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Triosephosphate isomerase deficiency

Triosephosphate isomerase deficiency



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Triose phosphate isomerase deficiency, a rare condition, is the only glycolytic enzymopathy that is lethal. This deficiency is characterized by severe hemolytic anemia and neurodegeneration.

How can I relate this enzyme deficiency to hemolysis?


My attempt:

1- Accumulation of DHAP is causing intracellular fluid to be more osmotic leading to cell bursting.( Then why don't we see the same in outer cells?)

2-Lack of glucose may lead to less ATP production, Na/K pumps work less, thus disturbing membrane potential, which finally may cause hyper-osmic ICF and then henolysis. ( But why don't RBC take twice the amount of glucose?)


Source: Biochemistry 8th edition by Jeremy M. Berg John L. Tymoczko Gregory J. Gatto, Jr. Lubert Stryer


Unlike most of the cells in a human body, erythrocytes (or red blood cells) don't have mitochondria (because they are basically O2 carriers), and don't perform Krebs Cycle or Oxidative Phosphorylation. Therefore, they depend exclusively on glycolysis to produce their ATPs.

According to the Genetics Home Reference (from the NIH, National Institutes of Health) page about triosephosphate isomerase deficiency:

The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia [… ] TPI1 gene mutations lead to the production of unstable enzymes or enzymes with decreased activity. As a result, glycolysis is impaired and cells have a decreased supply of energy. Red blood cells depend solely on the breakdown of glucose for energy, and without functional glycolysis, red blood cells die earlier than normal. (emphasis mine)

Thus, since erythrocytes depend solely on glycolysis as energy source, there is a marked accumulation of DHAP toxic sub-products (Ahmed et al., 2003).

Sources:

  • Reference, G. (2017). triosephosphate isomerase deficiency. [online] Genetics Home Reference. Available at: https://ghr.nlm.nih.gov/condition/triosephosphate-isomerase-deficiency#genes [Accessed 16 Jul. 2017].
  • Ahmed, N., Battah, S., Karachalias, N., Babaei-Jadidi, R., Horányi, M., Baróti, K., Hollan, S. and Thornalley, P. (2003). Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1639(2), pp.121-132.

Triosephosphate isomerase deficiency

Triosephosphate isomerase deficiency is a disorder characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function.

The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia. A shortage of red blood cells to carry oxygen throughout the body leads to extreme tiredness (fatigue), pale skin (pallor), and shortness of breath. When the red cells are broken down, iron and a molecule called bilirubin are released individuals with triosephosphate isomerase deficiency have an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice, which is a yellowing of the skin and the whites of the eyes.

Movement problems typically become apparent by age 2 in people with triosephosphate isomerase deficiency. The movement problems are caused by impairment of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. This impairment leads to muscle weakness and wasting (atrophy) and causes the movement problems typical of triosephosphate isomerase deficiency, including involuntary muscle tensing (dystonia), tremors, and weak muscle tone (hypotonia). Affected individuals may also develop seizures.

Weakness of other muscles, such as the heart (a condition known as cardiomyopathy) and the muscle that separates the abdomen from the chest cavity (the diaphragm ) can also occur in triosephosphate isomerase deficiency. Diaphragm weakness can cause breathing problems and ultimately leads to respiratory failure.

Individuals with triosephosphate isomerase deficiency are at increased risk of developing infections because they have poorly functioning white blood cells . These immune system cells normally recognize and attack foreign invaders , such as viruses and bacteria, to prevent infection. The most common infections in people with triosephosphate isomerase deficiency are bacterial infections of the respiratory tract.

People with triosephosphate isomerase deficiency often do not survive past childhood due to respiratory failure. In a few rare cases, affected individuals without severe nerve damage or muscle weakness have lived into adulthood.


Abstract

Deficiencies in around 20 enzymes, associated with widely different degrees of severity and complexity, have been identified for human erythrocytes. The fact that glycolysis is crucial for erythrocyte function is reflected by the large number of inherited glycolytic enzymopathies. Triosephosphate isomerase (TPI) deficiency, a rare autosomal disease, is usually associated with nonspherocytic hemolytic anemia, progressive neurologic dysfunction, and death in childhood. The two affected Hungarian brothers studied by us have less than 3% TPI activity and enormously (30–50-fold) increased dihydroxyacetone phosphate (DHAP) concentration in their erythrocytes.

The well-established concept of the metabolic control theory was used to test the contribution of TPI and some related enzymes to the control of a relevant segment of the glycolytic pathway in normal and deficient cells. Deviation indices,DE J = (ΔJE)E r /J r , which give a good estimation of flux control coefficients using a single large change in enzyme activity, were determined from the fluxes in the absence and presence of exogenous enzymes. We found that PFK and aldolase are the enzymes that predominantly control the flux, however, the quantitative values depend extensively on the pH:DE J values are 0.85 and 0.14 at pH 8.0 and 0.33 and 0.67 at pH 7.2 for aldolase and PFK, respectively. Neither the flux rates nor the capacities of the enzymes seem to be significantly different in normal and TPI deficient cells.

There is a discrepancy between DHAP levels and TPI activities in the deficient cells. In contrast to the experimental data the theoretical calculations predict elevation in DHAP level at lower than 0.1% of the normal value of TPI activity. Several possibilities suggested fail to explain this discrepancy. Specific associations of glycolytic enzymes to band-3 membrane proteins with their concomitant inactivation have been demonstrated. We propose that the microcompartmentation of TPI that could further decrease the reduced isomerase activity of the deficient cells is responsible for the high DHAP level.


Rare Disease Database

NORD gratefully acknowledges Barry Ganetzky, PhD, Professor of Genetics and Medical Sciences, Steenbock Professor of Biological Sciences, University of Wisconsin, for assistance in creating this report.

Synonyms of Triosephosphate Isomerase Deficiency

Subdivisions of Triosephosphate Isomerase Deficiency

General Discussion

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.

Signs & Symptoms

The symptoms of TPI deficiency vary from case to case. The disorder is characterized by hemolytic anemia and progressive neurological findings. Hemolytic anemia occurs before birth (neonatally) in approximately half of the cases.

Hemolytic anemia 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 cannot compensate for the loss. Hemolytic anemia may cause fatigue, lightheadedness, yellowing of the skin and whites of the eyes (jaundice), pale skin color, and difficulty breathing.

Additional symptoms associated with TPI deficiency include increased susceptibility to infections, an abnormally enlarged spleen (splenomegaly), breathing difficulties due to paralysis of the muscle that separates the stomach and the chest cavity (diaphragm), and disease of the heart muscle (cardiomyopathy).

In most cases, 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.

Progressive neurological symptoms are seen in infants with TPI deficiency usually between 6 and 30 months of age. Such symptoms include diminished muscle tone (hypotonia), weakness, muscular wasting or degeneration (amyotrophy), lack of deep tendon reflexes, and involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs.

Some individuals do not develop any additional neurological symptoms and intelligence is unaffected. In other cases, intellectual disability occurs along with tremors and dystonia. Dystonia is the name for 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).

Causes

TPI deficiency is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 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 to have children with a recessive genetic disorder.

