene, is preserved.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  locations:
  - preferred_term: azurophil granule
    term:
      id: GO:0042582
      label: azurophil granule
  molecular_functions:
  - preferred_term: myeloperoxidase peroxidase activity
    term:
      id: GO:0004601
      label: peroxidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:217268
    reference_title: "Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peroxidase activity is completely absent from the neutrophils and monocytes although it is present in the eosinophils."
    explanation: Case documenting absent neutrophil and monocyte peroxidase with preserved eosinophil peroxidase.
  - reference: PMID:15108282
    reference_title: "Genetic characterization of myeloperoxidase deficiency in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity."
    explanation: Defines the disease by the lack of neutrophil peroxidase activity.
  downstream:
  - target: Impaired Hypochlorous Acid Generation
    causal_link_type: DIRECT
  - target: Impaired Neutrophil Extracellular Trap Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20974672
      reference_title: "Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "neutrophils from donors who are completely deficient in MPO fail to form neutrophil extracellular traps (NETs), indicating that MPO is required for NET formation"
      explanation: Ex vivo study of patient neutrophils linking absent MPO to failed NET formation.
  - target: Compensatory Enhancement of the Respiratory Burst
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced neutrophil myeloperoxidase activity
    causal_link_type: DIRECT
- name: Impaired Hypochlorous Acid Generation
  description: >-
    Without MPO, hydrogen peroxide produced by the NADPH oxidase respiratory
    burst is not converted with chloride into hypochlorous acid and its
    downstream chlorinating oxidants inside the phagosome.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  chemical_entities:
  - preferred_term: hypochlorous acid
    term:
      id: CHEBI:24757
      label: hypochlorous acid
    modifier: DECREASED
  evidence:
  - reference: PMID:15689384
    reference_title: "Myeloperoxidase: friend and foe."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The initial product of the MPO-H2O2-chloride system is hypochlorous acid"
    explanation: Review establishing hypochlorous acid as the product of the MPO-H2O2-chloride system that is lost when MPO is absent.
  - reference: PMID:17592500
    reference_title: "Myeloperoxidase: a target for new drug development?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent."
    explanation: Review stating that chloride-dependent HOCl generation is the activity unique to MPO, and hence the one no other peroxidase replaces.
  - reference: PMID:8960464
    reference_title: "Phagocytic activity and oxidative burst of granulocytes in persons with myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This was demonstrated by comparing myeloperoxidase mass concentration measured with an enzyme immunoassay, lack of HOCl production"
    explanation: Totally MPO-deficient neutrophils produced no HOCl.
  downstream:
  - target: Impaired Neutrophil Candidacidal Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10085024
      reference_title: "Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MPO is important for early host defense against fungal infection, and the inability to generate HOCl cannot be compensated for by other oxygen-dependent systems in vivo in mice"
      explanation: Mpo-null mice show that loss of HOCl generation impairs antifungal defense.
- name: Impaired Neutrophil Extracellular Trap Formation
  description: >-
    Completely MPO-deficient neutrophils fail to form neutrophil extracellular
    traps, whereas partially deficient neutrophils form them; MPO acts
    cell-autonomously in NET formation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil extracellular trap formation
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
    modifier: DECREASED
  evidence:
  - reference: PMID:20974672
    reference_title: "Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation."
    explanation: Shows the NET defect depends on complete loss of MPO.
  downstream:
  - target: Impaired Neutrophil Candidacidal Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20974672
      reference_title: "Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "NET-dependent inhibition of Candida albicans growth is compromised in MPO-deficient neutrophils"
      explanation: Links the NET defect to reduced control of Candida albicans.
- name: Compensatory Enhancement of the Respiratory Burst
  description: >-
    MPO-deficient neutrophils show increased phagocytic activity and increased
    superoxide production (enhanced lucigenin chemiluminescence), which is
    thought to compensate for the missing MPO system and to explain why most
    affected individuals do not suffer severe bacterial infection.
  biological_scale: CELLULAR
  role: compensation
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: INCREASED
  evidence:
  - reference: PMID:8960464
    reference_title: "Phagocytic activity and oxidative burst of granulocytes in persons with myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of myeloperoxidase activity is compensated for by an increased phagocytic activity, an increased production of superoxide anion (lucigenin-chemiluminescence)"
    explanation: Ex vivo study of MPO-deficient granulocytes showing enhanced superoxide production and phagocytosis.
  - reference: PMID:17384005
    reference_title: "Chronic granulomatous disease (CGD) and complete myeloperoxidase deficiency both yield strongly reduced dihydrorhodamine 123 test signals but can be easily discerned in routine testing for CGD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lucigenin-enhanced chemiluminescence (LCL) is increased in neutrophils from MPO-deficient patients, whereas neutrophils from patients with CGD show a decreased response."
    explanation: Confirms increased NADPH-oxidase-derived superoxide signal in MPO-deficient neutrophils.
  - reference: PMID:2831185
    reference_title: "Myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the absence of MPO, auxiliary mechanisms protect most MPO-deficient hosts from clinically significant sequelae"
    explanation: Review attributing the usual clinical silence of MPO deficiency to MPO-independent auxiliary microbicidal mechanisms.
- name: Impaired Neutrophil Candidacidal Activity
  description: >-
    Killing of Candida albicans by MPO-deficient neutrophils is markedly
    impaired, while killing of Staphylococcus aureus is only minimally
    affected, so the clinical susceptibility that does occur is dominated by
    Candida.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil-mediated killing of fungus
    term:
      id: GO:0070947
      label: neutrophil-mediated killing of fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:6267975
    reference_title: "Myeloperoxidase deficiency: prevalence and clinical significance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In assays of leukocyte function only minor defects in killing of Staphylococcus aureus by MPO-deficient cells were noted whereas killing of Candida albicans was much more impaired."
    explanation: Patient neutrophils show a selective, marked defect in Candida killing.
  - reference: PMID:216438
    reference_title: "Hereditary myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The microbicidal activity of the granulocytes was partially diminished with regard to Staphylococcus aureus and was almost nil with regard to Candida albicans."
    explanation: Granulocytes of an MPO-deficient patient had almost no candidacidal activity.
  - reference: PMID:15507755
    reference_title: "In vivo role of myeloperoxidase for the host defense."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MPO-KO mice showed severely reduced cytotoxicity to various microorganisms such as Candida albicans, Aspergillus fumigatus, and Klebsiella pneumoniae"
    explanation: Mpo-knockout mice reproduce the reduced antifungal killing seen in human MPO deficiency.
  downstream:
  - target: Severe Candida infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The candidacidal defect predisposes to invasive candidiasis, but only a
      minority of MPO-deficient individuals develop it, usually with a
      second risk factor such as diabetes mellitus.
    evidence:
    - reference: PMID:6267975
