Glucose-6-phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) is a genetic disorder that occurs most often in males. This condition affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis and can cause anemia. The hemolytic anemia in G6PD deficiency is generally triggered by illness or infection, certain foods or medicines. Glucose-6-dehydrogenase deficiency is also a significant cause of mild to severe jaundice in newborns. Many people with this disorder have no symptoms.



Types

 * The severe Mediterranean type of G6PD deficiency has been associated with severe neonatal jaundice and favism. Favism is hemolytic anemia which results from ingestion of the fava bean. This type of G6PDD has very low enzyme activity and is common in Asian and Mediterranean populations.
 * A moderate type of G6PDD with low to moderate enzyme activity is more common in African American men in the United States.
 * There are rare types of G6PDD which have normal, high or slightly low G6PD activity.

Signs and Symptoms
Many people with G6PD deficiency have no symptoms. Signs and symptoms (which are primarily a result of hemolysis) include:
 * Dark urine
 * Enlarged spleen
 * Fatigue
 * Paleness
 * Rapid heart rate
 * Shortness of breath
 * Yellow skin color jaundice

Causes
Mutations in the G6PD gene cause glucose-6-phosphate dehydrogenase deficiency.

The G6PD gene provides instructions for making an enzyme called glucose-6-phosphate dehydrogenase. This enzyme is involved in the normal processing of carbohydrates. It also protects red blood cells from the effects of potentially harmful molecules called reactive oxygen species. Reactive oxygen species are byproducts of normal cellular functions. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells.

If mutations in the G6PD gene reduce the amount of glucose-6-phosphate dehydrogenase or alter its structure, this enzyme can no longer play its protective role. As a result, reactive oxygen species can accumulate and damage red blood cells.

G6PD deficiency is known to have over 400 variant alleles, or different forms of the same gene. A mutant G6PD enzyme may be different from person to person; mutations can be in the form of point mutations or can range from one to several base pair deletions as well as replacements in the DNA. Different populations have different types of mutations, but within a specific population, common mutations are usually shared. For example, in Egypt there exists only one type of allele, called the "Mediterranean" variant, among the population, whereas in Japan there is a different variant with a different type of mutation prevalent within that population, this one called the "Japan" variant.

Exams and tests
Likely results on laboratory testing of a patient with G6PD deficiency include:


 * Low red blood cell count and hemoglobin levels
 * Low serum haptoglobin
 * Hemolysis (the breaking open of red blood cells and release of hemoglobin)
 * An elevated reticulocyte count (an increase in the number of immature red blood cells in circulation
 * Reduced G-6-PD activity
 * Elevated bilirubin levels (due to hemolysis)
 * Elevated serum LDH (lactic acid dehydrogenase)
 * Heinz bodies (bars of precipitated hemoglobin that can be seen inside RBCs under the microscope) present on examination of the peripheral blood smear using special stains
 * Hemoglobin in the urine

Additional tests may include:
 * Methemoglobin reduction test (methemoglobin occurs when the iron that is part of hemoglobin is changed so that it does not carry oxygen well)
 * Methylene blue test (used to determine the type of methemoglobinemia)

A definitive diagnosis of G6PD deficiency is made by a quantitative spectrophotometric analysis or, more commonly, by a rapid fluorescent spot test detecting the generation of NADPH from NADP. The test is positive if the blood spot fails to fluoresce under ultraviolet light. Tests based on polymerase chain reaction]] detect specific mutations and are used for population screening, family studies, or prenatal diagnosis.

Treatment
The main treatment of G6PD deficiency is avoidance of stressors (mainly medications). Blood transfusion may be indicated if hemolysis is severe. Folic acid and iron supplementation may be helpful for treatment of anemia. There is no targeted medical therapy or gene therapy yet.

Heredity
This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Risk factors
Factors such as infections, certain drugs, or ingesting fava beans can increase levels of reactive oxygen species, causing red blood cells to be destroyed faster than the body can replace them. A reduction in the amount of red blood cells causes the signs and symptoms of hemolytic anemia. The drugs associated with precipitating hemolytic anemia in G6PDD are:


 * Antimalarial drugs
 * Aspirin
 * Nonsteroidal anti-inflammatory drugs (NSAIDs)
 * Quinidine
 * Quinine
 * Sulfonamide antibiotics
 * Nitrofurantoin

Other risk factors include:
 * Male sex
 * Family history of G6PD deficiency
 * African American or Mediterranean descent

Related disorders
G6PD deficiency has long been believed to have a protective effect against the development of malaria. The geographical distribution of G6PDD correlates with a lower incidence of malaria. It is also believed that the protection against malaria has led to an increased prevalence of G6PD deficiency than might otherwise occur. The mechanism of protection and population protected are being studied:
 * The malaria protection is present in male homozygotes (posessing two identical forms of a gene) and female heterozygotes (posessing two different forms of a gene) in a 1995 study from Africa.
 * A 2007 study verifies protection in hemizygote males but not in heterozygous females.

A possible connection between G6PD deficiency and sickle cell anemia has been proposed. A 2006 study from India failed to prove this theory.

Clinical Trials
A list of ongoing U.S. government-sponsored clinical trials is available at ClinicalTrials.gov: G6PD trials

Research

 * Clofibrate, a lipid-lowering medicine, was shown to be effective in lowering the elevated bilirubin levels causing neonatal jaundice in patients with G6PD deficiency.
 * G6PD deficiency has a protective effect on coronary heart disease, according to a recent study. The mechanism of this protection is discussed.
 * The prevalence of G6PD deficiency among patients at an HIV/AIDS clinic is discussed in a recent study. G6PD deficient patients may have hemolytic events after receiving drugs used to treat AIDS.
 * The benefits of consanguinity (common genetics) as related to G6PD deficiency are discussed. This study strongly support the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family.

Prevalence
An estimated 400 million people worldwide have glucose-6-phosphate dehydrogenase deficiency. This condition occurs most frequently in certain parts of Africa, Asia, and the Mediterranean. It affects about 1 in 10 African-American males in the United States.

Public health and policy
G6PD deficiency has high prevalence in many populations around the world. Some jurisidictions have implemented newborn screening for G6PD deficiency. In light of high immigration to some Western countries (e.g. Canada, UK, and the United States) from these areas, some have advocated including G6PDD screening more widely.