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 Sulphate Uric acid Acids MOLYBDENUM COFACTOR
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 g/kg/day restricted natural protein Rest as X MET CYS Analog
Methionine, Cystine and Sulphocysteine levels on Prospective dietary therapy Urine Sulphite negative LOWER LIMIT OF NORMAL
Clinical Course Growth appropriate on 3 rd 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 dGTP RNA SAICAR dATP dGDP GTP AICAR dADP ATP dGDP GTP AICAR dADP ATP GDP ADP GDP ADP XMP S-AMP XMP S-AMP GMP IMP AMP GMP IMP AMP guanosineinosineadenosine PRPP PRPP PRPP PRPP guanine hypoxanthine adenine guanine hypoxanthine adeninexanthine uric acid HPRT
Neutraceuticals S-adenosyl methionine Treatment of liver disease Depression Osteoarthritis Treatment of Alzheimers 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