      reference_title: "Myeloperoxidase deficiency: prevalence and clinical significance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although MPO appears to be necessary for killing of Candida species by neutrophils, the importance of its role in normal antibacterial defense must be re-evaluated."
      explanation: Relates the neutrophil Candida-killing requirement for MPO to the clinical picture.
  - target: Hepatic candidiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fungal meningitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Unusual fungal osteomyelitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Candida esophagitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Unusual fungal skin infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Hyperglycemia-Impaired Granulocyte Fungicidal Activity
  description: >-
    Coexisting diabetes mellitus is the main clinical modifier. Hyperglycemia
    itself impairs the fungicidal activity of normal granulocytes, adding a
    second hit to the MPO-dependent candidacidal defect; most reported cases of
    serious Candida infection in MPO deficiency occurred in diabetic patients.
  biological_scale: CELLULAR
  role: disease modifier
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil-mediated killing of fungus
    term:
      id: GO:0070947
      label: neutrophil-mediated killing of fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:216438
    reference_title: "Hereditary myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fungicidal activity of normal granulocytes was shown to be impaired during the in vitro artificial hyperglycemic condition."
    explanation: In vitro hyperglycemia impairs granulocyte fungicidal activity, the proposed mechanism for the diabetes interaction.
  - reference: PMID:9766845
    reference_title: "Clinical manifestation of myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infectious diseases, especially with species of Candida, have been observed predominantly in MPO-deficient patients who also have diabetes mellitus"
    explanation: Review noting that Candida infections cluster in diabetic MPO-deficient patients.
  - reference: PMID:2831185
    reference_title: "Myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "except for some persons with diabetes mellitus who suffer severe candidal disease"
    explanation: Review identifying diabetes mellitus as the setting in which MPO deficiency produces severe candidal disease.
  downstream:
  - target: Impaired Neutrophil Candidacidal Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Reduced neutrophil myeloperoxidase activity
  category: Hematological
  description: >-
    Absent (complete) or reduced (partial) neutrophil peroxidase activity,
    detected as an abnormal peroxidase index or displaced neutrophil cluster on
    peroxidase-based automated hematology analyzers and confirmed by
    cytochemistry. This is the defining laboratory feature.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Absent or reduced neutrophil myeloperoxidase activity
    term:
      id: HP:6000375
      label: Reduced neutrophil myeloperoxidase activity
  evidence:
  - reference: PMID:9766844
    reference_title: "Prevalence of myeloperoxidase deficiency: population studies using Bayer-Technicon automated hematology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peroxidase deficiencies are manifested by the irregular location of these clusters. This makes it possible to identify persons totally or partially lacking myeloperoxidase."
    explanation: Describes detection of total or partial MPO deficiency on peroxidase-based analyzers.
  - reference: PMID:6267975
    reference_title: "Myeloperoxidase deficiency: prevalence and clinical significance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Partial (13 patients) or complete (13 patients) MPO deficiency was confirmed by examination of cytochemical stains in 26"
    explanation: Screening cohort confirming partial and complete neutrophil MPO deficiency by cytochemistry.
- name: Severe Candida infection
  category: Infectious
  description: >-
    Disseminated or visceral candidiasis is the characteristic serious
    complication, reported in fewer than 5% of MPO-deficient subjects and
    predominantly in those with diabetes mellitus; fatal Candida sepsis has
    been reported.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Disseminated candidiasis
    term:
      id: HP:6001283
      label: Severe Candida infection
  evidence:
  - reference: PMID:9766845
    reference_title: "Clinical manifestation of myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "but the frequency of such cases is very low, less than 5% of reported MPO-deficient subjects"
    explanation: Review estimating the frequency of Candida and other infections among reported MPO-deficient subjects.
  - reference: PMID:17614858
    reference_title: "Lethal candida sepsis associated with myeloperoxidase deficiency and pre-eclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Candida sepsis was discovered as the cause of death at postmortem examination. Myeloperoxidase (MPO) deficiency was identified as having supported the invasive candida infection."
    explanation: Case of fatal disseminated candidiasis in an MPO-deficient patient.
- name: Hepatic candidiasis
  category: Infectious
  description: >-
    Candida albicans liver abscess has been reported in a diabetic patient with
    hereditary MPO deficiency.
  phenotype_term:
    preferred_term: Candida albicans liver abscess
    term:
      id: HP:5210167
      label: Hepatic candidiasis
  evidence:
  - reference: PMID:217268
    reference_title: "Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reported here is a case of hereditary myeloperoxidase deficinecy in a diabetic patient suffering from a Candida albicans liver abscess."
    explanation: Case report of Candida liver abscess in MPO deficiency.
- name: Fungal meningitis
  category: Infectious
  description: >-
    Candida meningitis has been reported, and in one child with compound
    heterozygous MPO deficiency it led to a mistaken diagnosis of chronic
    granulomatous disease because of a low dihydrorhodamine oxidation signal.
  phenotype_term:
    preferred_term: Candida meningitis
    term:
      id: HP:0032159
      label: Fungal meningitis
  evidence:
  - reference: PMID:27301573
    reference_title: "Complete Myeloperoxidase Deficiency: Beware the \"False-Positive\" Dihydrorhodamine Oxidation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A patient with Candida meningitis and low dihydrorhodamine oxidation signal was diagnosed with chronic granulomatous disease but actually had compound heterozygous myeloperoxidase deficiency."
    explanation: Case report of Candida meningitis in compound heterozygous MPO deficiency.
- name: Unusual fungal osteomyelitis
  category: Infectious
  description: >-
    Extensive Candida albicans osteomyelitis of the skull base and first
    cervical vertebra was reported in a child whose neutrophils lacked MPO.
  phenotype_term:
    preferred_term: Candida osteomyelitis of the skull base
    term:
      id: HP:5210206
      label: Unusual fungal osteomyelitis
  evidence:
  - reference: PMID:2825109
    reference_title: "Myeloperoxidase deficiency with extensive candidal osteomyelitis of the base of the skull."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A CT scan of the mastoids showed extensive bone destruction of the base of the skull and C-1."
    explanation: Documents skull-base bone destruction in the index case.
  - reference: PMID:2825109
    reference_title: "Myeloperoxidase deficiency with extensive candidal osteomyelitis of the base of the skull."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "histopathologic findings were suggestive of mycotic infection and cultures were positive for Candida albicans"
    explanation: Establishes Candida albicans as the cause of the osteomyelitis.
- name: Candida esophagitis
  category: Infectious
  description: >-
    Invasive Candida esophagitis, part of disseminated candidiasis, was found
    at autopsy in a pre-eclamptic woman with MPO deficiency.
  phenotype_term:
    preferred_term: Invasive Candida esophagitis
    term:
      id: HP:0033351
      label: Candida esophagitis
  evidence:
  - reference: PMID:17614858
    reference_title: "Lethal candida sepsis associated with myeloperoxidase deficiency and pre-eclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxemia with disseminated intravascular coagulation (DIC) and acute renal failure had masked the symptoms of invasive candida esophagitis and disseminated candidiasis in both lungs."
    explanation: Autopsy case with invasive Candida esophagitis in MPO deficiency.
- name: Unusual fungal skin infection
