Triosephosphate isomerase deficiency is a disorder characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function.

The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia. A shortage of red blood cells to carry oxygen throughout the body leads to extreme tiredness (fatigue), pale skin (pallor), and shortness of breath. When the red cells are broken down, iron and a molecule called bilirubin are released; individuals with triosephosphate isomerase deficiency have an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice, which is a yellowing of the skin and the whites of the eyes.

Movement problems typically become apparent by age 2 in people with triosephosphate isomerase deficiency. The movement problems are caused by impairment of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. This impairment leads to muscle weakness and wasting (atrophy) and causes the movement problems typical of triosephosphate isomerase deficiency, including involuntary muscle tensing (dystonia), tremors, and weak muscle tone (hypotonia). Affected individuals may also develop seizures.

Weakness of other muscles, such as the heart (a condition known as cardiomyopathy) and the muscle that separates the abdomen from the chest cavity (the diaphragm) can also occur in triosephosphate isomerase deficiency. Diaphragm weakness can cause breathing problems and ultimately leads to respiratory failure.

Individuals with triosephosphate isomerase deficiency are at increased risk of developing infections because they have poorly functioning white blood cells. These immune system cells normally recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The most common infections in people with triosephosphate isomerase deficiency are bacterial infections of the respiratory tract.

People with triosephosphate isomerase deficiency often do not survive past childhood due to respiratory failure. In a few rare cases, affected individuals without severe nerve damage or muscle weakness have lived into adulthood.

Triosephosphate isomerase deficiency is likely a rare condition; approximately 40 cases have been reported in the scientific literature.

Mutations in the TPI1 gene cause triosephosphate isomerase deficiency. This gene provides instructions for making an enzyme called triosephosphate isomerase 1. This enzyme is involved in a critical energy-producing process known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce energy for cells.

TPI1 gene mutations lead to the production of unstable enzymes or enzymes with decreased activity. As a result, glycolysis is impaired and cells have a decreased supply of energy. Red blood cells depend solely on the breakdown of glucose for energy, and without functional glycolysis, red blood cells die earlier than normal. Cells with high energy demands, such as nerve cells in the brain, white blood cells, and heart (cardiac) muscle cells are also susceptible to cell death due to reduced energy caused by impaired glycolysis. Nerve cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected in people with triosephosphate isomerase deficiency.

Death of red and white blood cells, nerve cells in the brain, and cardiac muscle cells leads to the signs and symptoms of triosephosphate isomerase deficiency.

Genetic Testing Information

• Genetic Testing Registry: Triosephosphate isomerase deficiency

Genetic and Rare Diseases Information Center

• Triose phosphate-isomerase deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• TRIOSEPHOSPHATE ISOMERASE DEFICIENCY; TPID

Scientific Articles on PubMed

• PubMed

• Aissa K, Kamoun F, Sfaihi L, Ghedira ES, Aloulou H, Kamoun T, Pissard S, Hachicha M. Hemolytic anemia and progressive neurologic impairment: think about triosephosphate isomerase deficiency. Fetal Pediatr Pathol. 2014 Aug;33(4):234-8. doi: 10.3109/15513815.2014.915365. Epub 2014 May 19. Citation on PubMed
• De La Mora-De La Mora I, Torres-Larios A, Mendoza-Hernandez G, Enriquez-Flores S, Castillo-Villanueva A, Mendez ST, Garcia-Torres I, Torres-Arroyo A, Gomez-Manzo S, Marcial-Quino J, Oria-Hernandez J, Lopez-Velazquez G, Reyes-Vivas H. The E104D mutation increases the susceptibility of human triosephosphate isomerase to proteolysis. Asymmetric cleavage of the two monomers of the homodimeric enzyme. Biochim Biophys Acta. 2013 Dec;1834(12):2702-11. doi: 10.1016/j.bbapap.2013.08.012. Epub 2013 Sep 20. Citation on PubMed
• Orosz F, Olah J, Ovadi J. Reappraisal of triosephosphate isomerase deficiency. Eur J Haematol. 2011 Mar;86(3):265-7. doi: 10.1111/j.1600-0609.2010.01484.x. No abstract available. Citation on PubMed
• Orosz F, Olah J, Ovadi J. Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life. 2006 Dec;58(12):703-15. doi: 10.1080/15216540601115960. Citation on PubMed
• Orosz F, Olah J, Ovadi J. Triosephosphate isomerase deficiency: new insights into an enigmatic disease. Biochim Biophys Acta. 2009 Dec;1792(12):1168-74. doi: 10.1016/j.bbadis.2009.09.012. Epub 2009 Sep 26. Citation on PubMed
• Rodriguez-Almazan C, Arreola R, Rodriguez-Larrea D, Aguirre-Lopez B, de Gomez-Puyou MT, Perez-Montfort R, Costas M, Gomez-Puyou A, Torres-Larios A. Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface. J Biol Chem. 2008 Aug 22;283(34):23254-63. doi: 10.1074/jbc.M802145200. Epub 2008 Jun 18. Citation on PubMed
• Serdaroglu G, Aydinok Y, Yilmaz S, Manco L, Ozer E. Triosephosphate isomerase deficiency: a patient with Val231Met mutation. Pediatr Neurol. 2011 Feb;44(2):139-42. doi: 10.1016/j.pediatrneurol.2010.08.016. Citation on PubMed