Glucose 6 Phosphatase Deficiency Disease

[Domenec Reynolds]

Glucose6-phosphate dehydrogenase deficiency is a genetic disorder that 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 causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis.

The most common medical problem associated with glucose-6-phosphate dehydrogenase deficiency is hemolytic anemia, which occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the skin and whites of the eyes (jaundice), dark urine, fatigue, shortness of breath, and a rapid heart rate. In people with glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs (such as some antibiotics and medications used to treat malaria). Hemolytic anemia can also occur after eating fava beans or inhaling pollen from fava plants (a reaction called favism).

Glucose-6-phosphate dehydrogenase deficiency is also a significant cause of mild to severe jaundice in newborns. Many people with this disorder, however, never experience any signs or symptoms and are unaware that they have the condition.

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

Glucose-6-phosphate dehydrogenase deficiency results from variants (also called mutations) in the G6PD gene. This 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, which 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 variants 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. Factors such as infections, certain drugs, or ingesting fava beans can increase the levels of reactive oxygen species, causing red blood cells to be destroyed faster than the body can replace them. A reduction in the number of red blood cells causes the signs and symptoms of hemolytic anemia.

Researchers believe that people who have a G6PD variant may be partially protected against malaria, an infectious disease carried by a certain type of mosquito. A reduction in the amount of functional glucose-6-phosphate dehydrogenase appears to make it more difficult for this parasite to invade red blood cells. Glucose-6-phosphate dehydrogenase deficiency occurs most frequently in areas of the world where malaria is common.

Glucose-6-phosphate dehydrogenase is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. Males have only one X chromosome and females have two copies of the X chromosome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In females, who have two copies of the X chromosome, one altered copy of the G6PD gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. However, many females with one altered copy of this gene have glucose-6-phosphate dehydrogenase deficiency similar to affected males because the X chromosome with the normal copy of the G6PD gene is turned off through a process calledX-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body cells. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.

Research shows that females with glucose-6-phosphate dehydrogenase deficiency caused by variants in the G6PD gene often have skewed X-inactivation, which results in the inactivation of the X chromosome with the normal copy of the G6PD gene in most cells of the body. This skewed X-inactivation causes the chromosome with the altered G6PD gene to be expressed in more than half of cells. As a result, not enough normal glucose-6-phosphate dehydrogenaseenzyme is produced, leading to hemolytic anemia and other signs and symptoms of glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span.

Glycogen storage disease type I (GSDI) is a group of rare inherited diseases resulting from a defect in the glucose-6-phosphatase (G6Pase) system which has a key role in glucose homeostasis as it is required for the hydrolysis of glucose-6-phosphate (G6P) into glucose and inorganic phosphate (Pi). The main diagnostic criteria are: hepatomegaly, fast-induced hypoglycemia with hyperlactacidemia, and hyperlipidemia. Two main subtypes are unambiguously recognized: GSD type Ia (GSDIa) due to a defect of the catalytic unit G6Pase-alpha (or G6PC), and GSD type Ib (GSDIb) due to a defect of the glucose-6-phosphate translocase (or G6PT) [1, 2]. The existence of other types (type Ic and type Id) has not been confirmed [3, 4].

GSDI has an estimated annual incidence of around 1/100,000 births, representing approximately 30% of hepatic GSD and with GSDIa being the most frequent type (about 80% of the GSDI patients)[1]. GSDIa is particularly common in the Ashkenazi Jewish population, in which the carrier frequency for the p.R83C allele was found to be 1.4%, predicting a prevalence five times higher than in the general Caucasian population [5].

GSDI patients may present with fast-induced hypoglycemia (sometimes occurring rapidly in about 2 to 2 and a half hours after a meal) and hyperlactacidemia in the neonatal period. More commonly, the first symptom is the presence of a protruded abdomen due to marked hepatomegaly around 3 months of age, though in some cases the liver may already be enlarged at birth. The liver size gradually increases and the lower border may reach below the umbilicus. It must be stressed that the hepatomegaly may be missed on physical examination, as the liver is soft. Hepatocellular adenomas are usually asymptomatic and physical examination is rarely contributive, except in very rare cases when adenomas are superficial. Fasting tolerance is very limited: hypoglycemia, which may cause convulsions, and lactic acidemia, account for the initial gravity of the disease. In some cases, the hypoglycemia may be less symptomatic since lactate may be used as a cerebral metabolic fuel. The other biological hallmarks are hyperlipemia and hyperuricemia. The full-cheeked, round "doll like" face, and a protruding abdomen contrast with the thin limbs. Growth delay and late onset of puberty [2, 7] are very frequent signs, which can be improved by good metabolic control [8]. Osteopenia [9] is commonly found and it has been suggested that the subclinical muscle weakness could also contribute to the low bone mass [10]. Chronic acidosis and hypertriglyceridemia also play an important role in the development of osteopenia. Kidneys are enlarged. Platelet dysfunction, which is related to dyslipidemia, explains the tendency for ecchymoses and bleeding. Anemia is commonly found. Intermittent diarrhea occurs in a number of patients. Ovarian cysts have also been reported. Recently, an increased prevalence of hypothyroidism (GSDIa and GSDIb) and thyroid autoimmunity (GSDIb) has been reported [11].

3a8082e126