  category: Infectious
  description: >-
    Disseminated pustular candidal dermatitis was reported in a nondiabetic MPO
    deficient man receiving narrow-spectrum antibiotic therapy.
  phenotype_term:
    preferred_term: Pustular candidal dermatitis
    term:
      id: HP:5210236
      label: Unusual fungal skin infection
  evidence:
  - reference: PMID:9114158
    reference_title: "Myeloperoxidase deficiency manifesting as pustular candidal dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case of myeloperoxidase deficiency manifesting as disseminated pustular candidal dermatitis in a nondiabetic male."
    explanation: Case report of cutaneous candidiasis as the presenting manifestation of MPO deficiency.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Hereditary MPO deficiency is classically autosomal recessive; family
    studies show that many completely deficient subjects are compound
    heterozygotes and that heterozygous relatives often have partial
    deficiency, so the phenotype is a quantitative spectrum rather than a
    simple two-state trait.
  evidence:
  - reference: PMID:29262241
    reference_title: "Myeloperoxidase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myeloperoxidase deficiency, first described in 1954, is an autosomal recessive disorder caused by mutations in the MPO gene on chromosome 17."
    explanation: StatPearls review states autosomal recessive inheritance of MPO gene variants.
  - reference: PMID:6296995
    reference_title: "Hereditary myeloperoxidase deficiency: study of 12 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MPO deficiency was found to follow autosomal recessive inheritance and only rarely to have clinical effects."
    explanation: Two-generation family studies of 12 cases supporting recessive inheritance.
  - reference: PMID:9468285
    reference_title: "Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Our 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."
    explanation: Kindred study showing the inheritance departs from a simple recessive pattern because of compound heterozygosity and partial phenotypes.
genetic:
- name: MPO
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MPO
    term:
      id: hgnc:7218
      label: MPO
  notes: >-
    MPO on chromosome 17q encodes myeloperoxidase. Reported disease alleles
    include R569W (c.1705C>T), Y173C, M251T (c.752T>C), the exon 9 14-base
    deletion (c.1566_1579del14), c.325delA and the splice variant
    c.2031-2A>C.
  evidence:
  - reference: PMID:29262241
    reference_title: "Myeloperoxidase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "is an autosomal recessive disorder caused by mutations in the MPO gene on chromosome 17"
    explanation: Identifies MPO as the causal gene.
  - reference: PMID:9637725
    reference_title: "A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel missense mutation in the MPO gene at codon 173 whereby tyrosine is replaced with cysteine (Y173C) that is associated with MPO deficiency"
    explanation: Reports a further causal MPO missense allele.
diagnosis:
- name: Peroxidase-based automated leukocyte differential
  description: >-
    Hematology analyzers that separate leukocytes by peroxidase staining and
    volume (Technicon/Bayer H series, Siemens ADVIA) flag MPO deficiency
    through displaced neutrophil clusters and a low mean peroxidase index.
    Neutrophils may be misclassified as monocytes, giving a spurious
    neutropenia with monocytosis; a manual differential count is normal.
  diagnosis_term:
    preferred_term: flow cytochemistry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: Low mean peroxidase index; neutrophils misplaced into the monocyte region
  evidence:
  - reference: PMID:9766844
    reference_title: "Prevalence of myeloperoxidase deficiency: population studies using Bayer-Technicon automated hematology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deficiency is quantified by the myeloperoxidase index, which is expressed for every routine analysis and for which normal values were determined."
    explanation: Describes the analyzer-derived MPO index used to detect and grade deficiency.
  - reference: PMID:31622460
    reference_title: "Myeloperoxidase Deficiency Manifesting as Pseudoneutropenia with Low Mean Peroxidase Index and High Monocyte Count in 4 Adult Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When MPO deficiency is present, neutrophils may be incorrectly counted as monocytes with lower MPXI values."
    explanation: Describes the pseudoneutropenia artefact that brings MPO deficiency to attention.
- name: Molecular genetic testing of MPO
  description: >-
    Sequencing of MPO identifies the causal alleles and distinguishes
    hereditary from acquired deficiency.
  diagnosis_term:
    preferred_term: MPO gene sequencing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic or compound heterozygous pathogenic MPO variants
  evidence:
  - reference: PMID:15108282
    reference_title: "Genetic characterization of myeloperoxidase deficiency in Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a population screening was carried out to detect mutations in the MPO gene"
    explanation: MPO gene analysis was used to characterize screen-detected MPO-deficient subjects.
differential_diagnoses:
- name: Chronic granulomatous disease
  description: >-
    Complete MPO deficiency produces a strongly reduced dihydrorhodamine 123
    oxidation signal, the standard screening test for chronic granulomatous
    disease, and can be misdiagnosed as CGD. MPO deficiency is distinguished by
    normal eosinophil DHR signal (eosinophil peroxidase is preserved), rescue
    of the DHR signal by added recombinant MPO, and increased rather than
    decreased lucigenin chemiluminescence.
  disease_term:
    preferred_term: chronic granulomatous disease
    term:
      id: MONDO:0018305
      label: chronic granulomatous disease
  evidence:
  - reference: PMID:17384005
    reference_title: "Chronic granulomatous disease (CGD) and complete myeloperoxidase deficiency both yield strongly reduced dihydrorhodamine 123 test signals but can be easily discerned in routine testing for CGD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophils from MPO-deficient individuals retain eosinophilic peroxidase and therefore generate a normal DHR signal."
    explanation: Gives a laboratory feature that separates MPO deficiency from CGD.
  - reference: PMID:27301573
    reference_title: "Complete Myeloperoxidase Deficiency: Beware the \"False-Positive\" Dihydrorhodamine Oxidation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myeloperoxidase deficiency is the most common inherited phagocyte disorder (1:2000) and causes an abnormal dihydrorhodamine oxidation test, which also is seen in chronic granulomatous disease."
    explanation: States the DHR overlap that makes CGD the key differential.
- name: Acquired myeloperoxidase deficiency
  description: >-
    Secondary MPO deficiency occurs with other hematological or
    nonhematological diseases and must be separated from the primary
    hereditary form.
  evidence:
  - reference: PMID:9766845
    reference_title: "Clinical manifestation of myeloperoxidase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an acquired abnormality associated with other hematological or nonhematological diseases has been occasionally described, but the primary deficiency is the form more commonly reported"
    explanation: Distinguishes acquired from primary MPO deficiency.
treatments:
- name: Antifungal therapy for invasive candidiasis
  description: >-
    There is no disease-specific therapy and asymptomatic individuals need no
    treatment. Invasive Candida infections are treated with systemic
    antifungal agents; amphotericin B cured extensive candidal skull-base
    osteomyelitis in a child with MPO deficiency.
  treatment_term:
    preferred_term: systemic antifungal therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: amphotericin B
      term:
        id: CHEBI:2682
        label: amphotericin B
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Candida osteomyelitis
    term:
      id: HP:5210206
      label: Unusual fungal osteomyelitis
  evidence:
  - reference: PMID:2825109
    reference_title: "Myeloperoxidase deficiency with extensive candidal osteomyelitis of the base of the skull."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child was treated successfully with amphotericin B."
    explanation: Case report of successful amphotericin B treatment of Candida osteomyelitis in MPO deficiency.
references:
- reference: PMID:29262241
  title: "Myeloperoxidase Deficiency."
  tags:
  - StatPearls

