Triosephosphate Isomerase Deficiency
What else is it called?
- Deficiency of phosphotriose isomerase
- Hereditary nonspherocytic haemolytic anaemia due to triosephosphate isomerase deficiency
- TPI deficiency
- Triose phosphate isomerase deficiency
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What causes it?
TPI Deficiency is caused by mutations (changes) in the TPI1 gene. This gene is responsible for providing instructions for making an enzyme called triosephosphate isomerase 1. This enzyme is needed for a vital energy-producing process called glycolysis. During this process, glucose (simple sugar) is broken down to produce energy for cells in the body.
Mutations (changes) in the TPI1 gene causes the production of unstable enzymes or enzymes with lowered activity. Due to this, glycolysis is weakened, and cells get a decreased supply of energy. Red blood cells rely completely on the breakdown of glucose of energy so without glycolysis functioning at a normal level, red blood cells die earlier than normal. Certain cells that have high energy demands such as nerve cells in the brain, white blood cells and heart muscle cells are also prone to cell death because of the reduced energy produced by the impaired glycolysis.
Nerve cells, specifically the part of the brain responsible for coordinating movements (the cerebellum) are particularly affected in people with this condition.
The death of red blood cells, white blood cells, nerve cells in the brain and cardiac (heart) muscle cells cause the signs and symptoms of TPI deficiency.
How common is it?
TPI deficiency is a very rare inherited condition. To date, approximately 40 cases have been reported.
What are the signs and symptoms?
The symptoms of TPI deficiency can differ from patient to patient. The most characteristic symptoms of this condition are haemolytic anaemia and progressive neurological symptoms. Haemolytic anaemia occurs before birth in approximately half of the cases.
Haemolytic anaemia causes low levels of circulating red blood cells that occur because red blood cells are prematurely destroyed, and the bone marrow cannot make up for the loss. Haemolytic anaemia may cause:
- Splenomegaly (abnormally enlarged spleen)
- Jaundice (yellowing of the skin and whites of the eyes)
- Pale skin colour
- Difficulty breathing
Other symptoms associated with TPI deficiency include:
- Increased susceptibility to infections
- Cardiomyopathy (disease of the heart muscle)
In most patients with TPI deficiency, life-threatening complications such as respiratory or heart failure occur during childhood. However, there are some adults with less severe symptoms of TPI deficiency that have been reported.
Progressive neurological symptoms are usually seen in TPID patients between 6 and 30 months of age. These symptoms may include:
- Hypotonia (decreased muscle tone)
- Amyotrophy (muscular wasting or degeneration)
- Involuntary muscle spasms
- Slow, stiff movement of the legs
In some patients, there are no additional neurological symptoms and intelligence is unaffected. In other patients, intellectual disability occurs along with tremors and dystonia (involuntary muscle contractions).
How is it diagnosed?
A diagnosis for TPID starts with a thorough clinical evaluation, a detailed patient and family history, identification of characteristic findings. A diagnosis can be confirmed through molecular genetic testing which will detect mutations in the TPI1 gene.
Can it be treated?
Treatment is aimed at specific symptoms present in each individual person. Treatment may require a team of different specialists including paediatricians, cardiologists, neurologists and other healthcare professionals.
A specific treatment may include blood transfusions to treat haemolytic anaemia when episodes of red blood cell destruction occurs.
Do my family need to be tested?
TPI Deficiency is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.
The pattern of inheritance of TPI deficiency is autosomal recessive. This means that carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with TPI deficiency are carriers.
When both parents are carriers, the risk to the baby in each pregnancy is
- 25% chance (1 in 4) of developing the condition
- 50% chance (1 in 2) for the baby to be a carrier of the condition
- 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier
Genetic counselling can be requested to get a full explanation.