TriosePhosphate Isomerase Deficiency

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Triose-Phosphate Isomerase Deficiency

• Wednesday, February 27th 2008

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Patient Zero

• In 1965 a girl of French, African-American
  descent
• Chronic hemolytic state since 5 weeks
• Died at 20 months
• Had erythrocyte TPI activity reduced to
  one-seventh that of normal

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Symptoms of TPI Deficiency

• Hemolytic anemia
• Neurological deficits
• Cardiomyopathy
• Diaphragm paralysis
• Dystonia, dyskinesia
• Immune system deficiencies
• Early death before age 6

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Triose-Phosphate Isomerase (TPI)

• Enzyme in glycolytic pathway
• Catalyzes interconversion between
  dihydroxyacetone phosphate (DHAP) and
  glyceraldehyde-3-phosphate (G3P)
• Only G3P continues in glycolysis

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Expected Outcome

• Glycolytic pathway is
• negatively affected
• Accumulation of DHAP
• Marked decrease of ATP production in RBC

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However

• Studies show
• Accumulation of DHAP
• Marked decrease of ATP production in RBC

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Compensation for TPI deficiency

• Pentose phosphate pathway
• d

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Mutations

• Autosomal recessive
• Diverse mutations of gene at chromosome 12

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Altered Dimerization

• TPI has catalytic activity only when dimerized
• In some mutant TPI (Glu104Asp)will lead to no
  dimerization
• Other mutations lead to improper dimerization

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Binding of Microtubules

• The Phe240Leu mutant TPI forms heterodimers with
  the wildtype
• Heterodimers bind to microtubules with greater
  efficiency than wild-type homodimeric TPI
• Binding of TPI to MT is thought to decrease its
  catalytic activity
• Neuronal cells have high microtubule composition
  resulting in exacerbated condition

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Accumulation of DHAP

• DHAP decomposition into methylglyoxal
• Methylglyoxal cause oxidative stress leading to
  DNA damage and apoptosis
• Oxidative stress damages RBC membrane resulting
  inhemolytic anaemia
• Damage to neuronal cells explainneurodegenerative
  effects

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Diagnosis of TPI Deficiency

• TPI level in RBCs
• Homozygotes 5-10 of normal
• Heterozygotes 50 of normal
• Prenatal diagnosis
• TPI concentration
• Screening for known TPI gene mutations

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Treatment and Management

• No treatment, symptomatic
• Transfusions for acute hemolysis
• Assisted ventilation diaphragm paralysis
• Neurological management
• Enzyme replacement therapy

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Summary

• TPI is required for interconversion between G3P
  and DHAP in the glycolytic pathway
• Mutations in TPI result in decreased catalytic
  activity through
• Failure to dimerize, or
• Association with microtubles
• Decreased catalytic activity causes accumulation
  of DHAP, leading to methylglyoxal production and
  oxidative stress
• Clinical symptoms haemolytic anaemia,
  susceptibility of bacterial infections,
  neurological deficits, neuromuscular degeneration
  and death
• Diagnosis test for enzymatic activity of TPI in
  blood sample
• Treatment mainly symptomatic

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References

• Livet, M.O. (2003). Triose-phosphate isomerase
  deficiency. Orphanet Encyclopedia, 1-3.
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• Olah, J., Orosz, F., Keseru, G.M., Kovari, Z.,
  Kovacs, J., Hollan, S.,
• and Ovadi, J. (2002). Triosephosphate isomerase
  deficiency a neurodegenerative misfolding
  disease. Biochemical Society Transactions, 30(2),
  30-38.
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• Olah, J., Orosz, F., Puskas, L.G., Hackler, L.,
  Jr, Horanyi, M., Polgar, L., Hollan, S., and
  Ovadi, J. (2005). Triosephosphate isomerase
  deficiency consequences of an inherited mutation
  at mRNA, protein and metabolic levels.
  Biochemical Journal, 392, 675-683.
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• Orosz, F., Olah, J., and Ovadi, J. (2006).
  Triosephosphate isomerase deficiency facts and
  doubts. International Union of Biochemistry and
  Molecular Biology Life, 58(12), 703-715.
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• Ralser M., Heeren G., Breitenbach M., Lehrach H.,
  Krobitsch S. (2006). Triose phosphate isomerase
  deficiency is caused by altered dimerization
  not catalytic inactivity of the mutant enzymes.
  PLoS ONE, 1, e30.1-12.
•  
• Schneider, A.S. (2000). Triosephosphate isomerase
  deficiency historical perspectives and molecular
  aspects. Clinical Haematology, 13(1), 119-140.

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