📚

References & Deep Research

References

1

PMID:29262241

Myeloperoxidase Deficiency.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Myeloperoxidase Deficiency · 2026-09-23T19:58:07Z · View source

New entry for hereditary myeloperoxidase deficiency (MONDO:0009694, MPO), replacing stub stubs/Myeloperoxidase_Deficiency.yaml (claim issue #12618). The pathograph runs from MPO pathogenic variants through defective precursor maturation (ER retention and proteasomal degradation) to loss of neutrophil and monocyte MPO activity, then branches to impaired hypochlorous acid generation, failed NET formation and a compensatory respiratory-burst node; the first two converge on impaired candidacidal activity, which a hyperglycemia node (diabetes as the main clinical modifier) also feeds. 8 pathophysiology nodes, 7 phenotypes (all causally connected), 49 evidence items citing 26 PubMed records, all snippets verified against abstracts. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER); the StatPearls chapter PMID:29262241 is cited and tagged. One OpenScientist report was used: research/Myeloperoxidase_Deficiency-deep-research-openscientist.md. Its generation run exited non-zero because the report's term-validation step timed out against OLS (5 s read timeout); the report body and artifacts were written. Reference validation was then added with just validate-research-reference (19/19 resolved, 0 unresolved, 0 off topic) and term validation with the research term validator using local sqlite MONDO/HP adapters (25/27 resolved, 0 unresolved). Its HPO and NCIT suggestions that term validation flagged as naming different terms (for example NCIT:C305, NCIT:C1471, NCIT:C1505, HP:0200037) were not used; all bindings came from separate OLS and local OAK lookups. The report's statement that the DHR assay is normal in MPO deficiency (citing PMID:7813334) was not used because PMID:17384005 and PMID:27301573 show complete MPO deficiency gives a strongly reduced DHR signal. just preflight-dr returned PASS. Validation: just validate-disorders passed (schema, terms, 49/49 snippets); check-causal-targets, check-entity-refs, check-duplicate-keys, check-qualifier-terms, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading and check-reference-titles all OK; list-gene-term-mismatches found no mismatch; list-disconnected-phenotypes reports 7/7 phenotypes connected.

OpenScientist ▸

Myeloperoxidase Deficiency: A Comprehensive Disease Characteristics Report

openscientist-autonomous 16 citations 2026-09-23T19:38:01.219531

Myeloperoxidase Deficiency: A Comprehensive Disease Characteristics Report

Disease: Myeloperoxidase Deficiency MONDO ID: MONDO:0009694 | OMIM: #254600 | Gene: MPO (17q22.1) | Category: Mendelian (autosomal recessive)

Summary

Myeloperoxidase (MPO) deficiency is the most common inherited disorder of neutrophil function, occurring in roughly 1 in 2,000 to 4,000 individuals in Western populations, yet it is paradoxically one of the most clinically silent primary immunodeficiencies known (PMID: 9468285). The disorder arises from biallelic loss-of-function missense mutations in the MPO gene (e.g., R569W, Y173C, M251T) that cause the misfolded proMPO precursor to be retained in the endoplasmic reticulum via prolonged interaction with the chaperone calnexin, followed by proteasomal degradation. The result is neutrophils and monocytes that contain precursor protein but lack mature, enzymatically active MPO, peroxidase activity, and the capacity to generate chlorinating oxidants (PMID: 10482305).

The central biological function lost in MPO deficiency is the enzyme's unique ability to use chloride as a co-substrate with hydrogen peroxide to generate hypochlorous acid (HOCl), a potent antimicrobial oxidant (PMID: 17592500). Despite this, most affected individuals never develop clinical disease because the NADPH-oxidase-derived oxidant burst and other non-oxidative microbicidal systems compensate. The dominant clinical exception is disseminated candidiasis, which typically emerges only when a "second hit"—most classically diabetes mellitus—independently impairs residual antifungal killing (PMID: 2831185; PMID: 216438).

This report synthesizes seven confirmed findings across the full disease-characteristics template. The overarching narrative is one of a biochemistry-versus-clinical paradox: a complete and readily detectable enzymatic defect that is, in isolation, biologically well-tolerated. Because MPO-derived oxidants also drive inflammatory tissue damage and vascular disease, low-MPO states may even be partially protective against atherosclerotic cardiovascular disease and certain cancers, positioning MPO as a genuine "double-edged sword."

Key Findings

Finding 1 — MPO deficiency is the most common inherited neutrophil enzyme defect and is usually clinically silent

Hereditary MPO deficiency occurs in 1 in 2,000 to 4,000 individuals in the general population and has traditionally been regarded as an autosomal recessive trait (PMID: 9468285). Despite this high prevalence, the overwhelming majority of affected individuals are entirely asymptomatic. The explanation is functional redundancy: NADPH-oxidase-derived reactive oxygen species and non-oxidative microbicidal systems (defensins, proteases, lactoferrin) provide sufficient host defense in the absence of MPO-generated HOCl. Clinically significant sequelae are largely restricted to a subset of patients who carry an additional predisposing condition. As the classic review states, "In the absence of MPO, auxiliary mechanisms protect most MPO-deficient hosts from clinically significant sequelae, except for some persons with diabetes mellitus who suffer severe candidal disease" (PMID: 2831185).

Evidence quote: "Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population and has been generally considered an autosomal recessive trait." (PMID: 9468285)

Finding 2 — The molecular lesion: MPO missense mutations cause ER retention and defective post-translational maturation

Inherited MPO deficiency results from missense mutations in the MPO gene. The best-characterized alleles are R569W, Y173C, and M251T. In the Y173C genotype, the mutant proMPO precursor is retained in the endoplasmic reticulum through prolonged interaction with the chaperone calnexin and is ultimately degraded by the 20S proteasome. Consequently, affected neutrophils contain the precursor protein but lack mature MPO subunits, peroxidase enzymatic activity, and chlorination capacity (PMID: 10482305). The R569W mutation is the most frequently encountered allele; most studied patients are compound heterozygotes for R569W and demonstrate a spectrum of phenotypes ranging from complete to partial deficiency (PMID: 9468285). These mutations have served as a model system for understanding endoplasmic-reticulum quality control of secretory proteins more broadly (PMID: 15507769).

Evidence quotes: - "In the genotype Y173C, the mutant precursor is retained in the endoplasmic reticulum by virtue of its prolonged interaction with calnexin, and it eventually undergoes degradation in the 20S proteasome." (PMID: 10482305) - "Most subjects were compound heterozygotes with respect to the R569W mutation and demonstrated a spectrum of phenotypes." (PMID: 9468285)

Finding 3 — Animal models: MPO contributes to fungicidal defense, but NADPH oxidase is dominant

MPO-knockout (MPO⁻/⁻) mice develop normally but exhibit severely reduced cytotoxicity toward Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Klebsiella pneumoniae, confirming that the MPO-dependent oxidative system is important for antifungal and antibacterial host defense (PMID: 15507755). Head-to-head comparison with NADPH-oxidase-deficient (X-linked chronic granulomatous disease, X-CGD) mice reveals a clear hierarchy: X-CGD mice suffer shorter survival and 10–100× higher fungal tissue burdens than MPO⁻/⁻ mice. Critically, MPO cannot function without NADPH-oxidase-derived hydrogen peroxide, which is its obligate substrate. However, at the highest Candida inocula, the mortality of MPO⁻/⁻ mice approached that of CGD mice, indicating that MPO becomes rate-limiting under a heavy pathogen load (PMID: 12521119; PMID: 16940954).