Investigators have determined that TPI deficiency occurs due to disruption or changes (mutations) of a gene located on the short arm of chromosome 12 (12p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Affected Populations

TPI deficiency affects males and females in equal numbers. Approximately 30 to 50 cases have been reported in the medical literature since the disorder initial description in 1965.

Related Disorders

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

Red cell pyruvate kinase deficiency is a hereditary blood disorder characterized by a deficiency of the enzyme pyruvate kinase. Physical findings associated with the disorder may include reduced levels of oxygen-carrying hemoglobulin in the blood due to premature destruction of red blood cells (hemolytic anemia) abnormally increased levels of bilirubin in the blood (hyperbilirubinemia) abnormal enlargement of the spleen (splenomegaly) and/or other abnormalities. Pyruvate kinase deficiency is inherited as an autosomal recessive genetic trait. It is one of a group of diseases known as hereditary nonspherocytic hemolytic anemias. Nonspherocytic refers to the fact that the red blood cells do not assume a spherical shape, as they do with some blood disorders. (For more information on this disorder, choose “pyruvate kinase deficiency” as your search term in the Rare Disease Database.)

Phosphoglycerate kinase deficiency is an extremely rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen, resulting in the release of energy. Symptoms and findings associated with the disorder may include low levels of circulating red blood cells (hemolytic anemia) varying degrees of mental retardation 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 enlargement of the spleen (splenomegaly) and/or paralysis of one side of the body (hemiplegia). In most cases, phosphoglycerate kinase deficiency is inherited as an X-linked trait. In such cases, the disorder is fully expressed in males only however, some females who carry one copy of the disease gene (heterozygotes) may have hemolytic anemia. (For more information on this disorder, choose “phosphoglycerate kinase deficiency” as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of TPI deficiency is 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 the characteristic genetic mutation associated with TPI deficiency.

Prenatal diagnosis is possible by measuring TPI enzyme activity in amniotic fluid cells and fetal blood cells. A procedure known as chorionic villus sampling (CVS) has also been used for prenatal diagnosis. This procedure involves the removal and study of tissue samples from the placenta.

Standard Therapies

No specific therapy exists for of TPI deficiency. 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 affect 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 individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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 web site.

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/

Supporting Organizations

    • PO Box 8126
    • Gaithersburg, MD 20898-8126
    • Phone: (301) 251-4925
    • Toll-free: (888) 205-2311
    • Website: http://rarediseases.info.nih.gov/GARD/
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    • Arlington, VA 22202 USA
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    • Website: http://www.marchofdimes.org
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    • Email: [email protected]
    • Website: https://www.metabolicsupportuk.org/
    • P.O. Box 5801
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    References

    TEXTBOOKS
    Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: Elsevier Saunders 2005:1636.

    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.

    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.

    JOURNAL ARTICLES
    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. 2006103:14987-93.

    Olah J, Orosz F, Puskas LG, et al., Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels. Biochem J. 2005392:675-83.

    Wilmshurst JM, Wise GA, Pollard JD, Ouvrier RA. Chronic axonal neuropathy with triosephosphate isomerase deficiency. Pediatr Neurol. 200430:146-8.

    Olah J, Orosz F, Keseru GM, et al., Triosephosphate deficiency: a neurodegenerative misfolding disease. Biochem Soc Trans. 200230:30-8.

    Schneider AS. Triosephosphate isomerase deficiency: historical perspectives and molecular aspects. Baillieres Best Pract Res Clin Haematol. 200013:119-40.

    Orosz F, Vertessy BG, Hollan S, Horanvi, Ovadi J. Triosephosphate isomerase deficiency: predictions and facts. J Theor Biol. 1996182:437-47.

    Arya R, Lalloz MR, Nicolaides KH, Bellingham AJ, Layton DM. Prenatal diagnosis of triosephosphate isomerase deficiency. Blood. 199687:4507-9.

    Schneider AS, Valentine WN, Hattori M, Heins HL Jr. Hereditary hemolytic anemia with triosephosphate isomerase deficiency. N Engl J Med. 1965272:229.

    INTERNET
    Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Triosephosphate Isomerase 1 TPI1. Entry No: 190450. Last Edited 06/13/2014. Available at: http://omim.org/entry/190450 Accessed May 14, 2015.

    Years Published

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    Red Blood Cell Enzymopathies

    Xylina T. Gregg , Josef T. Prchal , in Hematology (Seventh Edition) , 2018

    Triosephosphate Isomerase Deficiency

    Triosephosphate isomerase (TPI) catalyzes the reversible interconversion of the triose phosphate isomers, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. TPI deficiency is a rare autosomal recessive disorder characterized by chronic hemolytic anemia, increased susceptibility to bacterial infections, cardiomyopathy and progressive neuromuscular disease. Neonatal jaundice may also occur. The neuromuscular disease is likely caused by the formation of toxic protein aggregates of glycated proteins formed by elevated byproducts of dihydroxyacetone phosphate.

    Approximately 40 patients with several different mutations have been reported however, most patients have the same mutation and are descendants from a common British/French ancestor about 1000 years ago. There is no effective therapy and most patients die in childhood, although there are rare exceptions.


    Clinical case

    The proband was born at term after an uncomplicated pregnancy to a gravida 1 mother. Her birthweight was 3,409 g. She was diagnosed with hepatomegaly, nonspherocytic hemolytic anemia, and jaundice that required phototherapy in the neonatal intensive care unit. She experienced her first hemolytic crisis requiring blood transfusion at 4 months of age. Bone marrow biopsy at 5 months of age was consistent with congenital dyserythropoietic anemia. Her growth and development were normal. At age 13 months, she was hospitalized with pneumonia and respiratory failure that required intubation. Developmental motor delay was noted, which worsened during her acute illness. Multiple failed trials at extubation resulted in tracheostomy placement. Physical examination during this admission revealed an alert interactive child who could reach for and grasp objects and sit without assistance, but could not pull to a stand (figure 1A). Diffuse muscle weakness and increased tone was noted in all extremities, lower greater than upper, with normal deep tendon reflexes. Initial laboratory evaluations including complete blood count, comprehensive metabolic panel, thyroid studies, serum creatine phosphokinase level, botulinum toxin, carnitine, and CSF analysis were normal. Blood, urine, and CSF cultures were negative for infection. Brain and spine MRI were normal. Evaluation for a primary neuromuscular disorder was negative, including normal EMG and nerve conduction studies, muscle biopsy, Tensilon test, and DMPK trinucleotide repeat testing for congenital myotonic dystrophy. Our patient remained ventilator-dependent, and experienced slow progression of motor weakness and developmental delay. At age 4 years, her physical examination revealed macrocephaly, bifacial weakness including ptosis, nystagmus, and upper and lower extremity spasticity. Diffuse progressive muscle weakness with proximal muscles more severely affected, brisk upper and absent lower extremity deep tendon reflexes, and an action tremor of the upper extremities were noted. Additional evaluation including SMA gene testing, urine organic and plasma amino acid analyses, Canavan disease, Kennedy disease, and lysosomal storage diseases enzyme testing was negative. Repeat brain MRI was normal except frontal bossing and macrocrania were noted due to extramedullary hematopoiesis. At 20 years of age, our patient has developed quadriparesis with generalized hypotonia, muscle atrophy, loss of deep tendon reflexes of upper and lower extremities, and uses a wheelchair for mobility (figure 1, D and E). Progressive facial weakness has resulted in dysarthria, dysphagia, and tongue fasciculations. She experiences chronic mild hemolysis exacerbated by acute illness. Physical disease manifestations have exceeded intellectual impairment, with a diagnosis of moderate intellectual disability at age 19. The patient has 2 unaffected siblings, a healthy brother and sister.

