Purine & Pyrimidine Disorders: Dietary Aspects

1. Purine & Pyrimidine Disorders: Dietary Aspects Tony Marinaki Purine Research Laboratory

2. 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

3. 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 >4 h, give diet high in carbohydrates low in fat.

4. 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

5. 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.

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

7. 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

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

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

10. Purine salvage pathway DNA ribose-5-P PRPP DNA dGTP RNA SAICAR dATP dGDP GTP AICAR dADP ATP GDP ADP XMP S-AMP GMPIMPAMP guanosineinosine adenosine PRPPPRPP guanine hypoxanthine adenine xanthine uric acid HPRT

11. HPRT: Clinical Lesch Nyhan syndrome neuro renal LNS variants milder neuro Partial HPRT no neuro

12. 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

13. Uric acid, dietary purines and allopurinol

14. Neutraceuticals • Treatment of liver disease • Depression • Osteoarthritis • Treatment of Alzheimer’s disease S-adenosyl methionine

15. 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

16. HPRT deficiency Possible explanation: up regulation of HPRT gene expression and increase in residual enzyme activity

17. 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

18. Warning! Dietary supplements can seriously damage your health!There are side effects and the long term consequences are not known!

19. Our thanks to PUMPA for agreeing to fund our research on 5-fluoruracil pharmacogenetics NHS Innovations London award November 2008