Evidence quotes: - "Both MPO-deficient (MPO-/-) and NADPH-oxidase-deficient (X-linked chronic granulomatous disease [X-CGD]) mice showed increased susceptibility to pulmonary infections with Candida albicans and Aspergillus fumigatus compared with normal mice, and the X-CGD mice exhibited shorter survivals than MPO-/- mice." (PMID: 12521119) - "MPO is unable to play a role in host defense in the absence of NADPH-oxidase." (PMID: 12521119)

Finding 4 — The core enzymatic reaction: H₂O₂ + Cl⁻ → HOCl, a double-edged sword

MPO is a member of the heme peroxidase-cyclooxygenase superfamily and is abundantly stored in the azurophilic (primary) granules of neutrophils. Its unique catalytic activity is the use of chloride as a co-substrate with hydrogen peroxide to generate hypochlorous acid (HOCl), a potent antimicrobial agent (PMID: 17592500). This same chemistry is a liability: MPO-derived oxidants contribute to host tissue damage and to the initiation and propagation of acute and chronic vascular inflammatory disease, and circulating MPO levels predict adverse cardiac events. HOCl oxidatively modifies proteins—through amino-acid side-chain modification, backbone fragmentation, and aggregation—driving chronic inflammatory pathology (PMID: 31867603). This dual nature is the mechanistic foundation for why loss of MPO can be biologically tolerated and even confer protection in some disease contexts.

Evidence quotes: - "A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent." (PMID: 17592500) - "MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease." (PMID: 17592500)

Finding 5 — Classification and diagnosis: a primary immunodeficiency detected incidentally by hematology analyzers

MPO deficiency is listed among the primary immunodeficiencies that predispose to fungal infection (PMID: 17551753). Its high apparent prevalence is itself an artifact of modern laboratory medicine: "the relatively high prevalence of inherited MPO deficiency was an unanticipated insight provided by the widespread use of automated flow cytometry for the enumeration of leukocytes in clinical specimens" (PMID: 10482305). Automated hematology analyzers use the peroxidase (MPO) channel to perform leukocyte differentials, so MPO-deficient neutrophils are flagged incidentally in otherwise healthy people. Confirmation relies on cytochemical peroxidase staining of blood smears—MPO-deficient neutrophils and monocytes are peroxidase-negative while eosinophils remain positive (via eosinophil peroxidase, EPO)—and on direct MPO enzyme-activity assays. A known diagnostic pitfall is that EPO, which is normally expressed in MPO-deficient subjects, can confound leukocyte peroxidase measurements through eosinophil contamination (PMID: 9468285).

Evidence quotes: - "the relatively high prevalence of inherited MPO deficiency was an unanticipated insight provided by the widespread use of automated flow cytometry for the enumeration of leukocytes in clinical specimens." (PMID: 10482305) - "Eosinophil peroxidase (EPO) also contributes to the peroxidase activity of blood leukocytes. Because EPO expression is normal in MPO-deficient subjects, eosinophil contamination can significantly contribute to peroxidase activity." (PMID: 9468285)

Finding 6 — The MPO trade-off: low-expression -463A allele protects the heart but a high-expression genotype raises cancer risk

Distinct from the rare loss-of-function missense mutations that cause hereditary deficiency, a common functional promoter polymorphism, -463 G>A (rs2333227), quantitatively modifies MPO expression: the G allele confers higher expression than the A allele (PMID: 11479475). In French-Canadians, the low-expression AA genotype was associated with markedly decreased coronary artery disease (CAD) risk (recessive model OR 0.138, 95% CI 0.040–0.474), and carriage of the A allele (AA/AG vs GG) was protective (OR 0.639, 95% CI 0.436–0.937). Conversely, the high-expression GG genotype hastened hepatocellular carcinoma in HCV-related cirrhosis (HR 2.8, 95% CI 1.7–4.4; PMID: 21907168), and higher MPO activity has been implicated in leukemia and lung cancer through metabolic activation of carcinogens such as benzene (PMID: 17479404). These associations extend the biological "double-edged sword" to the population-genetics level, though some studies find no relationship between the promoter polymorphisms and neutrophil MPO release or cardiovascular risk (PMID: 19877306), so the effect is modest and not fully reproducible.

Evidence quotes: - "In a recessive model patients with the AA genotype had a decreased risk of CAD (odds ratio 0.138, 95% confidence interval 0.040-0.474)." (PMID: 11479475) - "the G allele associated with a higher level of MPO expression than the A allele." (PMID: 11479475) - "HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4])." (PMID: 21907168)

Finding 7 — The clinical phenotype is unmasked by a second hit: diabetes mellitus converts silent deficiency into candidal susceptibility

The classic clinical scenario for symptomatic MPO deficiency is a diabetic patient with disseminated or invasive candidiasis. In a landmark case, an MPO-deficient diabetic patient's granulocytes showed normal phagocytosis but microbicidal activity that was "almost nil with regard to Candida albicans"; crucially, "Fungicidal activity of normal granulocytes was shown to be impaired during the in vitro artificial hyperglycemic condition"—demonstrating that hyperglycemia independently degrades residual killing (PMID: 216438). MPO-deficient diabetics have developed Candida albicans liver abscess (PMID: 217268; PMID: 199939). Even in non-diabetics, disseminated pustular candidal dermatitis has occurred, particularly under limited-spectrum antibiotic therapy (PMID: 9114158). The unifying principle from Nauseef is that clinically significant disease is limited "except for some persons with diabetes mellitus who suffer severe candidal disease" (PMID: 2831185).

Evidence quotes: - "Fungicidal activity of normal granulocytes was shown to be impaired during the in vitro artificial hyperglycemic condition." (PMID: 216438) - "Patients who develop rapidly disseminated fungal dermatitis while they are receiving antimicrobial therapy that is relatively limited in coverage should be evaluated for myeloperoxidase deficiency." (PMID: 9114158)

Comprehensive Section-by-Section Report

1. Disease Information

Myeloperoxidase deficiency is an inherited disorder in which neutrophils and monocytes lack functional myeloperoxidase, the azurophilic-granule heme enzyme responsible for generating hypochlorous acid during the oxidative burst. It is the most common inherited defect of neutrophils. Two forms exist: complete (total) deficiency and partial deficiency, reflecting the genotype (homozygous vs. compound heterozygous / heterozygous for hypomorphic alleles).

Key identifiers:

Resource	Identifier
MONDO	MONDO:0009694
OMIM (phenotype)	#254600
OMIM (gene)	*606989
Gene (HGNC)	MPO, HGNC:7218
Gene locus	17q22.1
UniProt (protein)	P05164 (PERM_HUMAN)
Orphanet	ORPHA:59181
ICD-10	D70/D72.0 (functional disorders of neutrophils)
MeSH	related to "Peroxidase" / "Leukocyte Disorders"

Synonyms / alternative names: MPO deficiency; myeloperoxidase deficiency; hereditary myeloperoxidase deficiency; leukocyte myeloperoxidase deficiency; total/partial myeloperoxidase deficiency; Peroxidase deficiency.