    (A) At age 12 months, the child sits without support, cannot pull to a stand, and increased tone in lower extremities is noted. (B, C) At age 3 years, the child is ventilator- and wheelchair-dependent with progressive muscle weakness involving proximal muscles preferentially. (D, E) At age 12–18 years, the child remains interactive with quadriparesis, diffuse hypotonia, bilateral facial weakness, muscle wasting of all extremities, and contractures of upper extremities. Note macrocephaly secondary to extramedullary hematopoiesis.


    4 MATERIALS AND METHODS

    4.1 Generation of TPII le170Val/Ile170Val mice

    To create a vector for site-directed mutagenesis of mouse TPI1, the wild type TPI1 locus composed from C57BL/6J genomic DNA was PCR amplified and subcloned into an E. coli backbone (pTretight2, Addgene 19407). PCR mutagenesis was used to mutate codon 170 (ATT, encoding for isoleucine) in exon 5 to GTT, encoding for valine. Then, a loxP-flanked PGKneobpA cassette was introduced into the NdeI site of TPI1 intron 4. The final vector was digested with SalI and NotI to separate the mouse TPI locus from the vector backbone, and transformed into the 129×C57BL/6J hybrid embryonic stem cell line G4. One neomycin-resistant cell line (2G5) was identified to have the integration on the TPI1 locus and used to create a chimeric mouse. In brief, the cell line was expanded, injected into blastocysts and transplanted. Obtained chimera was crossed with Cre-recombinase-expressing C57BL/6J mouse line to remove the neomycin selection cassette. F1 littermates were tested for correct excision of the NEO + marker by PCR and re-sequenced to verify that only the mutation in exon 5, and one loxP site in intron 4 was retained. This line was then backcrossed to the C57BL/6J mouse line for nine generations.

    4.2 TPI activity assays

    TPI activity was determined using a spectrophotometric assay as previously described. 29, 38 Measurements were performed at 2-3 different protein concentrations per tissue lysate and repeated independently three times with freshly dissected tissues from 20-week-old male mice. NADH loss was measured using a Tecan M1000 PRO plate reader. TPI activity was calculated at the point of maximal reaction rate and normalized to lysate-free background activity.

    4.3 Western blotting

    Protein lysates were prepared from dissected tissues from 20-week-old male mice and western blots were performed using a polyclonal TPI serum (1:5000). 39

    4.4 Substrate measurements

    Immediately following dissection, tissues from 20-week-old male mice were freeze clamped in liquid nitrogen and stored at −80°C. Tissues were ground to a fine powder over liquid nitrogen and extracted in a mix of chloroform, methanol, and water in a ratio of 40:40:20 with 0.1 M formic acid, as previously described. 40

    The samples were analyzed by tandem mass spectrometry on an Agilent 1290 liquid chromatography system coupled to an Agilent 6470 triple quadrupole mass spectrometer. The LC-MS/MS method used was based on the Agilent Metabolomics dMRM Database and Method with a shortened chromatography. The compounds were resolved on a C18 column (Zorbax RRHD Extend-C18, 2.1 × 100 mm, 1.8 μm Agilent) with mobile buffer A1 (3% methanol, 10 mM tributylamine, 15 mM acetic acid), mobile buffer B1 (10 mM tributylamine, 15 mM acetic acid, 97% acetonitrile, 3% methanol), and mobile buffer B2 (acetonitrile) by gradient elution at a constant column temperature of 35°C. The gradient program started with 100% A and a flow rate of 0.35 mL/min. The organic fraction (B) was increased to 20% from 2 to 5 minutes and to 45% from 5 to 10 minutes. This was followed by a 2 minutes wash with 99% B1 and a 3 minutes wash of 99% B2 (1 mL/min) before returning to initial buffer conditions for equilibration at a flow rate of 0.6 mL/min for 1 minute and at a flow rate of 0.35 mL/min for 2 minutes, resulting in a total runtime of 18 minutes. The metabolites were quantified by external calibration (Sigma-Aldrich 37442, G5251).

    4.5 Phenotypic screen

    A cohort of 60 mice were phenotypically analyzed at the German Mouse Clinic (GMC) in two standardized pipelines for systematic primary phenotyping as previously described, 30, 41 with 15 mice per group utilized for each test (equal numbers of male and female, and mutant and wild-type animals). All animals were age-matched within 2 weeks of each other and ranged from 63 to 131 days old at the time of testing. All tests performed were approved by the responsible authority in the United Kingdom, as well as the district governments of Berlin and Upper Bavaria, Germany, respectively.

    All institutional and national guidelines for the care and use of laboratory animals were approved by the responsible authority in the United Kingdom, as well as the district governments of Berlin and Upper Bavaria, Germany.

    This manuscript does not contain studies with human subjects performed by any of the authors.


    Triosephosphate isomerase deficiency - Biology

    A number sign (#) is used with this entry because triosephosphate isomerase deficiency (TPID) is caused by homozygous or compound heterozygous mutation in the TPI1 gene (190450) on chromosome 12p13.

    ▼ Description

    Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).

    ▼ Clinical Features

    A form of nonspherocytic hemolytic anemia of Dacie's type II (in vitro autohemolysis is not corrected by added glucose) has been found to have a deficiency of red cell triosephosphate isomerase (Schneider et al., 1965). Association with recurrent infection, causing death in some, and a progressive neurologic disorder characterized by spasticity was noted. The homozygotes showed 6% of normal TPI activity in red cells and 20% in white cells. Heterozygotes showed about 50%. Schneider et al. (1965) raised the 'intriguing possibility that the marked reduction in leukocyte triosephosphate isomerase functionally impairs the activity of these cells.'

    Clay et al. (1982) reported a 12-year-old girl who died of TPI deficiency. Clinically, she had developmental and motor delay and muscular weakness, followed by cerebellar dysfunction and spasticity with hyperreflexia. Neuropathology showed abnormal hyaline cell bodies and axonal spheroids in the hypothalamus and cerebellar cortex, severe neuronal loss in the dentate and olivary nuclei, and partial loss of cerebellar Purkinje cells (olivocerebellar atrophy).

    Rosa et al. (1985) detected 7 homozygotes for TPI deficiency in 5 unrelated families. All showed hemolytic anemia, apparent soon after birth, and progressive neuromuscular symptoms.

