Triosephosphate isomerase deficiency

Triosephosphate isomerase deficiency

Description, Causes and Risk Factors:

Triosephosphate isomerase deficiency is a rare autosomal recessive metabolic disorder which was initially described in 1965. It is a unique glycolytic enzymopathy that is characterized by chronic hemolytic anemia, cardiomyopathy, susceptibility to infections, severe neurological dysfunction, and, in most cases, death in early childhood. The disease is exceptionally rare with fewer than 100 patients diagnosed worldwide.

The incidence is unknown but seems to be very low. Since the first description in 1965 by Schneider, approximately 30 cases have been reported. However, the frequency of heterozygotes in the general population appears to be between 3 and 8%. This difference leads us to think that TPI deficiency is eithe lethal before birth or poorly recognized.

Triosephosphate isomerase deficiency is caused by various mutations in the gene encoding the key glycolytic enzyme TPI. A drastic decrease in TPI activity and an increased level of its substrate, dihydroxyacetone phosphate, have been measured in unpurified cell extracts of affected individuals. These observations allowed concluding that the different mutations in the TPI alleles result in catalytically inactive enzymes. However, despite a high occurrence of TPI null alleles within several human populations, the frequency of this disorder is exceptionally rare. In order to address this apparent discrepancy, we generated a yeast model allowing us to perform comparative in vivo analyses of the enzymatic and functional properties of the different enzyme variants. We discovered that the majority of these variants exhibit no reduced catalytic activity per se. Instead, we observed, the dimerization behavior of TPI is influenced by the particular mutations investigated, and by the use of a potential alternative translation initiation site in the TPI gene. Additionally, we demonstrated that the overexpression of the most frequent TPI variant, Glu104Asp, which displays altered dimerization features, results in diminished endogenous TPI levels in mammalian cells. Thus, our results reveal that enzyme deregulation attributable to aberrant dimerization of TPI, rather than direct catalytic inactivation of the enzyme, underlies the pathogenesis of TPI deficiency. Finally, we discovered that yeast cells expressing a TPI variant exhibiting reduced catalytic activity are more resistant against oxidative stress caused by the thiol-oxidizing reagent diamide. This observed advantage might serve to explain the high allelic frequency of TPI null alleles detected among human populations.

So far thirteen different mutations located at chromosome 12p13 and encodes the ubiquitous housekeeping enzyme triosephosphate isomerase (TPI), have been discovered. TPI is a crucial enzyme of glycolysis and catalyzes the interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. A marked decrease in TPI activity and an accumulation of dihydroxyacetone phosphate have been detected in erythrocyte extracts of homozygous (two identical mutant alleles) and compound heterozygous (two different mutant alleles) TPI deficiency patients. Heterozygous individuals are clinically unaffected, even if their residual TPI activity is reduced. Recent work suggests that not a direct inactivation, but an alteration in TPI dimerization might underlie the pathology. This might explain why the disease is rare, but inactive TPI alleles have been detected at higher frequency implicating a heterozygote advantage of inactive TPI alleles.

The most common mutation causing TPI deficiency is TPI Glu104Asp. Interestingly, all carriers of the mutation are descendants of a common ancestor, a person that lived in what is today France or England more than 1000 years ago.


The symptoms comprise constant and early hemolytic anemia, moderate macrocytosis may present without any specific biological signs. The chronic anemia remains moderate but is aggravated by acute attacks of hemolysis, which are favored by infections. Progressive neurological involvement begins between 6 and 30 months of age. Its expression is variable. It is usually manifested by neuromuscular involvement starting in the legs with hypotonia, motor defect, amyotrophy, and abolition of the deep tendon reflex.

Diaphragmaticparalysis can occur and requires assisted ventilation. In some patients neuropathic signs seem to be the only manifestations and intelligence is unaffected. In others, central involvement has been reported, pyramidal signs, dystonia, dyskinesia with severe tremor and mental retardation.


Triosephosphate isomerase, a glycolytic enzyme is present in all the cells of the organism. The diagnosis of a TPI deficiency relies on the specific dosage of the enzyme in red blood cells: In affected homozygous subjects, the level is very low, between 5 and 10% of the normal; in heterozygous its concentration is about 50% of the normal.

Prenatal diagnosis can be obtained by dosage of TIP in cultured amniotic cells, chronic villi or a fetal blood sample. The latter method appears to be the best. It can be obtained also by molecular biology.


The treatment of hemolytic anemia remains symptomatic and consists of transfusions during episodes of acute hemolysis. Splenectomy and corticosteroids are not effective. Neurological management is the same as that for a progressive neuromuscular disease. Assisted ventilation can be required for diaphragmatic paralysis.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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