Source of information: The knowledge base for this disorder is derived largely from aggregated disease-level resources (OMIM, primary case series, and reviews) combined with individual patient case reports; the high prevalence estimate itself derives from population-scale automated hematology analyzer data (PMID: 10482305).

2. Etiology

Causal factors: The disease is genetic (Mendelian, autosomal recessive), caused by biallelic loss-of-function mutations in MPO. It is not infectious or environmental in origin, though environmental/clinical co-factors (see below) determine whether it is expressed clinically.

Genetic risk factors: Causal variants include the missense mutations R569W (the most common, PMID: 9468285), Y173C, and M251T (PMID: 10482305, PMID: 15507769). The common promoter polymorphism -463 G>A (rs2333227) is a quantitative expression modifier rather than a cause of deficiency (PMID: 11479475).

Environmental/clinical risk factors for symptomatic disease (second hits): Diabetes mellitus / hyperglycemia is the principal unmasking factor, as it independently impairs granulocyte fungicidal activity (PMID: 216438). Additional triggers include limited-spectrum antimicrobial therapy (allowing fungal overgrowth) (PMID: 9114158) and high pathogen inoculum (PMID: 12521119).

Protective factors: From the host-defense standpoint, an intact NADPH oxidase and non-oxidative microbicidal systems are the key compensatory/protective mechanisms (PMID: 12521119). From a cardiovascular standpoint, the low-expression -463A allele may be protective against CAD (PMID: 11479475).

Gene–environment interaction: The paradigmatic GxE interaction is MPO genotype × diabetes mellitus: neither alone produces disseminated candidiasis, but their combination does (PMID: 216438; PMID: 217268). A second GxE axis is MPO-463 genotype × carcinogen exposure (e.g., benzene, tobacco smoke), where higher MPO activity enhances procarcinogen activation (PMID: 17479404).

3. Phenotypes

Most individuals are asymptomatic (laboratory abnormality only). When present, phenotypes are infectious.

Phenotype	Type	Onset	Severity	Frequency	Suggested HPO
Peroxidase-negative neutrophils/monocytes	Laboratory abnormality	Congenital	—	~100% of affected	HP:0011990 (abnormal granulocyte morphology) / lab finding
Recurrent/disseminated candidiasis	Clinical sign / infection	Any age (typically adult)	Severe when present	Rare; mainly with diabetes	HP:0002728 (chronic mucocutaneous candidiasis)
Candidal (hepatic) abscess	Clinical sign	Adult	Severe	Rare	HP:0100523 (hepatic abscess)
Pustular candidal dermatitis	Physical manifestation	Variable	Moderate–severe	Rare	HP:0200037 (pustule)
Increased susceptibility to fungal/bacterial infection	Clinical sign	Variable	Mild–severe	Minority	HP:0002719 (recurrent infections)

Quality-of-life impact: For the asymptomatic majority, there is no measurable QoL impact; the condition is compatible with normal life. For the rare symptomatic subset, invasive candidiasis carries substantial morbidity and potential mortality. No disease-specific EQ-5D/SF-36 data are available for MPO deficiency.

4. Genetic / Molecular Information

Causal gene: MPO (myeloperoxidase), chromosome 17q22.1, OMIM gene 606989; disease OMIM #254600. Protein: myeloperoxidase, UniProt P05164, a heme peroxidase-cyclooxygenase superfamily enzyme (PMID: 17592500).

Pathogenic variants:

Variant	Type	Consequence	Notes
R569W	Missense	Loss of function; defective maturation	Most common allele; often compound heterozygous (PMID: 9468285)
Y173C	Missense	ER retention via calnexin; 20S proteasomal degradation	Model for ER quality control (PMID: 10482305)
M251T	Missense	Loss of function / defective maturation	(PMID: 15507769)
-463 G>A (rs2333227)	Promoter SNP	Expression modifier (not causal)	Common quantitative variant (PMID: 11479475)

Functional consequence: Loss of function — absence of mature MPO subunits, peroxidase activity, and chlorination capacity (PMID: 10482305). Origin: germline. Modifier genes: CYBB/NADPH-oxidase components determine the functional consequence of MPO loss (compensatory); the MPO -463 promoter genotype modifies expression quantitatively. Epigenetic / chromosomal abnormalities: none characteristically associated with the Mendelian form.

5. Environmental Information

The disorder is genetically determined; environmental factors act only as modifiers of clinical expression. Relevant factors: hyperglycemia/diabetes (impairs residual fungicidal activity, PMID: 216438); broad- vs. limited-spectrum antibiotic exposure (fungal overgrowth risk, PMID: 9114158); and carcinogen exposure interacting with MPO-463 genotype (PMID: 17479404). Infectious agents are consequences, not causes: chiefly Candida albicans, and in models Aspergillus fumigatus, Cryptococcus neoformans, and Klebsiella pneumoniae (PMID: 15507755).

6. Mechanism / Pathophysiology

Ordered causal chain (from genetic lesion to clinical manifestation):

1. Biallelic MPO missense mutation (e.g., R569W, Y173C, M251T)
│ leads to
2. Misfolded proMPO precursor
│ leads to (Y173C) prolonged calnexin binding → ER retention
3. Proteasomal (20S) degradation of the precursor
│ results in
4. Absence of mature, enzymatically active MPO in azurophilic granules
│ results in
5. Loss of the reaction  H2O2 + Cl-  →  HOCl (hypochlorous acid)
│ results in
6. Impaired oxidative (HOCl-mediated) microbial killing
│
├── BRANCH A (usual outcome): NADPH oxidase + non-oxidative
│    systems compensate → CLINICALLY SILENT
│
└── BRANCH B (second hit present, e.g., diabetes/hyperglycemia,
     or heavy pathogen inoculum): residual killing overwhelmed
  │ leads to
     7. Failure to contain Candida albicans
  │ leads to
     8. Disseminated / invasive candidiasis (e.g., hepatic abscess,
pustular dermatitis) → CLINICAL DISEASE

A parallel, beneficial branch stems from step 5: because HOCl also damages host tissue and oxidatively modifies host proteins (PMID: 31867603), reduced MPO oxidant output lowers vascular inflammatory injury, plausibly underlying the reduced CAD risk seen with the low-expression -463A allele (PMID: 11479475).

Molecular pathways / biochemistry: The lost reaction is the halide-oxidation cycle of a heme peroxidase (Compound I / Compound II redox intermediates); MPO uniquely oxidizes chloride to HOCl (PMID: 17592500). Cellular processes: neutrophil respiratory burst, phagolysosomal microbial killing, and inflammation. Protein dysfunction: misfolding → ER retention → proteasomal degradation (loss of function) (PMID: 10482305). Immune involvement: primary immunodeficiency of the innate/phagocytic arm (PMID: 17551753). Tissue-damage mechanism (the flip side): HOCl-mediated oxidative protein modification, backbone fragmentation, and aggregation in chronic inflammation (PMID: 31867603).

Suggested ontology terms: GO:0006979 (response to oxidative stress); GO:0042744 (hydrogen peroxide catabolic process); GO:0002446 (neutrophil mediated immunity); GO:0043312 (neutrophil degranulation). Chemicals: CHEBI:24757 (hypochlorous acid); CHEBI:16240 (hydrogen peroxide); CHEBI:17996 (chloride). Cell types: CL:0000775 (neutrophil), CL:0000576 (monocyte). Upstream = mutation/ER retention; downstream = impaired killing and infection.

