Version May 2024
INTRODUCTION — There are a small number of well-described genetic defects in hematopoietic cell enzymes or transporter proteins that result in neutrophil dysfunction and immunodeficiency. Two of these, myeloperoxidase (MPO) deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency, are relatively common. The others presented in this topic review, glutathione reductase (GR) deficiency, glutathione synthetase (GS) deficiency, and glycogen storage disease type Ib (GSD Ib), are rare.
This topic review provides an overview of the genetic defects responsible for each of these disorders, the underlying mechanism of neutrophil or leukocyte dysfunction in each condition that leads to immunodeficiency, and the clinical manifestations, diagnosis, and treatment for each disorder.
G6PD deficiency and glucose-6 phosphatase deficiency are mentioned briefly here and discussed in greater detail separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Congenital neutropenia".)
MYELOPEROXIDASE DEFICIENCY — MPO deficiency (MIM #254600) is an autosomal recessive inherited disorder with a variable clinical phenotype. It is also the most common primary phagocyte disorder [1-4]:
●1 in 4000 persons have complete MPO deficiency
●1 in 2000 have a partial defect
Genetics — MPO is encoded by a gene located at 17q23. MPO deficiency can either be inherited or acquired. The hereditary form is the most frequent. Primary (inherited) MPO deficiency has variable expression and penetrance. A number of germline pathogenic variants result in primary MPO deficiency. Some of these cause defective posttranslational processing of the MPO precursor protein, while pathogenic variants in the regulatory region cause pretranslational defects [5]. MPO loss-of-function genetic mutations are associated with increased neutrophil counts and inflammatory pustular skin disease [6]. The mechanism of development of an acquired MPO deficiency, observed in patients with hematopoietic stem cell neoplasms such as myelofibrosis, is unknown [7-9], except for a report of homozygous calreticulin mutations leading to acquired MPO deficiency in patients with Philadelphia chromosome-negative myeloproliferative neoplasms [9].
Biology of myeloperoxidase — MPO is a tetramer of 150 kDa consisting of two heavy chains, two light chains, and two iron atoms. MPO is synthesized in neutrophils and monocytes, packaged in azurophilic (primary) granules, and released either into the phagosome or the extracellular space. MPO is the most abundant enzyme in the azurophilic granules and plays a critical role in bacterial killing by neutrophils. Deficient cells take approximately twice as long as normal cells to kill pathogens in vitro [10,11]. MPO serves many other roles in the human organism. It is important in the homeostasis of reactive oxidants and also can act as both a proinflammatory and an antiinflammatory mediator [12].
MPO catalyzes the conversion of hydrogen peroxide (H2O2) to hypohalous acid (in neutrophils, the halide is chloride [Cl-] and the acid is bleach) (figure 1). This reaction is thought to amplify the toxicity of the reactive oxygen species generated during the respiratory burst against bacteria and fungi.
Neutrophils release neutrophil extracellular traps (NETs), structures composed of decondensed chromatin and granule proteins that are thought to trap and kill pathogens, as part of their extracellular killing tools. Reactive oxygen species are required to initiate NET formation. Neutrophil elastase and MPO synergize to drive chromatin decondensation, contributing to this mechanism of extracellular killing of microorganisms [13].
Clinical manifestations — The majority of patients with MPO deficiency are asymptomatic, even though in vitro studies reveal that MPO-deficient neutrophils are markedly less efficient than normal neutrophils in killing Candida albicans and hyphal forms of Aspergillus fumigatus [14,15].
Fungal infections — Infections due to different Candida strains are the most frequently reported clinical finding in the small percentage of patients with MPO deficiency who are symptomatic. Mucocutaneous, meningeal, and bone infections, as well as sepsis, have been described [4,16-20]. The presence of diabetes mellitus [1,21,22] or cancer [23,24] appears to increase the risk for Candida infections in patients with MPO deficiency. Patients with MPO deficiency do not generally develop invasive aspergillosis, indicating the existence of a critical MPO-independent system.
Noninfectious diseases — MPO deficiency is associated with an increased risk for chronic inflammatory diseases (eg, polyarthritis, autoimmune lupus nephritis, diabetes mellitus) due to its role as an antiinflammatory mediator [12,25]. This is consistent with the finding that anti-MPO antibodies are strongly associated with vasculitis (eg, granulomatosis with polyangiitis and microscopic polyangiitis) (see "Clinical spectrum of antineutrophil cytoplasmic autoantibodies"). However, MPO deficiency may also have beneficial effects, which is an expanding area of investigation [25-27]. As examples, MPO deficiency may protect against cardiovascular damage, progression of chronic kidney disease, and skin injury due to an acute inflammatory response [28-30].
