Triosephosphate Isomerase Deficiency

Disease Overview

Triosephosphate isomerase (TPI) deficiency is a rare genetic multisystem disorder. It is characterized by lack or reduced activity of the enzyme triosephosphate isomerase, an enzyme necessary for the breakdown (metabolism) of certain sugars in the body. Affected individuals experience low levels of circulating red blood cells due to premature destruction of red blood cells (hemolytic anemia) and severe, progressive neurological symptoms. Specific symptoms vary from case to case. Intellectual disability is a variable finding. Additional symptoms may develop including disease of the heart muscle (cardiomyopathy) and a susceptibility to developing chronic infections. Affected individuals usually develop life-threatening complications early during childhood. TPI deficiency is inherited as an autosomal recessive trait.

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Synonyms

• TPI
• TPID
• deficiency of phosphotriose isomerase
• hereditary nonspherocytic hemolytic anemia due to triosephosphate isomerase deficiency
• triose phosphate isomerase deficiency

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Signs & Symptoms

The symptoms of TPI deficiency vary from person to person. In most people, life-threatening complications such as respiratory or heart (cardiac) failure occur during childhood. However, adults with TPI deficiency with less severe symptoms have been reported.

The disorder is characterized by hemolytic anemia and progressive neurological findings.^1,2

• Hemolytic anemia (occurs before birth in about half of the cases) is a condition characterized by low levels of circulating red blood cells (erythrocytes) that occurs because red blood cells are prematurely destroyed, and the bone marrow, the tissue inside of the bones that produce blood cells, cannot compensate for the loss.³ Symptoms of hemolytic anemia may include:
  • Fatigue
  • Lightheadedness
  • Yellowing of the skin and whites of the eyes (jaundice)
  • Pale skin color
  • Difficulty breathing
• Progressive neurological symptoms (usually between 6 and 30 months of age) including: ^9,10,11
  • Low muscle tone (hypotonia)
  • Weakness
  • Muscular wasting or degeneration (amyotrophy)
  • Lack of deep tendon reflexes
  • Involuntary muscle spasms (spasticity) resulting in slow, stiff movements of the legs
  • Intellectual disability may occur along with tremors and dystonia in some people
  • Dystonia, a group of movement disorders that is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures)

Additional symptoms associated with TPI deficiency may include: ^{2, 3}

• Increased susceptibility to infections due to poorly functioning white blood cells, which are immune system cells that normally recognize and attack foreign invaders such as viruses and bacteria, to prevent infection
• Most common infections are bacterial infections of the respiratory tract
• Abnormally enlarged spleen (splenomegaly)
• Breathing difficulties due to paralysis of the muscle that separates the stomach and the chest cavity (diaphragm)
• Disease of heart muscle (cardiomyopathy)

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Causes

Triose phosphate-isomerase deficiency is caused by changes (variants) in the TPI1 gene.¹ The TPI1 gene tells the body to produce triosephosphate isomerase 1, which plays a key role in glycolysis, a process where cells turn sugar into energy. The energy produced in this process is needed for the cells to do their jobs, grow and stay healthy. The triosephosphate isomerase 1 enzyme is important for the conversion of a molecule called dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate.¹² Both of these molecules are needed for cells to continue producing energy.

The most common TPI1 gene variant is Glu105Asp (older literature may refer to the same variant as Glu104Asp). This variant has been found in about 80% of people with TPI deficiency so it is often referred to as the “common TPI deficiency variant”. This variant often leads to the most serious symptoms. However, there are other TPI1 gene variants that can cause less damage to the nervous system, slowing down the disease and allowing people to live longer.⁷

Inheritance

TPI deficiency is inherited in an autosomal recessive pattern.² Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry some abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.

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Affected populations

TPI deficiency is very rare (fewer than 1,000 people in the US).¹ It affects males and females in equal numbers. Approximately 30 to 50 cases have been reported in the medical literature since the initial description of the condition in 195.¹³ The carrier frequency for having one TPI1 gene variant is estimated to be 0.4-1% among Caucasians and Asians and 4% among African Americans. These high values suggest that babies with TPI deficiency often die before birth. Frequent miscarriages in the affected families support this theory.⁷

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of TPI deficiency. Comparisons may be useful for a differential diagnosis.

Pyruvate kinase deficiency is a genetic blood disorder characterized by a deficiency of the enzyme pyruvate kinase. Physical findings associated with the disorder may include hemolytic anemia, abnormally increased levels of bilirubin in the blood (hyperbilirubinemia), splenomegaly and/or other abnormalities. Pyruvate kinase deficiency is inherited in an autosomal recessive pattern. While both pyruvate kinase deficiency and TPI deficiency affect the glycolytic pathway in red blood cells, leading to hemolytic anemia, TPI deficiency is generally considered much more severe.