    Poll-The et al. (1985) reported a Bulgarian sister and brother with TPI deficiency. The patients, aged 7 and 4 years at the time of the report, developed hemolytic anemia in early infancy, followed by a progressive neuromuscular syndrome beginning at about age 2 years. They were easily fatigued and had muscle weakness and progressive gait abnormalities resulting in a loss of independent ambulation after a few years. The girl had a scissoring gait, areflexia of the legs, and extensor plantar responses, as well as generalized hypotonia, muscle atrophy, intention tremor, and jerky movements of the proximal muscles. The boy was unable to walk, even with support, and showed upper limb weakness, dystonic posturing of the hands, intention tremor, and abnormal jerks of the proximal arms and legs. Both had pallor of the optic discs. EMG in both patients suggested anterior horn cell impairment. Intelligence was preserved. Laboratory studies showed significantly decreased TPI activity.

    Bellingham et al. (1989) reported a family in which a child with triosephosphate isomerase deficiency died at the age of 13 months because of early central nervous system degeneration and cardiac failure. Death usually occurs in this disorder before the age of 15 years.

    Eber et al. (1991) described the disorder in an 8-year-old Turkish girl who had chronic hemolytic anemia, myopathy, and developmental retardation since early infancy. The concentration of enzyme substrate dihydroxyacetone phosphate (DHAP) was elevated. They concluded that low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply. They referred to the variant as TPI Hamm for the city where the child was hospitalized. Accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte, was a characteristic of this variant and was apparently responsible for the altered electrophoretic pattern.

    Hollan et al. (1993) and Chang et al. (1993) reported a Hungarian family in which 2 brothers had TPI deficiency. The older brother, a 23-year-old amateur wrestler, had congenital hemolytic anemia but no neurologic symptoms, whereas his 13-year-old brother had congenital hemolytic anemia and hyperkinetic torsion dyskinesia. Both had less than 10% TPI activity and a greatly increased DHAP level in their red blood cells. Their TPI had a slow electrophoretic mobility and was heat unstable. Both parents and a third brother were healthy heterozygotes. The older brother represented a unique phenotype since all published homozygotes had severe neurologic alterations from infancy or early childhood except 1 infant who died at 11 months, probably too young for neurologic symptoms to be noted. Furthermore, in contrast to the 2 affected Hungarian brothers, all but 1 homozygote had died before the age of 6 years.

    Pekrun et al. (1995) reported a 2-year-old girl, born of consanguineous Turkish parents, with TPI deficiency. She presented with hemolytic anemia shortly after birth, and later developed neuromuscular problems, including progressive hypotonia and loss of reflexes. She had recurrent respiratory infections and developed respiratory failure requiring intermittent mechanical ventilation. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block. During a second pregnancy, examination of a cord blood sample obtained at 19 weeks' gestation showed that the infant was homozygous wildtype, and an unaffected, healthy newborn was delivered.

    Fermo et al. (2010) reported 2 unrelated children with TPI deficiency. The first was an Italian girl born of nonconsanguineous parents. The pregnancy was complicated by oligohydramnios and reduced fetal growth. At birth, she had jaundice and macrocytic anemia, eventually requiring blood transfusions. Neuromuscular complications, including hypotonia and severe difficulty breathing, occurred at 2 months of age. Brain MRI at 9 months showed cerebral atrophy with myelination defects. She had recurrent infections and progressive neuromuscular impairment, resulting in death from respiratory failure at age 6 years. The second child was a male infant born of unrelated parents of Turkish and English origin. Soon after birth he developed hemolytic anemia, jaundice, and respiratory distress. He later developed recurrent infections and showed decreased muscle tone with abnormal posturing he died from respiratory failure at age 10 weeks.

    Harris et al. (2020) reported a 20-year-old woman with TPID, the oldest reported individual with this disease. In infancy, she had hepatomegaly, nonspherocytic hemolytic anemia, and jaundice requiring phototherapy. She had her first hemolytic crisis at age 4 months, and a bone marrow biopsy at age 5 months showed congenital dyserythropoietic anemia. At age 13 months, she had pneumonia and respiratory failure leading to tracheostomy placement. She developed progressive motor weakness and developmental delay. At age 4 years, she had bifacial weakness with ptosis, nystagmus, macrocephaly, and spasticity. Brain MRI was normal except for bossing and macrocrania. At age 20 years, she had moderately impaired intellectual development, quadriparesis with generalized hypotonia, muscle atrophy, and loss of deep tendon reflexes. She required a wheelchair for mobility. She had chronic mild hemolysis exacerbated by acute illness.

    ▼ Diagnosis

    Prenatal Diagnosis

    Bellingham et al. (1989) made a prenatal diagnosis of the heterozygous state by analysis of fetal red cells obtained by cordocentesis at 19 weeks' gestation. Bellingham et al. (1989) recognized that study of chorion villus biopsy material is a more satisfactory approach to prenatal diagnosis. Bellingham and Lestas (1990) suggested that there are reasons to be cautious about the use of enzyme activity in amniocytes or trophoblastic material because of the likelihood that nucleated cells will metabolize the marker material through the presence of an alternative enzyme. They suggested that reliance be placed on assay of red cells in the second trimester pending availability of DNA diagnosis.

    ▼ Inheritance

    The transmission pattern of TPI deficiency in the families reported by Chang et al. (1993) was consistent with autosomal recessive inheritance.

    ▼ Molecular Genetics

    Daar et al. (1986) and Pekrun et al. (1995) identified homozygosity for a missense mutation in the TPI1 gene (E104D 190450.0001) in patients with triosephosphate isomerase deficiency.

    Arya et al. (1997) found that the E104D mutation accounted for 11 (79%) of 14 mutant alleles among 7 unrelated families of northern European origin with TPI deficiency. Haplotype analysis supported a founder effect.

    In 2 Hungarian brothers with TPI deficiency, Chang et al. (1993) and Orosz et al. (2001) identified compound heterozygous mutations in the TPI1 gene (F240L, 190450.0003 and E145X, 190450.0006).

    In 2 unrelated children with TPI deficiency, Fermo et al. (2010) identified compound heterozygous mutations in the TPI gene. Each patient carried the E104D mutation on 1 allele and a different mutation on the other allele (190450.0007 and 190450.0008).

    Harris et al. (2020) identified homozygosity for the E104D mutation in the TPI1 gene in a 20-year-old woman with TPID. The patient was the oldest reported individual with TPID.

    ▼ Clinical Management

    Ationu et al. (1999) noted that the metabolic defect of TPI deficiency can be corrected in vitro in deficient primary skeletal muscle myoblasts and lymphoblastoid cells cultured in the presence of exogenous TPI. They reported a trial of red cell transfusion for replacing enzyme in a 4-year-old child homozygous for the common glu104-to-asp (E104D) mutation. The patient had typical features of TPI deficiency, including chronic hemolytic anemia, and severe generalized muscle weakness with hypotonia and dystonia. TPI deficiency is the most severe of the red cell enzymopathies most reported patients die before 6 years of age. The data obtained in this trial showed a significant increase in lymphocyte TPI activity accompanied by a reduction of DHAP levels following red cell transfusion. The transient nature of the biochemical changes suggested that sustained reversal of the metabolic effects of TPI deficiency would require continuous delivery of active enzyme.