Diagnosis — MPO deficiency is one of the diagnoses that should be suspected in patients with unexplained, recurrent, invasive Candida infections. However, the vast majority of patients with MPO deficiency never develop invasive Candida infections. Definitive diagnosis is established by histochemical staining of neutrophils for MPO, which is available through commercial labs. The clinical relevance of identifying MPO deficiency in a particular patient, however, is less straightforward. Because so many patients with MPO deficiency are completely asymptomatic, patients with recurrent mucocutaneous candidiasis should be carefully evaluated for acquired immunodeficiency states, such as diabetes mellitus and human immunodeficiency virus (HIV) infection, as well as other primary immune defects, even if MPO deficiency is identified.
MPO deficiency was previously a common incidental finding because the machines that performed automated leukocyte differential counts used to rely upon staining for MPO activity to obtain the neutrophil count [31]. Patients with MPO deficiency had populations of "large unstained cells" in their automated differential counts that were not borne out by manual performance of the differential count. Additionally, patients with MPO deficiency are sometimes erroneously diagnosed with chronic granulomatous disease (CGD) [32].
Differential diagnosis — The differential diagnosis in a patient with invasive Candida infections, without external immune suppression, includes CGD and autosomal dominant signal transducer and activator of transcription (STAT) 3 deficiency (Job syndrome or autosomal dominant hyperimmunoglobulin E syndrome [HIES]), STAT1 gain of function, and autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) [33]. Complete MPO deficiency causes an abnormal dihydrorhodamine oxidation (DHR) test [32] and may therefore be misdiagnosed as CGD. (See "Primary disorders of phagocyte number and/or function: An overview" and "Autosomal dominant hyperimmunoglobulin E syndrome" and "Chronic mucocutaneous candidiasis" and "Approach to the child with recurrent infections".)
Treatment — There is no specific treatment for MPO deficiency. Infections should be aggressively treated when they occur, and control of blood glucose may be beneficial in patients with associated diabetes. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Primary disorders of phagocyte number and/or function: An overview".)
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY — Glucose-6-phosphate dehydrogenase (G6PD; Xq28) deficiency (MIM #305900) is the most common enzymopathy in humans, affecting 400 million persons worldwide. However, most persons with G6PD deficiency are asymptomatic. There are five classes of variants based upon the functional severity of the deficiency, with class I characterized by severe deficiency resulting in chronic, nonspherocytic, hemolytic anemia, ranging to class V with greater than 150 percent of normal activity [34,35].
G6PD is required for nicotinamide adenine dinucleotide phosphate (NADPH) generation through the hexose monophosphate pathway. NADPH is necessary for the respiratory burst and is also crucial in preserving red blood cells from oxidative damage (figure 1). However, neutrophil dysfunction in G6PD deficiency is less frequent than expected. This may be because most affected patients have more than 20 percent of G6PD activity in neutrophils, a threshold sufficient to maintain the respiratory burst within the normal range [36,37].
Rarely, patients with severe G6PD deficiency (less than 5 percent of the enzyme activity in neutrophils) have increased susceptibility to infections due to impairment of the neutrophil respiratory burst. Recurrent bacterial pulmonary infections and one death due to Chromobacterium violaceum sepsis have been described [36-43]. G6PD deficiency predisposes to septic complications and anemia in patients who have suffered severe traumatic injuries. This is accompanied by increased monocyte oxidative stress, decreased apoptotic response, increased cell adhesion, and diminished interleukin (IL) 10 response [44]. Prophylactic antibiotics (eg, cephalosporins, quinolones) may be helpful in the few cases with recurrent infections. Cotrimoxazole should be avoided as it may exacerbate hemolysis in G6PD deficiency. As in other primary phagocyte immunodeficiencies, infections must be aggressively treated. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Primary disorders of phagocyte number and/or function: An overview".)
G6PD deficiency is discussed in greater detail separately. (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
GLUTATHIONE PATHWAY ALTERATIONS — The reduced form of glutathione (GSH) protects cells from the deleterious effects of reactive oxygen species that are produced during the respiratory burst and the metabolism of uric acid. In neutrophils, GSH is critical for preserving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.
