Glucose phosphate isomerase deficiency

Glucose phosphate isomerase (GPI) deficiency is an inherited disorder that affects red blood cells, which carry oxygen to the body's tissues. People with this disorder have a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). An enlarged spleen (splenomegaly), an excess of iron in the blood, and small pebble-like deposits in the gallbladder or bile ducts (gallstones) may also occur in this disorder.

Hemolytic anemia in GPI deficiency can range from mild to severe. In the most severe cases, affected individuals do not survive to birth. Individuals with milder disease can survive into adulthood. People with any level of severity of the disorder can have episodes of more severe hemolysis, called hemolytic crises, which can be triggered by bacterial or viral infections.

A small percentage of individuals with GPI deficiency also have neurological problems, including intellectual disability and difficulty with coordinating movements (ataxia).

GPI deficiency is a rare cause of hemolytic anemia; its prevalence is unknown. About 50 cases have been described in the medical literature.

GPI deficiency is caused by mutations in the GPI gene, which provides instructions for making an enzyme called glucose phosphate isomerase (GPI). This enzyme has two distinct functions based on its structure. When two GPI molecules form a complex (a homodimer), the enzyme plays a role in a critical energy-producing process known as glycolysis, also called the glycolytic pathway. During glycolysis, the simple sugar glucose is broken down to produce energy. Specifically, GPI is involved in the second step of the glycolytic pathway; in this step, a molecule called glucose-6-phosphate is converted to another molecule called fructose-6-phosphate.

When GPI remains a single molecule (a monomer) it is involved in the development and maintenance of nerve cells (neurons). In this context, it is often known as neuroleukin (NLK).

Some GPI gene mutations may result in a less stable homodimer, impairing the activity of the enzyme in the glycolytic pathway. The resulting imbalance of molecules involved in the glycolytic pathway eventually impairs the ability of red blood cells to maintain their structure, leading to hemolysis.

Other GPI gene mutations may cause the monomer to break down more easily, thereby interfering with its function in nerve cells. In addition, the shortage of monomers hinders homodimer formation, which impairs the glycolytic pathway. These mutations have been identified in individuals with GPI deficiency who have both hemolytic anemia and neurological problems.

Genetic Testing Information

• Genetic Testing Registry: Hemolytic anemia due to glucophosphate isomerase deficiency

Genetic and Rare Diseases Information Center

• Glucosephosphate isomerase deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• ANEMIA, CONGENITAL, NONSPHEROCYTIC HEMOLYTIC, 4; CNSHA4

Scientific Articles on PubMed

• PubMed

• Baronciani L, Zanella A, Bianchi P, Zappa M, Alfinito F, Iolascon A, Tannoia N, Beutler E, Sirchia G. Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia. Blood. 1996 Sep 15;88(6):2306-10. Citation on PubMed
• Beutler E, West C, Britton HA, Harris J, Forman L. Glucosephosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA). Blood Cells Mol Dis. 1997 Dec;23(3):402-9. doi: 10.1006/bcmd.1997.0157. Citation on PubMed
• Fujii H, Kanno H, Hirono A, Miwa S. Hematologically important mutations: molecular abnormalities of glucose phosphate isomerase deficiency. Blood Cells Mol Dis. 1996;22(2):96-7. doi: 10.1006/bcmd.1996.0014. No abstract available. Citation on PubMed
• Kanno H, Fujii H, Hirono A, Ishida Y, Ohga S, Fukumoto Y, Matsuzawa K, Ogawa S, Miwa S. Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. Blood. 1996 Sep 15;88(6):2321-5. Citation on PubMed
• Kugler W, Breme K, Laspe P, Muirhead H, Davies C, Winkler H, Schroter W, Lakomek M. Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency. Hum Genet. 1998 Oct;103(4):450-4. doi: 10.1007/s004390050849. Citation on PubMed
• Lakomek M, Winkler H. Erythrocyte pyruvate kinase- and glucose phosphate isomerase deficiency: perturbation of glycolysis by structural defects and functional alterations of defective enzymes and its relation to the clinical severity of chronic hemolytic anemia. Biophys Chem. 1997 Jun 30;66(2-3):269-84. doi: 10.1016/s0301-4622(97)00057-4. Citation on PubMed
• Repiso A, Oliva B, Vives-Corrons JL, Beutler E, Carreras J, Climent F. Red cell glucose phosphate isomerase (GPI): a molecular study of three novel mutations associated with hereditary nonspherocytic hemolytic anemia. Hum Mutat. 2006 Nov;27(11):1159. doi: 10.1002/humu.9466. Citation on PubMed
• Warang P, Kedar P, Ghosh K, Colah RB. Hereditary non-spherocytic hemolytic anemia and severe glucose phosphate isomerase deficiency in an Indian patient homozygous for the L487F mutation in the human GPI gene. Int J Hematol. 2012 Aug;96(2):263-7. doi: 10.1007/s12185-012-1122-x. Epub 2012 Jul 11. Citation on PubMed
• Xu W, Beutler E. The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia. J Clin Invest. 1994 Dec;94(6):2326-9. doi: 10.1172/JCI117597. Citation on PubMed or Free article on PubMed Central