    ▼ Pathogenesis

    In a review of TPI deficiency, Orosz et al. (2006) noted that some evidence suggests that accumulated DHAP may decompose to form advanced glycation end products that are toxic to cells and/or that presence of the mutant protein may result in the formation of toxic protein aggregates both may result in neurodegeneration in addition to the enzymatic defect that primarily affects red cell survival.

    ▼ Population Genetics

    Mohrenweiser (1981) studied the frequency of enzyme deficiency variants in 675 newborn infants and about 200 adults. Seven children were observed with heterozygous TPI deficiency. In each case one parent was also an apparent heterozygote. In Germany, Eber et al. (1984) found a frequency of heterozygotes of 3.7 per 1000.

    Watanabe et al. (1996) reviewed briefly the frequency of the reduced TPI trait. Direct determination enzymatic activity in erythrocytes of unselected Caucasians and Japanese indicated that approximately 4.8 per 1,000 individuals had a level of TPI activity that was 50% of normal. The frequency of heterozygosity was estimated as 9 in 1,713 among Caucasians and 7 in 168 among African Americans. Genetic transmission of the trait was confirmed in all families. The high frequency of the presumptive deficiency allele is not consistent with the rarity of clinically identified TPI deficiency in humans and suggests, as has been reported in studies of TPI-deficient mice (Merkle and Pretsch, 1989), that complete TPI deficiency is an embryo-lethal condition.

    ▼ See Also:

    ▼ REFERENCES

    Arya, R., Lalloz, M. R. A., Bellingham, A. J., Layton, D. M. Evidence for founder effect of the glu104-to-asp substitution and identification of new mutations in triosephosphate isomerase deficiency. Hum. Mutat. 10: 290-294, 1997. [PubMed: 9338582, related citations] [Full Text]

    Ationu, A., Humphries, A., Lalloz, M. R. A., Arya, R., Wild, B., Warrilow, J., Morgan, J., Bellingham, A. J., Layton, D. M. Reversal of metabolic block in glycolysis by enzyme replacement in triosephosphate isomerase-deficient cells. Blood 94: 3193-3198, 1999. [PubMed: 10556207, related citations] [Full Text]

    Ationu, A., Humphries, A., Wild, B., Carr, T., Will, A., Arya, R., Layton, D. M. Towards enzyme-replacement treatment in triosephosphate isomerase deficiency. Lancet 353: 1155-1156, 1999. [PubMed: 10209987, related citations] [Full Text]

    Bellingham, A. J., Lestas, A. N., Williams, L. H. P., Nicolaides, K. H. Prenatal diagnosis of a red-cell enzymopathy: triose phosphate isomerase deficiency. Lancet 334: 419-421, 1989. Note: Originally Volume II. [PubMed: 2569601, related citations] [Full Text]

    Bellingham, A. J., Lestas, A. N. Prenatal diagnosis of triose phosphate isomerase deficiency. (Letter) Lancet 335: 230 only, 1990. [PubMed: 1967698, related citations] [Full Text]

    Chang, M.-L., Artymiuk, P. J., Wu, X., Hollan, S., Lammi, A., Maquat, L. E. Human triosephosphate isomerase deficiency resulting from mutation of phe-240. Am. J. Hum. Genet. 52: 1260-1269, 1993. [PubMed: 8503454, related citations]

    Clay, S. A., Shore, N. A., Landing, B. H. Triosephosphate isomerase deficiency: a case report with neuropathological findings. Am. J. Dis. Child. 136: 800-802, 1982. [PubMed: 7114003, related citations]

    Daar, I. O., Artymiuk, P. J., Phillips, D. C., Maquat, L. E. Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. Proc. Nat. Acad. Sci. 83: 7903-7907, 1986. [PubMed: 2876430, related citations] [Full Text]

    Eber, S. W., Dunnwald, M., Heinemann, G., Hofstatter, T., Weinmann, H. M., Belohradsky, B. H. Prevalence of partial deficiency of red cell triosephosphate isomerase in Germany--a study of 3000 people. Hum. Genet. 67: 336-339, 1984. [PubMed: 6381286, related citations] [Full Text]

    Eber, S. W., Pekrun, A., Bardosi, A., Gahr, M., Krietsch, W. K. G., Kruger, J., Matthei, R., Schroter, W. Triosephosphate isomerase deficiency: haemolytic anaemia, myopathy with altered mitochondria and mental retardation due to a new variant with accelerated enzyme catabolism and diminished specific activity. Europ. J. Pediat. 150: 761-766, 1991. [PubMed: 1959537, related citations] [Full Text]

    Fermo, E., Bianchi, P., Vercellati, C., Rees, D. C., Marcello, A. P., Barcellini, W., Zanella, A. Triose phosphate isomerase deficiency associated with two novel mutations in TPI gene. Europ. J. Haemat. 85: 170-173, 2010. [PubMed: 20374271, related citations] [Full Text]

    Harris, C., Nelson, B., Farber, D., Bickel, S., Huxol, H., Asamoah, A., Morton, R. Child neurology: triosephosphate isomerase deficiency. Neurology 95: e3448-e3451, 2020. [PubMed: 32873690, related citations] [Full Text]

    Hollan, S., Fujii, H., Hirono, A., Hirono, K., Karro, H., Miwa, S., Harsanyi, V., Gyodi, E., Inselt-Kovacs, M. Hereditary triosephosphate isomerase (TPI) deficiency: two severely affected brothers one with and one without neurological symptoms. Hum. Genet. 92: 486-490, 1993. [PubMed: 8244340, related citations] [Full Text]

    Merkle, S., Pretsch, W. Characterization of triosephosphate isomerase mutants with reduced enzyme activity in Mus musculus. Genetics 123: 837-844, 1989. [PubMed: 2693209, related citations]

    Mohrenweiser, H. W. Frequency of enzyme deficiency variants in erythrocytes of newborn infants. Proc. Nat. Acad. Sci. 78: 5046-5050, 1981. [PubMed: 6946452, related citations] [Full Text]

    Orosz, F., Olah, J., Alvarez, M., Keseru, G. M., Szabo, B., Wagner, G., Kovari, Z., Horanyi, M., Baroti, K., Martial, J. A., Hollan, S., Ovadi, J. Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency. Blood 98: 3106-3112, 2001. [PubMed: 11698297, related citations] [Full Text]

    Orosz, F., Olah, J., Ovadi, J. Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life 58: 703-715, 2006. [PubMed: 17424909, related citations] [Full Text]

    Pekrun, A., Neubauer, B. A., Eber, S. W., Lakomek, M., Seidel, H., Schroter, W. Triosephosphate isomerase deficiency: biochemical and molecular genetic analysis for prenatal diagnosis. Clin. Genet. 47: 175-179, 1995. [PubMed: 7628118, related citations] [Full Text]

    Poll-The, B. T., Aicardi, J., Girot, R., Rosa, R. Neurological findings in triosephosphate isomerase deficiency. Ann. Neurol. 17: 439-443, 1985. [PubMed: 4004168, related citations] [Full Text]

    Rosa, R., Prehu, M.-O., Calvin, M.-C., Badoual, J., Alix, D., Girod, R. Hereditary triose phosphate isomerase deficiency: seven new homozygous cases. Hum. Genet. 71: 235-240, 1985. [PubMed: 4065896, related citations] [Full Text]

