Triosephosphate Isomerase Deficiency - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Triosephosphate isomerase deficiency is a multisystem disorder due to a genetic defect. The lack or reduced activity of the enzyme triosephosphate isomerase is responsible for characteristic features of the disease, such as shortage of red blood cells, muscle weakness, fatigue, or increased susceptibility to infection. It is a rare autosomal recessive disorder where the affected individuals develop life-threatening complications from the early stages of life.

It is also called :

• Deficiency of phosphotriose isomerase.

• Hereditary nonspherocytic hemolytic anemia due to triosephosphate enzyme deficiency.

What Causes Triosephosphate Isomerase Deficiency?

• Triosephosphate isomerase is an enzyme necessary for glycolysis (breakdown of glucose). Glycolysis is breaking down glucose to produce the energy required for the cells.

• Mutations in the gene TPI1 cause the deficiency of the triosephosphate isomerase or the decreased production of the enzyme. The reduced activity or amount of the enzyme causes a reduction in glycolysis. This further decreases the energy needed for the body, making the person tired.

• Red blood cells depend on glucose for energy. When glycolysis is affected, there is not enough energy for the red blood cells, and they die earlier than under normal conditions. Cells with high demand for energy, such as nerve cells, cardiac muscle cells, and white blood cells, get affected due to decreased energy supply. Nerve cells located in the cerebellum, the part of the brain responsible for the coordination of movements when affected, cause difficulty in movements for such patients.

• The premature death of red and white blood cells and the involvement of muscle and nerve cells are responsible for the typical disease symptoms.

How Does the Disease Progress?

• Triosephosphate isomerase deficiency causes impairment in the metabolism of certain sugars in the body. This leads to the premature destruction of red blood cells. The severity of the symptoms varies in different individuals, from hemolytic anemia and severe progressive neurological symptoms to cardiomyopathy and susceptibility to infections.

• Anemia: It is seen in infants with the disease. Excessive and premature breakdown of red blood cells leads to a reduction in RBC count, which is known as hemolytic anemia.

• Red Blood Cell (RBC) Reduction: The shortage of red blood cells reduces the amount of oxygen delivered to the cells, making the individual tired (fatigue), having shortness of breath, and making the skin pale (pallor).

• Jaundice: RBCs are broken down into iron and bilirubin. Destruction of erythrocytes causes a rise in bilirubin in the bloodstream. The excessive amount of bilirubin causes jaundice, where the eyes and the skin become yellow in color.

• Weakness of Muscle: Various muscles in the body become weaker, and their function gets impaired. Cardiomyopathy affecting the heart and diaphragm weakness leads to breathing problems and ultimately, respiratory failure. The diaphragm muscle is the muscle that separates the abdomen from the chest cavity.

• Movement Problems: Motor neurons get affected in individuals with triosephosphate isomerase deficiency; this is expressed by the age of two. Motor neurons are nerve cells in the brain and the spinal cord that are specialized in muscle movement. The involvement of the nerve cells causes problems in movement due to muscle wasting and weakness (atrophy). The triosephosphate enzyme deficiency causes dystonia (involuntary muscle tensing), tremors, and hypotonia (reduced muscle tone). Some individuals also develop seizures.

• Susceptibility to Infections: The triosephosphate enzyme deficiency can also affect the functioning of white blood cells; this puts the patients at increased risk of infections. The white blood cells, which typically recognize and destroy external infections such as bacteria and viruses, are impaired, and thereby individuals with this disease have respiratory tract infections.

• Individuals affected do not survive past childhood due to respiratory failure. In extremely rare cases, affected individuals with nerve damage or muscle weakness survive till adulthood.

What Are the Symptoms of Triosephosphate Isomerase Deficiency?

Triosephosphate enzyme deficiency is a rare disease, and the symptoms and their severity vary for each individual.

• Hemolytic Anemia: it is a characteristic feature of the disease presented from birth in about half of the cases. Breakdowns of red blood cells are called hemolysis. In this disease, the RBCs get prematurely destroyed, and the loss is not compensated by the bone marrow, leading to an overall decrease in red blood cells. This, in turn, causes fatigue, difficulty breathing, and lightheadedness due to decreased oxygen supply. Jaundice occurs due to the increased amount of bilirubin (a by-product of RBC breakdown) in the blood.

• Susceptibility to Infections: Due to white blood cell impairment.

• Splenomegaly: Enlargement of the spleen.

• Difficulty Breathing: Due to weakness of the diaphragm.

• Cardiomyopathy: Heart muscle impairment.

• Neurological Symptoms: These symptoms appear as early as six months of age or by 30 months of age. Loss of muscle tone, muscle wasting, involuntary muscle spasms, and lack of deep tendon reflexes cause difficulty in movement.

• Neurological Involvement: This can also affect intelligence, along with tremors and dystonia. Whereas in some cases, the neurological symptoms do not develop, nor is the intelligence affected.

• Dystonia: Involuntary muscle contractions causing painful and abnormal movements or postures.

Most symptoms appear in the early stages of life, making it difficult for the patients to survive to adulthood. Patients with less severe symptoms have lived to adulthood.

How Is the Disease Inherited?

• Triose phosphate enzyme deficiency is a rare autosomal recessive disorder. That is, both pairs of chromosomes have to be affected for the disease to be expressed. That is, both genes inherited from the father and mother have to be faulty.

• If the individual receives only one abnormal gene, the individual will have a 25 percent chance of passing the disease to their offspring with each pregnancy. The risk of the offspring being a carrier of the faulty gene is 25 percent in each pregnancy.

• Parents who are related to each other have a higher chance of having a child with the disease.

• Both men and women have equal chances of getting the disease.

How Is the Disease Diagnosed?

• Triosephosphate enzyme deficiency is diagnosed based on clinical features, patient history, and family history.

• Confirmation is done by molecular genetic testing, which enables the identification of the faulty gene.

• Prenatal testing can be done where there is a family history of the disease. Chorionic villus sampling (CVS) is done for this purpose.

• Genetic counseling is done for affected individuals.

How Is the Disease Treated?

• Since it is a genetic disorder, there is no curative treatment; symptomatic treatment is done. A multispecialty treatment may be required consisting of pediatricians, neurologists, and cardiologists based on the symptoms of the patient.

• Blood transfusion can be done for hemolytic anemia.

• Assisted ventilation can be used for patients with respiratory difficulties due to paralysis of the diaphragm.

Conclusion

Triosephosphate enzyme deficiency is a rare autosomal recessive genetic disorder that causes difficulty in the metabolism of glucose in the body. The enzyme is a necessary step in glucose breakdown. When glucose metabolism is affected, there is not enough energy supply to cells such as red blood cells, nerves, and muscle cells. This leads to anemia, infections, motor movement impairment, and muscle wastage. Symptomatic treatment is given according to the severity of the clinical features.