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Purine & Pyrimidine Disorders: Dietary Aspects Tony Marinaki Purine Research Laboratory Clinical Spectrum of PP disorders 23 enzyme defects, 17 clinically significant Anaemia Immune Drug metab Renal stones Renal Neurology UMPS, UMPH, CPT, superactive ADA ADA, PNP, UMPS UMPS, DPD, DHPA, TPMT, AOX MoCoD, XDH, LNS, HPRT, PRPS, APRT XDH, PNP, LNS, HPRT, PRPS, APRT,FJHN, UMPS HPRT, MoCoD, PNP, PRPS, ASA, MDA, UMPS DPD, DHPA Simmonds 1997 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. 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 MOLYBDENUM COFACTOR Sulphate Uric acid Acids 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. Dietary Therapy • Dietary restriction of sulphur containing amino acids • Isolated case reports – biochemical/clinical improvement with dietary therapy :Boles (1993), Touati (2000) 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 Urine Sulphite negative Date 05/01/2002 05/12/2001 05/11/2001 05/10/2001 05/09/2001 05/08/2001 05/07/2001 05/06/2001 05/05/2001 05/04/2001 05/03/2001 05/02/2001 05/01/2001 05/12/2000 05/11/2000 05/10/2000 05/09/2000 Micromol/L Methionine, Cystine and Sulphocysteine levels on Prospective dietary therapy 40 35 30 25 20 15 10 LOWER LIMIT OF NORMAL 5 0 Sulphocysteine Methionine Cystine Clinical Course • Growth appropriate on 3rd centile • Intractable seizures - worsening EEG • Neurodevelopmental regression • Recurrent admissions with aspiration pneumonia and respiratory failure Purine salvage pathway DNA ribose-5-P PRPP DNA dGTP RNA SAICAR dATP dGDP GTP AICAR dADP GDP ATP ADP XMP GMP S-AMP IMP AMP inosine adenosine HPRT guanosine PRPP guanine PRPP hypoxanthine xanthine uric acid adenine HPRT: Clinical Lesch Nyhan syndrome neuro renal LNS variants milder neuro Partial HPRT no neuro 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 Uric acid, dietary purines and allopurinol Neutraceuticals • • • • S-adenosyl methionine Treatment of liver disease Depression Osteoarthritis Treatment of Alzheimer’s disease 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 HPRT deficiency Possible explanation: up regulation of HPRT gene expression and increase in residual enzyme activity 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 Warning! Dietary supplements can seriously damage your health! There are side effects and the long term consequences are not known! Our thanks to PUMPA for agreeing to fund our research on 5-fluoruracil pharmacogenetics NHS Innovations London award November 2008