    Schneider, A. S., Valentine, W. N., Hattori, M., Heins, H. L., Jr. Hereditary hemolytic anemia with triosephosphate isomerase deficiency. New Eng. J. Med. 272: 229-235, 1965. [PubMed: 14242501, related citations] [Full Text]

    Vives-Corrons, J.-L., Rubinson-Skala, H., Mateo, M., Estella, J., Feliu, E., Dreyfus, J.-C. Triosephosphate isomerase deficiency with hemolytic anemia and severe neuromuscular disease: familial and biochemical studies of a case found in Spain. Hum. Genet. 42: 171-180, 1978. [PubMed: 669702, related citations] [Full Text]

    Watanabe, M., Zingg, B. C., Mohrenweiser, H. W. Molecular analysis of a series of alleles in humans with reduced activity at the triosephosphate isomerase locus. Am. J. Hum. Genet. 58: 308-316, 1996. [PubMed: 8571957, related citations]

    Zanella, A., Mariani, M., Colombo, M. B., Borgna-Pignatti, C., De Stefano, P., Morgese, G., Sirchia, G. Triosephosphate isomerase deficiency: 2 new cases. Scand. J. Haemat. 34: 417-424, 1985. [PubMed: 4012221, related citations] [Full Text]

    # 615512

    TRIOSEPHOSPHATE ISOMERASE DEFICIENCY TPID

    ORPHA: 868 DO: 0050884

    Phenotype-Gene Relationships

    Location Phenotype Phenotype
    MIM number
    Inheritance Phenotype
    mapping key
    Gene/Locus Gene/Locus
    MIM number
    12p13.31 Hemolytic anemia due to triosephosphate isomerase deficiency 615512 Autosomal recessive 3 TPI1 190450

    TEXT

    A number sign (#) is used with this entry because triosephosphate isomerase deficiency (TPID) is caused by homozygous or compound heterozygous mutation in the TPI1 gene (190450) on chromosome 12p13.

    Description

    Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).

    Clinical Features

    A form of nonspherocytic hemolytic anemia of Dacie's type II (in vitro autohemolysis is not corrected by added glucose) has been found to have a deficiency of red cell triosephosphate isomerase (Schneider et al., 1965). Association with recurrent infection, causing death in some, and a progressive neurologic disorder characterized by spasticity was noted. The homozygotes showed 6% of normal TPI activity in red cells and 20% in white cells. Heterozygotes showed about 50%. Schneider et al. (1965) raised the 'intriguing possibility that the marked reduction in leukocyte triosephosphate isomerase functionally impairs the activity of these cells.'

    Clay et al. (1982) reported a 12-year-old girl who died of TPI deficiency. Clinically, she had developmental and motor delay and muscular weakness, followed by cerebellar dysfunction and spasticity with hyperreflexia. Neuropathology showed abnormal hyaline cell bodies and axonal spheroids in the hypothalamus and cerebellar cortex, severe neuronal loss in the dentate and olivary nuclei, and partial loss of cerebellar Purkinje cells (olivocerebellar atrophy).

    Rosa et al. (1985) detected 7 homozygotes for TPI deficiency in 5 unrelated families. All showed hemolytic anemia, apparent soon after birth, and progressive neuromuscular symptoms.

    Poll-The et al. (1985) reported a Bulgarian sister and brother with TPI deficiency. The patients, aged 7 and 4 years at the time of the report, developed hemolytic anemia in early infancy, followed by a progressive neuromuscular syndrome beginning at about age 2 years. They were easily fatigued and had muscle weakness and progressive gait abnormalities resulting in a loss of independent ambulation after a few years. The girl had a scissoring gait, areflexia of the legs, and extensor plantar responses, as well as generalized hypotonia, muscle atrophy, intention tremor, and jerky movements of the proximal muscles. The boy was unable to walk, even with support, and showed upper limb weakness, dystonic posturing of the hands, intention tremor, and abnormal jerks of the proximal arms and legs. Both had pallor of the optic discs. EMG in both patients suggested anterior horn cell impairment. Intelligence was preserved. Laboratory studies showed significantly decreased TPI activity.

    Bellingham et al. (1989) reported a family in which a child with triosephosphate isomerase deficiency died at the age of 13 months because of early central nervous system degeneration and cardiac failure. Death usually occurs in this disorder before the age of 15 years.

    Eber et al. (1991) described the disorder in an 8-year-old Turkish girl who had chronic hemolytic anemia, myopathy, and developmental retardation since early infancy. The concentration of enzyme substrate dihydroxyacetone phosphate (DHAP) was elevated. They concluded that low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply. They referred to the variant as TPI Hamm for the city where the child was hospitalized. Accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte, was a characteristic of this variant and was apparently responsible for the altered electrophoretic pattern.

    Hollan et al. (1993) and Chang et al. (1993) reported a Hungarian family in which 2 brothers had TPI deficiency. The older brother, a 23-year-old amateur wrestler, had congenital hemolytic anemia but no neurologic symptoms, whereas his 13-year-old brother had congenital hemolytic anemia and hyperkinetic torsion dyskinesia. Both had less than 10% TPI activity and a greatly increased DHAP level in their red blood cells. Their TPI had a slow electrophoretic mobility and was heat unstable. Both parents and a third brother were healthy heterozygotes. The older brother represented a unique phenotype since all published homozygotes had severe neurologic alterations from infancy or early childhood except 1 infant who died at 11 months, probably too young for neurologic symptoms to be noted. Furthermore, in contrast to the 2 affected Hungarian brothers, all but 1 homozygote had died before the age of 6 years.

    Pekrun et al. (1995) reported a 2-year-old girl, born of consanguineous Turkish parents, with TPI deficiency. She presented with hemolytic anemia shortly after birth, and later developed neuromuscular problems, including progressive hypotonia and loss of reflexes. She had recurrent respiratory infections and developed respiratory failure requiring intermittent mechanical ventilation. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block. During a second pregnancy, examination of a cord blood sample obtained at 19 weeks' gestation showed that the infant was homozygous wildtype, and an unaffected, healthy newborn was delivered.

    Fermo et al. (2010) reported 2 unrelated children with TPI deficiency. The first was an Italian girl born of nonconsanguineous parents. The pregnancy was complicated by oligohydramnios and reduced fetal growth. At birth, she had jaundice and macrocytic anemia, eventually requiring blood transfusions. Neuromuscular complications, including hypotonia and severe difficulty breathing, occurred at 2 months of age. Brain MRI at 9 months showed cerebral atrophy with myelination defects. She had recurrent infections and progressive neuromuscular impairment, resulting in death from respiratory failure at age 6 years. The second child was a male infant born of unrelated parents of Turkish and English origin. Soon after birth he developed hemolytic anemia, jaundice, and respiratory distress. He later developed recurrent infections and showed decreased muscle tone with abnormal posturing he died from respiratory failure at age 10 weeks.

