Purine

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Purine Pyrimidine Disorders Dietary Aspects

• Tony Marinaki
• Purine Research Laboratory

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Clinical Spectrum of PP disorders

• 23 enzyme defects, 17 clinically significant
• Anaemia UMPS, UMPH, CPT, superactive ADA
• Immune ADA, PNP, UMPS
• Drug metab UMPS, DPD, DHPA, TPMT, AOX
• Renal stones MoCoD, XDH, LNS, HPRT, PRPS, APRT
• Renal XDH, PNP, LNS, HPRT, PRPS, APRT,FJHN, UMPS
• Neurology HPRT, MoCoD, PNP, PRPS, ASA, MDA, UMPS
• DPD, DHPA
• Simmonds 1997

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Aims of dietary intervention

• Limit exposure to a toxic metabolite PKU
  inability to convert Phe to Tyr. High
  phenylalanine severe mental retardation.
  Treatment, low Phe diet
• Replace a deficient metabolite MCAD, defect in
  fatty acid metabolism. Cause of SID. Low glucose.
  Avoid fasting for gt4 h, give diet high in
  carbohydrates low in fat.

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Molybdenum Cofactor Deficiency (MoCoD)

• Molybdenum Co Factor is essential to the
  function of 3 enzymes
• 1.Sulphite oxidase
• 2.Xanthine dehydrogenase
• 3.Aldehyde oxidase
• Sulphite Xanthine Aldehydes
• Sulphate Uric acid Acids

MOLYBDENUM COFACTOR
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Clinical features

• Usually a severe paediatric disorder (intractable
  neonatal fitting)
• Late onset milder form in juveniles and adults
• Xanthine stones, acute or acute-on-chronic renal
  failure
• Lens dislocation.

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Dietary Therapy

• Dietary restriction of sulphur containing amino
  acids
• Isolated case reports biochemical/clinical
  improvement with dietary therapy Boles (1993),
  Touati (2000)

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Prospective Dietary Management

• Methionine and cystine restriction diet
• 3.0 g/kg/day protein
• 1-1.7 g/kg/day restricted natural protein
• Rest as X MET CYS Analog

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Methionine, Cystine and Sulphocysteine levels on
Prospective dietary therapy
LOWER LIMIT OF NORMAL
Urine Sulphite negative
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Clinical Course

• Growth appropriate on 3rd centile
• Intractable seizures - worsening EEG
• Neurodevelopmental regression
• Recurrent admissions with aspiration pneumonia
  and respiratory failure

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Purine salvage pathway

• DNA ribose-5-P PRPP DNA
• dGTP RNA SAICAR dATP
• dGDP GTP AICAR dADP ATP
• GDP ADP
• XMP S-AMP
• GMP IMP AMP
• guanosine inosine adenosine
• PRPP PRPP
• guanine hypoxanthine adenine
• xanthine
• uric acid

HPRT
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HPRT Clinical

• Lesch Nyhan syndrome neuro
• renal
• LNS variants milder neuro
• Partial HPRT no neuro

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HPRT Management

• Seating posture Mx
• Relaxation techniques
• OT aids
• Allopurinol citrate fluids
• Self injury communication skills
• consistent handling
• relaxation techniques
• protective devices
• Diet
• L-Dopa

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Uric acid, dietary purines and allopurinol
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Neutraceuticals

• Treatment of liver disease
• Depression
• Osteoarthritis
• Treatment of Alzheimers disease

S-adenosyl methionine
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S-Adenosyl methionine

• Source of adenine, methionine and ribose
• Donor for methylation reactions in the cell
  regulation of gene expression
• Feeds into polyamine biosynthesis poorly
  understood, bind to DNA and may influence gene
  expression

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HPRT deficiency
Possible explanation up regulation of HPRT gene
expression and increase in residual enzyme
activity
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Italian Lesch-Nyhan patient

• Treated with intrathecal injection of buffy coat
  on a two week cycle. Significant residual enzyme
  activity 1.7
• Completely unethical !!!!
• Crude form of enzyme replacement therapy ?
• Possible explanation inflammatory reaction
  leading to up-regulation of HPRT gene expression
  and increase in residual enzyme activity

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Warning! Dietary supplements can seriously damage
your health!There are side effects and the long
term consequences are not known!
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Our thanks to PUMPA for agreeing to fund our
research on 5-fluoruracil pharmacogenetics
NHS Innovations London award November 2008
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