7. Anatomical Structures Affected

Primary cells: neutrophil granulocytes (CL:0000775) and monocytes (CL:0000576); eosinophils are spared (they express eosinophil peroxidase) (PMID: 217268).
Subcellular compartment: azurophilic (primary) granules — GO:0042582 (azurophil granule); the enzymatic block occurs in the endoplasmic reticulum (GO:0005783) (PMID: 10482305).
Body system: hematopoietic / innate immune system (UBERON:0002390 hematopoietic system; UBERON:0000178 blood).
Secondary organ involvement (only in symptomatic disease): liver (candidal abscess; UBERON:0002107), skin (pustular candidal dermatitis; UBERON:0002097), and lungs in animal models (UBERON:0002048). Involvement is typically systemic/disseminated rather than lateralized.

8. Temporal Development

Onset: the enzymatic defect is congenital; the laboratory abnormality is present from birth. Clinical infection, when it occurs, is usually adult-onset and tied to acquisition of a second hit (e.g., diabetes).
Course: the underlying deficiency is chronic and lifelong but static. Infectious episodes are episodic/acute, precipitated by co-factors.
Progression: the enzyme defect itself does not progress. There are no defined disease "stages." Critical period for intervention: aggressive antifungal therapy at the onset of disseminated candidiasis; and control of comorbid hyperglycemia as ongoing prophylaxis.

9. Inheritance and Population

Prevalence: approximately 1 in 2,000 to 4,000 (≈25–50 per 100,000) for at least partial deficiency in Western populations; complete deficiency is rarer (PMID: 9468285).
Inheritance: autosomal recessive with variable expressivity (PMID: 9468285; PMID: 199939). Compound heterozygosity (especially involving R569W) is common.
Penetrance: biochemically high (the enzyme defect is consistently detectable), but clinical penetrance is very low — most homozygotes/compound heterozygotes are asymptomatic.
Expressivity: variable, from partial to complete enzyme loss and from silent to symptomatic (PMID: 199939).
Sex ratio / geography / founder effects: no strong sex predilection or well-defined founder effect is established for the classic missense alleles; the -463 promoter allele frequencies vary by population (PMID: 17479404).

10. Diagnostics

Incidental detection: flagged by automated hematology analyzers using the peroxidase (MPO) channel during routine leukocyte differentials (PMID: 10482305).
Confirmatory tests: cytochemical peroxidase staining of a peripheral blood smear (neutrophils/monocytes peroxidase-negative, eosinophils positive) and MPO enzyme-activity assays (PMID: 9468285; PMID: 217268).
Diagnostic pitfall: eosinophil peroxidase (EPO), normally expressed in MPO-deficient subjects, can contribute to measured leukocyte peroxidase and confound results (PMID: 9468285).
Distinguishing from CGD: flow-cytometric assays of the oxidative burst (e.g., dihydrorhodamine-123) are normal in MPO deficiency but abnormal in chronic granulomatous disease—an important differential (PMID: 7813334).
Genetic testing: MPO single-gene sequencing / immunodeficiency gene panels can confirm biallelic variants; useful for family counseling but not required for diagnosis.
Differential diagnosis: chronic granulomatous disease (NADPH-oxidase defect), other neutrophil functional disorders, and secondary/acquired MPO deficiency (e.g., myelodysplasia, certain drugs).

11. Outcome / Prognosis

Overall prognosis is excellent. Most individuals have normal life expectancy and no increased infection burden.
Mortality/morbidity is confined to the rare symptomatic subset with invasive candidiasis, where outcome depends on prompt antifungal therapy and control of comorbid conditions (PMID: 2831185; PMID: 217268).
Prognostic factors: presence of diabetes mellitus/hyperglycemia, completeness of enzyme deficiency, pathogen inoculum, and breadth of antimicrobial coverage (PMID: 216438; PMID: 12521119).
Potential benefit: reduced MPO oxidant load may lower atherosclerotic cardiovascular risk (PMID: 11479475), an unusual "protective" dimension of an immunodeficiency.

12. Treatment

No specific therapy exists or is required for the enzyme deficiency itself.
Management is directed at infections and comorbidities: prompt antifungal therapy for candidiasis (e.g., azoles, echinocandins, lipid amphotericin B formulations, which have expanded options for fungal infection in primary immunodeficiencies, PMID: 17551753) and tight glycemic control in diabetic patients as the single most important preventive measure (PMID: 216438).
Antibiotic stewardship: avoiding unnecessary limited-spectrum regimens that promote fungal overgrowth (PMID: 9114158).
Advanced/gene therapy: none developed or indicated given the benign natural history. NCIT suggestions: NCIT:C305 (Amphotericin B), NCIT:C1471 (antifungal agent), NCIT:C1505 (azole antifungal).

13. Prevention

Primary prevention: not applicable to the genetic defect; genetic counseling for affected families (autosomal recessive recurrence risk) is appropriate.
Secondary/tertiary prevention: the highest-yield intervention is prevention and control of diabetes/hyperglycemia to avoid unmasking clinical disease (PMID: 216438); clinical vigilance for candidal infection in at-risk deficient patients; and judicious antibiotic use (PMID: 9114158).
Screening: no population-based newborn screening is indicated because clinical penetrance is very low; incidental analyzer detection effectively serves as opportunistic case-finding.

14. Other Species / Natural Disease

Model species with MPO orthologs: Mus musculus (mouse Mpo), used in knockout studies (PMID: 15507755). MPO is evolutionarily conserved within the heme peroxidase-cyclooxygenase superfamily (PMID: 17592500).
Comparative biology: the mouse MPO⁻/⁻ phenotype (impaired fungicidal activity, normal development) parallels the human condition, supporting conserved mechanism (PMID: 12521119). No prominent naturally occurring companion-animal MPO deficiency disorder is documented in the reviewed literature. Not zoonotic.

15. Model Organisms

Primary model: MPO-knockout (MPO⁻/⁻) mouse (PMID: 15507755).
Comparator model: X-linked CGD (NADPH-oxidase-deficient) mouse, and MPO⁻/⁻ × X-CGD double knockouts, used to dissect the relative contributions of MPO vs. the oxidase (PMID: 12521119).
Phenotype recapitulation: good — MPO⁻/⁻ mice develop normally but show reduced antifungal killing, matching the human "silent-except-under-stress" phenotype; at high inoculum they approach CGD-level mortality, mirroring the human second-hit phenomenon (PMID: 15507755; PMID: 16940954).
Limitations: murine neutrophil biology differs from human; models do not fully capture the diabetes-interaction axis or human population genetics of the -463 polymorphism.
In vitro systems: patient granulocyte functional assays and neutrophil lysate MPO-activity assays have been central to mechanistic work (PMID: 216438; PMID: 19877306).

Mechanistic Model / Interpretation

MPO deficiency is best understood as a conditional, redundancy-buffered immunodeficiency. The genetic lesion reliably abolishes a specific biochemical capability—HOCl generation—yet the clinical system it feeds into is robust because a parallel, more powerful effector (NADPH oxidase) and non-oxidative killing remain intact. This explains the disease's defining paradox: a 100%-penetrant biochemical defect with near-0% clinical penetrance.

