Triose phosphate isomerase deficiency
Triose phosphate isomerase (TPI) deficiency is a rare non-sex-linked (autosomal) disorder that is a result of an insufficient amount of the enzyme triose phosphate isomerase. This disorder is inherited as a dominant trait and it is known to be caused by more than one different mutation in the same gene (allelic variants).
Triose phosphate isomerase is an enzyme involved in the breakdown of glucose into the energy required to sustain cellular metabolism. Glucose is first converted into the chemical pyruvate. Pyruvate then enters the tricarboxylic acid cycle (TCA cycle) to produce ATP, the chemical form of energy used by the cells. Glucose is broken down to the chemical pyruvate via a chemical pathway that involves 10 enzymes. TPI is the fifth enzyme in this reaction chain. The two major products of the reaction proceeding the TPI reaction are D-glyceraldehyde-3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). These two chemicals are isomers, which means that they have the same chemical formulas but different chemical structures. TPI is the enzyme that converts DHAP into GAP. This conversion (isomerization) is important because it is only GAP that is used in the subsequent steps in the reaction pathway to the essential pyruvate molecules.
Under normal physiological conditions, DHAP is produced in much greater quantities than GAP (approximately 20:1). Therefore, it is essential that TPI convert the DHAP to GAP to increase the overall efficiency of pyruvate production from glucose. Individuals affected with TPI deficiency have extremely low levels of TPI activity because the enzyme that they do produce is not properly formed and, thus, it is highly inefficient.
The gene that is responsible for the production of TPI has been localized to a region on chromosome 12. There are at least five mutations in this gene that lead to TPI deficiency. In every case, very slight changes in the chemical structure of TPI occur such that the TPI produced is less effective than a normal TPI molecule, especially when the body is hot, either from the weather or from exercise.
TPI deficiency is extremely rare. In 1998, there were only 13 people known to be living with TPI deficiency, eleven children and two adult Hungarian brothers affected with an extremely mild form of the disease. Since 1998, at least five of these children have passed away. The documented rarity of this disorder does not seem to coincide with the observed frequency of reduced TPI activity in the population.
In a 1996 study of unselected individuals of Caucasian and Japanese descent, a Japanese researcher found that approximately five out of every 1,000 individuals had TPI activity that was only half of the normal TPI activity. In a separate study, it was estimated that nine in 1,713 Caucasians and seven in 168 African-Americans showed these low levels of TPI activity. One possible explanation is that complete TPI deficiency is an embryolethal condition. In other words, if complete TPI deficiency is inherited at conception, this embryo is miscarried before the mother even knows that conception had occurred.
All of the mutations in the gene responsible for the production of TPI are expressed as dominant traits. This means that a child can inherit this condition from just one of his or her parents. Also, if one child has been born affected with TPI deficiency, the likelihood that a second child, of the same parents, will also be affected is 50%. This likelihood is increased to 75% if both parents carry the defective gene.
Signs and symptoms
TPI deficiency affects primarily the circulatory and nervous systems. Disorders of the circulatory system include at least four separate forms of anemia (a lack of properly functioning red blood cells) that cause a lack of oxygen transport to the tissues and organs of the body. Disorders of the nervous system include developmental retardation and degenerative neurologic disorder with spasticity, a condition in which the nervous system progressively degenerates and the affected person suffers from spasticity similar to that seen in people with multiple sclerosis.
Because of the malformations of the red blood cells in TPI deficiency affected individuals, the liver, the organ that is responsible for cleaning the blood, often becomes overworked. This causes jaundice (an abnormal yellowing of the skin and the whites of the eyes). Heart failure is also quite common and is often the cause of death in TPI deficiency patients.
People affected with TPI deficiency are generally highly susceptible to recurrent infections. This tendency is believed to be due to a depression of the immune system caused by improper blood function.
If a family history of the disease leads to suspicion, TPI deficiency can be detected prenatally by a test of umbilical cord blood. A device recognized by the U. S. Food and Drug Administration is available to measure the activity of TPI on red blood cells taken in a sample. This device provides a definitive test for TPI deficiency. A blood test indicating extremely elevated levels of DHAP is also indicative of TPI deficiency.
Another blood test that can be performed is an autohemolysis test. This test allows TPI deficiency to be differentially diagnosed from certain other enzymatic deficiencies. In this test, samples of blood are drawn and incubated at body temperature for 48 hours. After this time, the amount of breakdown of the red blood cells is recorded. One sample is left untreated, one sample has added glucose, and a third sample has added ATP. If the untreated sample shows higher than normal breakdown of the red blood cells, but those samples treated with glucose or ATP show a lessened breakdown of red blood cells, this is indicative of TPI deficiency. If glucose, but not ATP, slows the breakdown of the red blood cells, this indicates a diagnosis of G6PD deficiency. If ATP, but not glucose, slows the breakdown of the red blood cells, this indicates a diagnosis of pyruvate kinase deficiency. G6PD and pyruvate kinase are two other enzymes involved in the breakdown of glucose to pyruvate to ATP.
Treatment and management
No treatment is currently available for TPI deficiency. Studies are ongoing to determine the feasibility of bone marrow transplants and enzyme replacement therapies. In 1999, TPI deficiency was corrected in a four-year-old boy by an enzyme replacement blood transfusion treatment. However, due to the temporary nature of the observed corrections in the biochemistry, it was concluded that a sustained reversal of the symptoms of TPI deficiency would require a continuous delivery of an active form of the TPI enzyme.
There are only two reported cases of TPI deficiency affected individuals living beyond the age of six. These
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National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
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Paul A. Johnson