Lesch-Nyhan Disease By: Lindsey Kost Background Very rare - PowerPoint PPT Presentation

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Lesch-Nyhan Disease By: Lindsey Kost Background Very rare

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Lesch-Nyhan Disease By: Lindsey Kost Background Very rare disease X-linked recessive disorder HPRT1 gene Long arm of x chromosome Xq26 Found predominantly in males ... – PowerPoint PPT presentation

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Title: Lesch-Nyhan Disease By: Lindsey Kost Background Very rare


1
Lesch-Nyhan Disease
  • By Lindsey Kost

2
Background
  • Very rare disease
  • X-linked recessive disorder
  • HPRT1 gene
  • Long arm of x chromosome Xq26
  • Found predominantly in males, few female cases
  • Over 300 cases identified

3
Symptoms/Characteristics
  • Motor dysfunction
  • Hyperuricemia
  • Overproduction of uric acid
  • Cognitive and behavioral problems
  • Aggressive, self-injurious behavior

4
History
  • First case with symptoms of the disease in 1963
  • First described in 1964 by William Nyhan and
    Michael Lesch
  • First genetically-determined cause of
    hyperuricemia, or overproduction of uric acid, to
    be defined at the enzymatic level

5
History
  • first experience was with a 4-year-old boy
  • Examined crystals in urine
  • Showed elevated levels of uric acid in blood and
    urine
  • Concluded there was a defect in purine metabolism

6
Testing
  • Urine sample
  • Urate to creatinine ratio is calculated using
    concentrations of uric acid and creatinine found
    in sample
  • Positive results (in males) show ratio 2-4 fold
    higher than that of normal male

7
Purine Metabolism
  • 1) De novo pathway binding of purine
    nucleotide onto 5-phosphoribosyl-alpha-1-pyrophosp
    hate, or PRPP
  • - 5-phosphoribosyl-alpha-1- pyrophosphate
    amidotransferase (PRPP)
  • 2) Salvage pathway recovery of adenine and
    guanine from hypoxanthine and xanthine and
    degradation products produced from nucleotide
    metabolism
  • - hypoxanthine phosphoribosyltransferase (HPRT)

8
(No Transcript)
9
Regulation
  • Pathways in purine metabolism are highly
    regulated and feedback inhibition occurs,
    especially where IMP, ATP, and GTP are
    synthesized
  • Synthesis of IMP and 5-phosphoribosylamine are
    highly regulated
  • Driven by ribose phosphate pyrophosphokinase,
    inhibited by ADP and GDP
  • Rate of IMP production is controlled according to
    adenine and guanine nucleotide levels

10
Regulation
  • Also regulated where IMP branches off to AMP and
    GMP
  • Excess of these nucleotides stops the reaction
    from proceeding
  • AMP and GMP depend on one another
  • AMP is needed for conversion of IMP to GMP and
    GMP is needed for conversion of IMP to AMP
  • increased concentration of one nucleotide
    increases the rate of synthesis of the other

11
Purine Metabolism
12
So why does this disease occur?
  • Enzyme hypoxanthine-guanine posphoribosyl
    transferase, HPRT
  • Responsible for catalyzing conversion of
    hypoxanthine and guanine to their respective
    nucleotides inosinic acid (IMP) and guanylic
    acid (GMP)

13
HPRT Enzyme
  • Deficiency in HPRT enzyme activity results in
    overproduction of hypoxanthine via the de novo
    pathway and accumulation of uric acid in urine
  • Blood of Lesch-Nyhan patient has a shortage of
    HPRT enzymes
  • HPRT enzyme activity measured in erythrocytes is
    near zero (common method)

14
Effects of HPRT Deficiency
  • Results in dysfunction of basal ganglia dopamine
    systems
  • Study performed on brains from Lesch-Nyhan
    patients showed 60-90 decrease in dopamine and
    its metabolite within the putamen, caudate,
    nucleus accumbens and globus pallidus
  • A decrease in enzymes involved with dopamine
    synthesis was also found in brains of these
    patients

15
Effects of HPRT Deficiency
  • Adenosine transport
  • Compared peripheral blood lymphocytes from
    patients with and without the disease
  • Lymphocytes from Lesch-Nyhan patient incubated
    with 25µM hypoxanthine showed to have a
    significant decrease in adenosine transport
  • Mechanism by which this occurs remains unknown

16
Pathogenesis
  • Exact pathogenesis of diesease is unknown
  • 4 models have been generated

17
1) Simple Linear Model
  • mutation of the HPRT gene and defect of the
  • HPRT enzyme results in irregular purine
    metabolism
  • leads to a defect in the basal ganglia dopamine
  • systems
  • defect in dopamine systems causes the
    neurobehavioral problems

18
2) Red Herring Model
  • Defective HPRT enzyme and its HPRT gene does
    result in abnormal purine metabolism and
    deficient dopamine systems
  • It is the abnormal purine metabolism that results
    in the neurobehavioral disorder, not the
    deficient dopamine systems

19
3) Synergy Model
  • The defective HPRT gene and enzyme result in
  • problems with both purine metabolism and dopamine
  • systems in the brain
  • Both resulting problems are required to cause
  • the neurobehavioral abnormalities

20
4) Parallel Model
  • Suggests that deficiencies in purine metabolism
  • and dopamine systems both result in
    neurobehavioral
  • abnormalities, but are each specific for what
    behaviors
  • occur

Synergy model or Parallel model are most
realistic
21
Cures/Treatments
  • No known cure for disease
  • Medication such as carbamazepine or gabapentin
    are administered to curb self-inflicting
    behaviors but not proven effective
  • Partial exchange transfusion and bone marrow
    transplanation have been attempted to reduce
    behavioral and neurological symptoms but have
    failed
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