Triosephosphate isomerase deficiency

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 haemolytic anaemia, 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.

Genetics

Thirteen different mutations in the respective gene, which is located at chromosome 12p13 and encodes the ubiquitous housekeeping enzyme triosephosphate isomerase (TPI), have been discovered so far. 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. 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Signs and symptoms include anemia, fatigue, pallor, yellowing of the skin and the white of the eyes (jaundice), and shortness of breath. Other symptoms are muscle weakness and wasting (atrophy), movement problems (such as involuntary muscle contractions (dystonia), tremors and weak muscle tone), seizures, cardiomyopathy, and diaphragm weakness which may cause breathing problems and lead to respiratory failure.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of immune system physiology
• Central nervous system degeneration
• Muscular hypotonia
• Low or weak muscle tone
• Skeletal muscle atrophy(Muscle degeneration)

30%-79% of people have these symptoms

• Diaphragmatic paralysis(Paralyzed diaphragm)

5%-29% of people have these symptoms

• Decreased nerve conduction velocity
• Hypertrophic cardiomyopathy(Enlarged and thickened heart muscle)

Diagnosis

Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells.

Treatment

• Treatment is directed toward the specific symptoms that are apparent in each person. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, and other healthcare professionals may need to systematically and comprehensively create a plan for each child's treatment.
• Specific therapies may include blood transfusions to treat hemolytic anemia during episodes of red blood cell destruction (hemolysis) and assisted ventilation to treat paralysis of the diaphragm.
• Genetic counseling may be of benefit for affected people and their families.
• Other treatment is symptomatic and supportive.

See also

• List of hematologic conditions

External links

Classification	ICD-10: D55.2 ICD-9-CM: 282.3 OMIM: 190450 DiseasesDB: 30116
External resources	Orphanet: 868