    Harris et al. (2020) reported a 20-year-old woman with TPID, the oldest reported individual with this disease. In infancy, she had hepatomegaly, nonspherocytic hemolytic anemia, and jaundice requiring phototherapy. She had her first hemolytic crisis at age 4 months, and a bone marrow biopsy at age 5 months showed congenital dyserythropoietic anemia. At age 13 months, she had pneumonia and respiratory failure leading to tracheostomy placement. She developed progressive motor weakness and developmental delay. At age 4 years, she had bifacial weakness with ptosis, nystagmus, macrocephaly, and spasticity. Brain MRI was normal except for bossing and macrocrania. At age 20 years, she had moderately impaired intellectual development, quadriparesis with generalized hypotonia, muscle atrophy, and loss of deep tendon reflexes. She required a wheelchair for mobility. She had chronic mild hemolysis exacerbated by acute illness.

    Diagnosis

    Prenatal Diagnosis

    Bellingham et al. (1989) made a prenatal diagnosis of the heterozygous state by analysis of fetal red cells obtained by cordocentesis at 19 weeks' gestation. Bellingham et al. (1989) recognized that study of chorion villus biopsy material is a more satisfactory approach to prenatal diagnosis. Bellingham and Lestas (1990) suggested that there are reasons to be cautious about the use of enzyme activity in amniocytes or trophoblastic material because of the likelihood that nucleated cells will metabolize the marker material through the presence of an alternative enzyme. They suggested that reliance be placed on assay of red cells in the second trimester pending availability of DNA diagnosis.

    Inheritance

    The transmission pattern of TPI deficiency in the families reported by Chang et al. (1993) was consistent with autosomal recessive inheritance.

    Molecular Genetics

    Daar et al. (1986) and Pekrun et al. (1995) identified homozygosity for a missense mutation in the TPI1 gene (E104D 190450.0001) in patients with triosephosphate isomerase deficiency.

    Arya et al. (1997) found that the E104D mutation accounted for 11 (79%) of 14 mutant alleles among 7 unrelated families of northern European origin with TPI deficiency. Haplotype analysis supported a founder effect.

    In 2 Hungarian brothers with TPI deficiency, Chang et al. (1993) and Orosz et al. (2001) identified compound heterozygous mutations in the TPI1 gene (F240L, 190450.0003 and E145X, 190450.0006).

    In 2 unrelated children with TPI deficiency, Fermo et al. (2010) identified compound heterozygous mutations in the TPI gene. Each patient carried the E104D mutation on 1 allele and a different mutation on the other allele (190450.0007 and 190450.0008).

    Harris et al. (2020) identified homozygosity for the E104D mutation in the TPI1 gene in a 20-year-old woman with TPID. The patient was the oldest reported individual with TPID.

    Clinical Management

    Ationu et al. (1999) noted that the metabolic defect of TPI deficiency can be corrected in vitro in deficient primary skeletal muscle myoblasts and lymphoblastoid cells cultured in the presence of exogenous TPI. They reported a trial of red cell transfusion for replacing enzyme in a 4-year-old child homozygous for the common glu104-to-asp (E104D) mutation. The patient had typical features of TPI deficiency, including chronic hemolytic anemia, and severe generalized muscle weakness with hypotonia and dystonia. TPI deficiency is the most severe of the red cell enzymopathies most reported patients die before 6 years of age. The data obtained in this trial showed a significant increase in lymphocyte TPI activity accompanied by a reduction of DHAP levels following red cell transfusion. The transient nature of the biochemical changes suggested that sustained reversal of the metabolic effects of TPI deficiency would require continuous delivery of active enzyme.

    Pathogenesis

    In a review of TPI deficiency, Orosz et al. (2006) noted that some evidence suggests that accumulated DHAP may decompose to form advanced glycation end products that are toxic to cells and/or that presence of the mutant protein may result in the formation of toxic protein aggregates both may result in neurodegeneration in addition to the enzymatic defect that primarily affects red cell survival.

    Population Genetics

    Mohrenweiser (1981) studied the frequency of enzyme deficiency variants in 675 newborn infants and about 200 adults. Seven children were observed with heterozygous TPI deficiency. In each case one parent was also an apparent heterozygote. In Germany, Eber et al. (1984) found a frequency of heterozygotes of 3.7 per 1000.

    Watanabe et al. (1996) reviewed briefly the frequency of the reduced TPI trait. Direct determination enzymatic activity in erythrocytes of unselected Caucasians and Japanese indicated that approximately 4.8 per 1,000 individuals had a level of TPI activity that was 50% of normal. The frequency of heterozygosity was estimated as 9 in 1,713 among Caucasians and 7 in 168 among African Americans. Genetic transmission of the trait was confirmed in all families. The high frequency of the presumptive deficiency allele is not consistent with the rarity of clinically identified TPI deficiency in humans and suggests, as has been reported in studies of TPI-deficient mice (Merkle and Pretsch, 1989), that complete TPI deficiency is an embryo-lethal condition.

    See Also:

    REFERENCES

    Arya, R., Lalloz, M. R. A., Bellingham, A. J., Layton, D. M. Evidence for founder effect of the glu104-to-asp substitution and identification of new mutations in triosephosphate isomerase deficiency. Hum. Mutat. 10: 290-294, 1997. [PubMed: 9338582] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:4<290::AID-HUMU4>3.0.CO2-L]

    Ationu, A., Humphries, A., Lalloz, M. R. A., Arya, R., Wild, B., Warrilow, J., Morgan, J., Bellingham, A. J., Layton, D. M. Reversal of metabolic block in glycolysis by enzyme replacement in triosephosphate isomerase-deficient cells. Blood 94: 3193-3198, 1999. [PubMed: 10556207] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)71061-X]

    Ationu, A., Humphries, A., Wild, B., Carr, T., Will, A., Arya, R., Layton, D. M. Towards enzyme-replacement treatment in triosephosphate isomerase deficiency. Lancet 353: 1155-1156, 1999. [PubMed: 10209987] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(99)00474-2]

    Bellingham, A. J., Lestas, A. N., Williams, L. H. P., Nicolaides, K. H. Prenatal diagnosis of a red-cell enzymopathy: triose phosphate isomerase deficiency. Lancet 334: 419-421, 1989. Note: Originally Volume II. [PubMed: 2569601] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(89)90593-X]

    Bellingham, A. J., Lestas, A. N. Prenatal diagnosis of triose phosphate isomerase deficiency. (Letter) Lancet 335: 230 only, 1990. [PubMed: 1967698] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/0140-6736(90)90327-2]

    Chang, M.-L., Artymiuk, P. J., Wu, X., Hollan, S., Lammi, A., Maquat, L. E. Human triosephosphate isomerase deficiency resulting from mutation of phe-240. Am. J. Hum. Genet. 52: 1260-1269, 1993. [PubMed: 8503454]

    Clay, S. A., Shore, N. A., Landing, B. H. Triosephosphate isomerase deficiency: a case report with neuropathological findings. Am. J. Dis. Child. 136: 800-802, 1982. [PubMed: 7114003]

    Daar, I. O., Artymiuk, P. J., Phillips, D. C., Maquat, L. E. Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. Proc. Nat. Acad. Sci. 83: 7903-7907, 1986. [PubMed: 2876430] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2876430]