Glutathione reductase (GR; 8p21.1) and glutathione synthetase (GS; 20q11.2) are involved in maintaining adequate intracellular levels of GSH (figure 1) [36]. GR deficiency (MIM #138300) and GS deficiency (MIM #266130, #231900) are rare, autosomal recessive inherited diseases. (See "Rare RBC enzyme disorders".)
Clinical manifestations — Both GR and GS deficiencies are associated with hemolysis after increased oxidant stress such as infection, diet, and certain medications such as dapsone and sulfa-based medications, as well as primaquine (table 1). GS- but not GR-deficient patients have an increased risk of infections.
Glutathione synthetase deficiency — Mild, moderate, and severe clinical presentations are described for GS deficiency. Mutations causing frameshifts, premature stop codons, or aberrant splicing are associated with moderate or severe clinical phenotypes [45].
●Mildly affected patients have isolated hemolytic anemia.
●Moderately affected patients have hemolytic anemia and metabolic acidosis with increased 5-oxoproline levels.
●Severely affected patients have hemolytic anemia, metabolic acidosis with increased 5-oxoproline levels, and progressive dysfunction of the central nervous system (CNS). These patients also have recurrent bacterial infections. Impairments in phagocytosis and intracellular bacterial killing have been described [46-48].
Glutathione reductase deficiency — Premature termination of the respiratory burst is described in patients with GR deficiency. These patients have hemolytic anemia, but no increased infection rate has been reported.
Diagnosis — The diagnoses of GS and GR deficiency are based upon the presence of characteristic clinical manifestations (hemolytic anemia with or without metabolic acidosis, progressive neurodevelopmental defects, and recurrent bacterial infections) and results of specific laboratory tests:
●Patients with GS deficiency present with elevated 5-oxoprolinuria (pyroglutamic aciduria) in the urine and low GSH in erythrocytes (as measured by a standard colorimetric test). GS activity in cultured fibroblasts can also be measured.
●GR activity is low in GR deficiency and can be measured in red cell hemolysates both in the presence or absence of flavin adenine dinucleotide (FAD).
The abovementioned tests are commercially available, although the number of laboratories performing them is small [49].
Neonatal screening for GS deficiency is effective since the most important determinants for outcome and survival in these patients are early diagnosis and initiation of treatment [50].
In children who present with early-onset hemolysis, metabolic acidosis, and neurologic changes, the differential diagnosis includes other inborn errors of metabolism such as X-linked ornithine transcarbamylase deficiency, urea cycle defects, tyrosinemia, and homocystinuria [51].
Treatment — Exposure to drugs and chemicals with oxidant potential should be avoided, as in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (table 1). Daily supplementation with vitamin E 400 international units has shown neutrophil functional improvement in vitro and reduced infection rates in patients with GS deficiency in vivo [52,53]. As in other primary phagocyte immunodeficiencies, infections must be aggressively treated. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Management' and "Primary disorders of phagocyte number and/or function: An overview".)
GLYCOGEN STORAGE DISEASE Ib — Glycogen storage disease (GSD) type Ib (MIM #232200) is characterized by the inability to convert glucose-6-phosphate to glucose within the liver due to an autosomal recessive defect in the glucose-6-phosphate transporter 1 (also called the G6P translocase) encoded on chromosome 11q23 [54]. The incidence of GSD I is 1 in 100,000 livebirths [55]. GSD Ib may present early in life with fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly, and seizures, as well as neutropenia and neutrophil dysfunction with recurrent sinopulmonary infections. (See "Congenital neutropenia" and "Laboratory evaluation of neutrophil disorders".)
Deficient neutrophil chemotaxis and defective respiratory burst result in an increased incidence of infections [56,57]. In one study, 15 of 21 subjects with GSD Ib deficiency had moderate-to-severe infections, which were primarily due to bacteria affecting the ears, lungs, and skin. However, in a study of 25 GSD Ib patients, no correlation was found between individual pathogenic variants and the presence of neutropenia, bacterial infections, and systemic complications [55]. Therefore, background genetics and other influences likely modulate neutrophil differentiation, maturation, and apoptosis and thus the severity and frequency of infections.
The diagnosis of GSD Ib should be considered in patients with any combination of the characteristic clinical manifestations, including lactic acidosis, hyperlipidemia, neutropenia, neutrophil dysfunction, and an increased rate of infections. These patients can have oral disease, ranging from ulcers to severe periodontal disease [58]. Increased autoimmunity including inflammatory bowel disease [8], Crohn disease [59,60], thyroid autoimmunity [61], and myasthenia gravis [62] has been reported in patients with GSD Ib. Identification of pathogenic variants confirms the diagnosis [54].
Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used successfully to counter neutropenia and immune dysfunction, as well as improve the symptoms of inflammatory bowel disease [63-66]. In a study of seven patients with severe and/or recurrent bacterial infections, G-CSF at a median dose of 5 mcg/kg per day increased the absolute neutrophil count in six and prevented recurrent infection in all seven [65]. The use of G-CSF may also improve phagocytic function through calcium mobilization and superoxide anion generation, although defective neutrophil chemotaxis persisted after G-CSF treatment in one study [64]. Splenomegaly is a potential consequence of G-CSF therapy. All 13 patients in one study developed splenomegaly [63], but this was mild in five individuals, and none required splenectomy. A review of 103 adults and children with GSD Ib who received low-dose G-CSF revealed that, overall, there was a decrease in severity and frequency of infections and an improvement in enterocolitis and cytopenia [67]. However, even at low doses 1 to 2 mcg/kg/day, 70 percent of patients had worsening splenomegaly. Abdominal pain and early satiety also limited therapy with G-CSF. There are reports of several cases of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) developing in GDS Ib patients after receiving long-term therapy with G-CSF [68-70]. Monitoring long-term response to G-CSF is critical given these reports. As in other primary phagocyte immunodeficiencies, infections, when present, should be aggressively treated. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Primary disorders of phagocyte number and/or function: An overview".)
Preliminary evidence suggests that empagliflozin has the potential to become the first-line treatment for neutropenia and neutrophil dysfunction-related symptoms in persons with GSD Ib [71]. Dietary therapy maintains the patient's blood glucose levels and reduces the early symptoms. However, long-term complications such as hepatocellular adenoma (HCA), hepatocellular carcinoma (HCC), and kidney failure still occur. Liver-directed gene therapy in a GSD Ib mouse model showed promise in correcting metabolic abnormalities and preventing development of HCA, but did not correct myeloid and kidney dysfunction [71-74].
GSD Ib is discussed in greater detail separately. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Overview – Genetic defects in hematopoietic cell enzymes or transporter proteins can cause neutrophil dysfunction and immunodeficiency. Myeloperoxidase (MPO) deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency are relatively common disorders, while others are rare. (See 'Introduction' above.)
●Myeloperoxidase deficiency – MPO deficiency is the most common primary disorder of phagocytes, although the vast majority of affected individuals are asymptomatic. Recurrent Candida infections are seen in the small number of patients who do manifest symptoms, and MPO deficiency may play a role in the development of Candida infections in patients with diabetes mellitus or malignancies. The diagnosis is established genetically or by histochemical staining of neutrophils for MPO, and there is no specific corrective therapy. (See 'Myeloperoxidase deficiency' above.)
●Glucose-6-phosphate deficiency – G6PD deficiency is the most common enzymopathy in humans. G6PD is necessary for the neutrophil respiratory burst and also protects red blood cells from oxidative damage. It is an X-linked disorder that most often presents with hemolytic anemia. Patients with severe deficiency may have increased susceptibility to bacterial infections and sepsis. Treatment of immune dysfunction may include prophylactic antibiotics and aggressive treatment of infections. (See 'Glucose-6-phosphate dehydrogenase deficiency' above and "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
●Glutathione pathway deficiencies – Deficiencies of glutathione reductase (GR) and glutathione synthetase (GS) are extremely rare, autosomal recessive diseases. Severe GS deficiency may present with hemolytic anemia, metabolic acidosis, progressive central nervous system (CNS) defects, and recurrent bacterial infections. Daily vitamin E supplementation can improve neutrophil function in GS deficiency. Infections are not a feature of GR deficiency. (See 'Glutathione pathway alterations' above.)
●Glycogen storage disease Ib – GSD Ib is a rare, recessive disorder that presents in childhood with fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly, seizures, neutropenia, and neutrophil dysfunction. Sinopulmonary infections and mucosal ulcers are observed, and there is associated inflammatory bowel disease. The diagnosis is made by genetic analysis. Treatment involves maintaining normal blood glucose levels, and granulocyte colony-stimulating factor (G-CSF) therapy improves immune function. (See 'Glycogen storage disease Ib' above and "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Sergio D Rosenzweig, MD, who contributed as an author to earlier versions of this topic review.
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