Phosphoglycerate kinase deficiency is a very rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen. Symptoms may include hemolytic anemia, intellectual disability varying degrees, rapidly changing emotions (emotional lability), an impaired ability to communicate through and/or to comprehend speech or writing (aphasia), exercise-induced pain, stiffness, or cramps, splenomegaly and/or paralysis of one side of the body (hemiplegia). In most people, this condition is inherited in an X-linked pattern so most people who have symptoms are males. TPI deficiency is generally considered more severe than phosphoglycerate kinase deficiency, often leading to more significant neurological complications and a faster disease progression .^14,15,16

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Diagnosis

A diagnosis of TPI deficiency may be suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing that identifies two variants in the TPI1 gene. Identification of the specific gene variants can help predict life expectancy.⁷

Clinicians may also order additional blood tests (serological), tests of electrical activity in muscles (electrodiagnostic), medical imaging like MRI or CT (radiologic) and tissue sample studies (histopathologic) as part of the diagnostic workup.¹⁷  People with TPI deficiency have a deficiency of the TPI enzyme and greatly increased (15 to 100 fold) and accumulation of DHAP (a molecule that helps in making energy and breaking down sugars).¹⁷ Muscle biopsy shows myopathic changes and nerve biopsy can show chronic axonal neuropathy, the microscopic observation of significant damage to the axons (the long, slender projections of nerve cells) within the nerve tissue.

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Standard Therapies

Treatment

No specific therapy exists for TPI deficiency. There is a lack of effective clinical treatment as the pathogenesis underlying TPI deficiency remains largely unknown.⁸ Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.

Treatment may include blood transfusions to treat hemolytic anemia during episodes of red blood cell destruction (hemolysis), assisted ventilation to help with the breathing difficulties due to paralysis of the diaphragm, physical and speech therapy and assistive devices to improve mobility as well as standard medications to control seizures, and antibiotic therapy to prevent infections. ⁷ Other treatment is symptomatic and supportive.^18,19,20

The prognosis for TPI deficiency is variable and depends on the severity of the symptoms. Some people do not survive past childhood due to respiratory failure, but other affected people without severe nerve damage or muscle weakness have lived into adulthood.²

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Research is underway to study various treatment options for individuals with TPI deficiency. Such treatment options include enzyme replacement therapy and bone marrow transplantation.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Triose Phosphate Isomerase Deficiency. Genetic and Rare Diseases Information Center (GARD). Updated August 16, 2018. https://rarediseases.info.nih.gov/diseases/5287/triose-phosphate-isomerase-deficiency Accessed March 3, 2025.
2. Triosephosphate isomerase deficiency. Online Mendelian Inheritance in Man (OMIM). OMIM. 02/12/2021. https://omim.org/entry/615512?search=TRIOSEPHOSPHATE%20ISOMERASE%20DEFICIENCY&highlight=deficiency%2Cisomerase%2Ctriosephosphate Accessed March 3, 2025.
3. Triosephosphate isomerase deficiency. MedlinePlus. Last updated August 1, 2014. https://medlineplus.gov/genetics/condition/triosephosphate-isomerase-deficiency/#inheritance. Accessed March 3, 2025.
4. Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: Elsevier Saunders; 2005:1636.
5. Rimoin D, Connor JM, Pyeritz RP, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. New York, NY: Churchill Livingstone; 2002:1909.
6. Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Companies; 2001:4647-8.
7. Triosephosphate Isomerase Deficiency. Orphanet. April 2012. https://www.orpha.net/en/disease/detail/868?name=Triosephosphate%20Isomerase%20Deficiency&mode=name Accessed March 3, 2025.
8. Sun P, Li Y, Liu F, Wang L. Generation and analysis of TPI deficiency zebrafish model. Yi Chuan. 2024 Mar 20;46(3):232-241. doi: 10.16288/j.yczz.23-316. PMID: 38632101.
9. Gnerer JP, Kreber RA, Ganetzky B. Wasted away, a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death. Proc Natl Acad Sci USA. 2006;103:14987-93.
10. Olah J, Orosz F, Puskas LG, et al. Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels. Biochem J. 2005;392:675-83.
11. Wilmshurst JM, Wise GA, Pollard JD, Ouvrier RA. Chronic axonal neuropathy with triosephosphate isomerase deficiency. Pediatr Neurol. 2004;30:146-8.
12. TPI1 gene. MedlinePlus. Last updated August 1, 2014. https://medlineplus.gov/genetics/gene/tpi1/. Accessed December 3, 2024.
13. Gendelman H, Balcerzak S, Richards S, et al. TPI deficiency in the pediatric population: a case study. J Med Genet. 1999;36:533-7.
14. Mazzola C, Tortorella G, Losito M, et al. Pyruvate kinase deficiency and its differential diagnosis from triosephosphate isomerase deficiency. Blood Cells Mol Dis. 2001;27:370-9.
15. Topham PS, Reiss D, McAlister V, et al. Phosphoglycerate kinase deficiency. J Pediatr Hematol Oncol. 2003;25:205-7.
16. Renshaw M, Harrison R, O’Neil T, et al. Genetic characterization of phosphoglycerate kinase deficiency: molecular analysis. J Med Genet. 2007;44:497-503.
17. Beecher G, Fleming MD, Liewluck T. Hereditary myopathies associated with hematological abnormalities. Muscle Nerve. 2022;65(4):374-390. doi:10.1002/mus.27474
18. Scriver CR. Therapeutic advances in managing enzyme deficiencies. Neurotherapeutics. 2012;9:297-305.
19. Zaretsky J, Finegold D, Wainwright L, et al. Advances in care for rare genetic disorders: A case study on TPI deficiency. J Rare Dis Med. 2015;3(4):225-31.
20. Keenan A, Richards P, Patel R, et al. Genetic counseling in autosomal recessive metabolic diseases. Am J Med Genet A. 2014;164A(4):930-5.

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