    Eber, S. W., Dunnwald, M., Heinemann, G., Hofstatter, T., Weinmann, H. M., Belohradsky, B. H. Prevalence of partial deficiency of red cell triosephosphate isomerase in Germany--a study of 3000 people. Hum. Genet. 67: 336-339, 1984. [PubMed: 6381286] [Full Text: https://dx.doi.org/10.1007/BF00291364]

    Eber, S. W., Pekrun, A., Bardosi, A., Gahr, M., Krietsch, W. K. G., Kruger, J., Matthei, R., Schroter, W. Triosephosphate isomerase deficiency: haemolytic anaemia, myopathy with altered mitochondria and mental retardation due to a new variant with accelerated enzyme catabolism and diminished specific activity. Europ. J. Pediat. 150: 761-766, 1991. [PubMed: 1959537] [Full Text: https://dx.doi.org/10.1007/BF02026706]

    Fermo, E., Bianchi, P., Vercellati, C., Rees, D. C., Marcello, A. P., Barcellini, W., Zanella, A. Triose phosphate isomerase deficiency associated with two novel mutations in TPI gene. Europ. J. Haemat. 85: 170-173, 2010. [PubMed: 20374271] [Full Text: https://doi.org/10.1111/j.1600-0609.2010.01451.x]

    Harris, C., Nelson, B., Farber, D., Bickel, S., Huxol, H., Asamoah, A., Morton, R. Child neurology: triosephosphate isomerase deficiency. Neurology 95: e3448-e3451, 2020. [PubMed: 32873690] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=32873690]

    Hollan, S., Fujii, H., Hirono, A., Hirono, K., Karro, H., Miwa, S., Harsanyi, V., Gyodi, E., Inselt-Kovacs, M. Hereditary triosephosphate isomerase (TPI) deficiency: two severely affected brothers one with and one without neurological symptoms. Hum. Genet. 92: 486-490, 1993. [PubMed: 8244340] [Full Text: https://dx.doi.org/10.1007/BF00216456]

    Merkle, S., Pretsch, W. Characterization of triosephosphate isomerase mutants with reduced enzyme activity in Mus musculus. Genetics 123: 837-844, 1989. [PubMed: 2693209]

    Mohrenweiser, H. W. Frequency of enzyme deficiency variants in erythrocytes of newborn infants. Proc. Nat. Acad. Sci. 78: 5046-5050, 1981. [PubMed: 6946452] [Full Text: https://dx.doi.org/10.1073/pnas.78.8.5046]

    Orosz, F., Olah, J., Alvarez, M., Keseru, G. M., Szabo, B., Wagner, G., Kovari, Z., Horanyi, M., Baroti, K., Martial, J. A., Hollan, S., Ovadi, J. Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency. Blood 98: 3106-3112, 2001. [PubMed: 11698297] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)56847-X]

    Orosz, F., Olah, J., Ovadi, J. Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life 58: 703-715, 2006. [PubMed: 17424909] [Full Text: https://doi.org/10.1080/15216540601115960]

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    Abstract

    In a Hungarian family with severe decrease in triosephosphate isomerase (TPI) activity, 2 germ line–identical but phenotypically differing compound heterozygote brothers inherited 2 independent (Phe240Leu and Glu145stop codon) mutations. The kinetic, thermodynamic, and associative properties of the recombinant human wild-type and Phe240Leu mutant enzymes were compared with those of TPIs in normal and deficient erythrocyte hemolysates. The specific activity of the recombinant mutant enzyme relative to the wild type was much higher (30%) than expected from the activity (3%) measured in hemolysates. Enhanced attachment of mutant TPI to erythrocyte inside-out vesicles and to microtubules of brain cells was found when the binding was measured with TPIs in hemolysate. In contrast, there was no difference between the binding of the recombinant wild-type and Phe240Leu mutant enzymes. These findings suggest that the missense mutation by itself is not enough to explain the low catalytic activity and “stickiness” of mutant TPI observed in hemolysate. The activity of the mutant TPI is further reduced by its attachment to inside-out vesicles or microtubules. Comparative studies of the hemolysate from a British patient with Glu104Asp homozygosity and with the platelet lysates from the Hungarian family suggest that the microcompartmentation of TPI is not unique for the hemolysates from the Hungarian TPI-deficient brothers. The possible role of cellular components, other than the mutant enzymes, in the distinct behavior of TPI in isolated form versus in hemolysates from the compound heterozygotes and the simple heterozygote family members is discussed.


    Health Conditions Related to Genetic Changes

    Triosephosphate isomerase deficiency

    At least 12 mutations in the TPI1 gene have been found to cause triosephosphate isomerase deficiency. This condition is characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function.

    TPI1 gene mutations can lead to the production of an enzyme with decreased activity. As a result, glycolysis is impaired and cells have a decreased supply of energy. One TPI1 gene mutation accounts for approximately 80 percent of triosephosphate isomerase deficiency cases. This change replaces the protein building block (amino acid) glutamic acid with the amino acid aspartic acid at position 104 in the triosephosphate isomerase 1 enzyme (written as Glu104Asp or E104D). This mutation causes the enzyme to be unstable and impairs its ability to form a dimer and become active.

    Red blood cells depend solely on the breakdown of glucose for energy. Without functional triosephosphate isomerase 1 enzyme to convert DHAP to glyceraldehyde 3-phosphate, red blood cells accumulate DHAP, which is toxic in large quantities. Unlike other cells, red blood cells do not have alternative pathways to break down DHAP. Due to the buildup of DHAP and the lack of cellular energy, red blood cells die earlier than normal.

    Cells with high energy demands, such as nerve cells in the brain, white blood cells, and heart (cardiac) muscle cells are also susceptible to cell death due to reduced energy caused by impaired glycolysis. Nerve cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected in people with triosephosphate isomerase deficiency. Death of red and white blood cells, nerve cells in the brain, and cardiac muscle cells leads to the signs and symptoms of triosephosphate isomerase deficiency.


    Triosephosphate isomerase deficiency - Biology

    Experimental Data Snapshot

    • Method: X-RAY DIFFRACTION
    • Resolution: 1.60 Å
    • R-Value Free: 0.187 
    • R-Value Work: 0.153 
    • R-Value Observed: 0.155 

    wwPDB Validation   3D Report Full Report

    Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency.

    (2015) Biochim Biophys Acta 1852: 61-69

    • PubMed: 25463631  Search on PubMedSearch on PubMed Central
    • DOI: 10.1016/j.bbadis.2014.10.010
    • Primary Citation of Related Structures:  
      4POC, 4POD, 4ZVJ
    • PubMed Abstract: 

    Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability .

    Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability. In this report, we genetically and physically characterize a human disease-associated TPI mutation caused by an I170V substitution. Human TPI(I170V) elicits behavioral abnormalities in Drosophila. An examination of hTPI(I170V) enzyme kinetics revealed this substitution reduced catalytic turnover, while assessments of thermal stability demonstrated an increase in enzyme stability. The crystal structure of the homodimeric I170V mutant reveals changes in the geometry of critical residues within the catalytic pocket. Collectively these data reveal new observations of the structural and kinetic determinants of TPI Deficiency pathology, providing new insights into disease pathogenesis.


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