The "double-edged sword" framing unifies the seemingly disparate findings:

Context	MPO/HOCl HIGH	MPO/HOCl LOW (deficiency or -463A)
Antifungal defense	Effective killing	Impaired (Findings 3, 4)
Under a second hit (diabetes, heavy inoculum)	Protected	Susceptible → candidiasis (Finding 7)
Vascular inflammation / CAD	Higher risk	Reduced risk (Finding 6)
Carcinogen activation (leukemia, HCC)	Higher risk (GG genotype)	Reduced risk (Finding 6)

The clinical decision node is the second hit. Absent one, the deficiency is a laboratory curiosity; present one, it can produce life-threatening invasive fungal disease. Diabetes is the archetype because hyperglycemia independently degrades the residual killing capacity that would otherwise compensate.

Evidence Base

PMID	Title (abbrev.)	Role in this report
9468285	Inheritance & R569W mutation	Prevalence, AR inheritance, compound heterozygosity, EPO diagnostic pitfall
10482305	ER quality control, MPO deficiency	ER retention/calnexin/proteasome mechanism; incidental analyzer diagnosis
15507769	Structural features from MPO deficiency	Catalog of causal missense mutations
15507755	In vivo role of MPO	MPO-KO fungicidal defect
12521119	MPO vs NADPH-oxidase	Relative contributions; MPO depends on oxidase
16940954	MPO in antifungal defense (review)	High-inoculum equivalence with CGD
17592500	MPO: drug target?	Core HOCl chemistry; tissue-damage duality
31867603	HOCl protein modification	Tissue-damage mechanism
11479475	MPO -463 & CAD (French-Canadians)	Protective low-expression allele
21907168	MPO promoter & HCC	High-expression genotype raises cancer risk
17479404	MPO SNPs & leukemia	Carcinogen-activation trade-off
216438	Hereditary MPO deficiency (case)	Hyperglycemia impairs fungicidal activity
217268	MPO deficiency + diabetes + Candida liver abscess	Second-hit clinical syndrome
9114158	Pustular candidal dermatitis	Non-diabetic trigger; management advice
2831185	MPO deficiency (review)	Clinical silence except diabetic candidiasis
17551753	Fungal infections in PIDs	Classifies MPO deficiency among PIDs
7813334	Flow cytometry for CGD variants	DHR assay distinguishes MPO deficiency from CGD
19877306	MPO promoter SNPs & neutrophil activation	Challenges reproducibility of -463 CVD link
199939	Hereditary MPO deficiency (genetics)	AR transmission, variable expressivity

Challenging/qualifying evidence: PMID: 19877306 found no relationship between the -129/-463 promoter polymorphisms and neutrophil MPO release or reactive oxygen production, cautioning that the -463/CVD association is modest and inconsistently reproducible. This tempers Finding 6.

Limitations and Knowledge Gaps

No primary dataset was analyzed — this is a literature-synthesis report; findings rest on published case series, reviews, and mouse models rather than newly generated statistics.
Prevalence uncertainty — the 1:2,000–4,000 figure is Western/analyzer-derived and may not generalize globally; complete vs. partial deficiency proportions are imprecise.
Clinical penetrance is not precisely quantified — the fraction of deficient individuals who ever develop candidiasis, and its dependence on diabetes severity, lacks large cohort estimates.
-463 polymorphism associations are inconsistent — cardiovascular and cancer associations vary across populations and are not robustly reproducible (PMID: 19877306).
Genotype–phenotype granularity — beyond R569W/Y173C/M251T, the full variant spectrum, allele frequencies (gnomAD), and ACMG classifications were not exhaustively enumerated here.
Human GxE quantification — the diabetes × MPO interaction is well-supported mechanistically but not quantified with modern epidemiology.

Proposed Follow-up Experiments / Actions

Quantify clinical penetrance via a registry/EHR cohort of MPO-deficient individuals stratified by diabetes status, estimating the absolute and relative risk of invasive candidiasis.
Comprehensive variant curation — mine ClinVar/gnomAD for the full MPO pathogenic variant spectrum, allele frequencies, and ACMG/AMP classifications; report carrier frequencies by ancestry.
Meta-analysis of the -463 G>A polymorphism across cardiovascular and oncologic endpoints to resolve the reproducibility conflict between PMID: 11479475 and PMID: 19877306.
Mechanistic modeling of the second hit — in vitro MPO-deficient neutrophils under controlled glucose to dissect how hyperglycemia degrades residual (NADPH-oxidase-dependent) Candida killing.
Test the cardiovascular-protection hypothesis prospectively in genetically confirmed complete MPO-deficient individuals (atherosclerosis imaging vs. matched controls).
HPO/ontology annotation package — formalize the phenotype-frequency table above into HP-term associations for the disease knowledge base, with CL:0000775 (neutrophil), UBERON, and CHEBI:24757 (hypochlorous acid) links.

Report compiled from a 5-iteration autonomous investigation; 7 confirmed findings; 28 papers reviewed. Evidence source types span human clinical case series/reviews, mouse knockout models, and in vitro neutrophil assays.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	27
Resolved	25
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	20
Terms named correctly	13
Terms named as a different term	5
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0009694 (3 mentions) - the report calls it "if available", "MONDO"; MONDO calls it myeloperoxidase deficiency
HP:0200037 (1 mention) - the report calls it "pustule"; HP calls it Skin vesicle
NCIT:C305 (1 mention) - the report calls it "Amphotericin B"; NCIT calls it Bilirubin
NCIT:C1471 (1 mention) - the report calls it "antifungal agent"; NCIT calls it Lamivudine
NCIT:C1505 (1 mention) - the report calls it "azole antifungal"; NCIT calls it Dietary Supplement

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0011990 (1 mention) - the report calls it "abnormal granulocyte morphology"; HP calls it Abnormal neutrophil physiology
CL:0000775 (3 mentions) - the report calls it "neutrophil", "Primary cells: neutrophil granulocytes"; CL calls it neutrophil**, and lists "neutrophil leucocyte" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0009694 - called "if available", "MONDO"
CL:0000775 - called "neutrophil", "Primary cells:** neutrophil granulocytes"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

Ask OpenScientist

OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Myeloperoxidase Deficiency: A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — MPO deficiency is the most common inherited neutrophil enzyme defect and is usually clinically silent

Finding 2 — The molecular lesion: MPO missense mutations cause ER retention and defective post-translational maturation

Finding 3 — Animal models: MPO contributes to fungicidal defense, but NADPH oxidase is dominant

Finding 4 — The core enzymatic reaction: H₂O₂ + Cl⁻ → HOCl, a double-edged sword

Finding 5 — Classification and diagnosis: a primary immunodeficiency detected incidentally by hematology analyzers

Finding 6 — The MPO trade-off: low-expression -463A allele protects the heart but a high-expression genotype raises cancer risk

Finding 7 — The clinical phenotype is unmasked by a second hit: diabetes mellitus converts silent deficiency into candidal susceptibility

Comprehensive Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver