Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited genetic disorder affecting red blood cells. It is the most common enzyme deficiency worldwide. G6PD is an enzyme involved in the normal function of red blood cells, and its deficiency can lead to hemolysis, where red blood cells break down more quickly than usual.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Glucose-6-phosphate dehydrogenase deficiency include:
- Enzyme Deficiency: G6PD deficiency is caused by mutations in the G6PD gene, leading to reduced or absent activity of the G6PD enzyme.
- X-Linked Inheritance: The G6PD gene is located on the X chromosome. Since it follows an X-linked inheritance pattern, the disorder primarily affects males. Females can also be affected if they inherit the mutated gene from both parents or if they inherit it from one parent and have skewed X-inactivation.
- Hemolysis: A deficiency of G6PD can increase red blood cell susceptibility to oxidative stress, leading to hemolysis. Certain medications, infections, or exposure to certain foods and chemicals can trigger hemolysis.
- Episodic Symptoms: Individuals with G6PD deficiency may not experience symptoms under normal conditions. However, when exposed to certain triggers, they may develop symptoms such as jaundice (yellowing of the skin and eyes), dark urine, fatigue, and abdominal pain.
- Protective Against Malaria: It has been observed that individuals with G6PD deficiency may have some protection against malaria, as the parasite that causes malaria is sensitive to the oxidative stress induced by G6PD deficiency.
- Variability in Severity: The severity of G6PD deficiency can vary among affected individuals, ranging from mild to severe.
Diagnosis of G6PD deficiency is typically confirmed through blood tests that measure enzyme activity. However, it's important to note that G6PD deficiency is not always symptomatic, and symptoms may only occur when triggered by specific factors.
Managing G6PD deficiency involves avoiding known triggers, such as certain medications (e.g., certain antimalarial drugs, sulfa drugs, and some antibiotics), foods (e.g., fava beans), and exposure to certain chemicals. In cases of severe hemolysis or complications, medical intervention may be necessary.
Genetic counseling is essential for families with a history of G6PD deficiency, as it helps assess the risk of passing the condition to future generations and provides guidance on managing the disorder.
Individuals with G6PD deficiency can lead every day and healthy lives by being aware of potential triggers and taking precautions to avoid them.
More Information
The G6PD gene is located on the X chromosome. Males with one copy of a pathogenic variant in this gene develop the deficiency. Women with a single copy of a pathogenic variant tend to think that they are only carriers of the disease and will not manifest it, but inactivation of one of the two X chromosomes can occur so that they would produce normal red blood cells and G6PD-deficient red blood cells. Female carriers could also have more or less severe externally induced hemolytic anemia depending on whether they have more or less G6PD-deficient red cells.
More than 200 pathogenic variants have been described in the G6PD gene, all of which produce to a greater or lesser extent a decrease in enzyme activity, but some activity always remains. Variants that completely suppress activity would be lethal.
The c.292G>A (p.Val98Met) variant is common in African populations and is thought to result from partial protection against malaria. This variant has been shown to only mildly affect enzyme activity. Still, it has been detected in combination with another common variant (compound heterozygosis) of G6PD that causes a drastic reduction in the stability and enzymatic activity of the G6PD protein.
The variant c.653C>T (p.Ser218Phe) in the G6PD gene, also known as the "Mediterranean variant", is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and India, and is detected in 60-96% of biochemically diagnosed individuals. This variant produces a non-conservative amino acid substitution, which affects the structure of the secondary protein. Functional studies demonstrate decreased enzyme activity in circulating erythrocytes of individuals with this variant, increased affinity for G6P, and decreased thermostability in vitro.
Another variant typical of the Mediterranean region is c.934G>C (p.Asp312His), which produces a decrease in G6PD activity of up to 85%.
Some pathogenic variants that are more predominant in Asia are also tested, e.g., c.1466G>T (p.Arg489Leu), c.1478G>A (p.Arg493His), and c.961G>A (p.Val321Met).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency genetic testing analyzes the 18 most frequent pathogenic mutations of the G6PD gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
