3Aims of dietary intervention Limit exposure to a toxic metabolite – PKU: inability to convert Phe to Tyr. High phenylalanine = severe mental retardation. Treatment, low Phe dietReplace 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.
4Molybdenum Cofactor Deficiency (MoCoD) Molybdenum Co Factor is essential to the function of 3 enzymes1.Sulphite oxidase2.Xanthine dehydrogenase3.Aldehyde oxidaseSulphite Xanthine AldehydesSulphate Uric acid AcidsMOLYBDENUM COFACTOR
5Clinical featuresUsually a severe paediatric disorder (intractable neonatal fitting)Late onset milder form in juveniles and adultsXanthine stones, acute or acute-on-chronic renal failureLens dislocation.
6Dietary Therapy Dietary restriction of sulphur containing amino acids Isolated case reports – biochemical/clinical improvement with dietary therapy :Boles (1993), Touati (2000)
7Prospective Dietary Management Methionine and cystine restriction diet3.0 g/kg/day protein1-1.7 g/kg/day restricted natural proteinRest as X MET CYS Analog
8Urine Sulphite negative Methionine, Cystine and Sulphocysteine levels on Prospective dietary therapyLOWER LIMIT OF NORMALUrine Sulphite negative
9Clinical Course Growth appropriate on 3rd centile Intractable seizures - worsening EEGNeurodevelopmental regressionRecurrent admissions with aspiration pneumonia and respiratory failure
14S-adenosyl methionine NeutraceuticalsTreatment of liver diseaseDepressionOsteoarthritisTreatment of Alzheimer’s diseaseS-adenosyl methionine
15S-Adenosyl methionine Source of adenine, methionine and riboseDonor for methylation reactions in the cell – regulation of gene expressionFeeds into polyamine biosynthesis – poorly understood, bind to DNA and may influence gene expression
16HPRT deficiencyPossible explanation: up regulation of HPRT gene expression and increase in residual enzyme activity
17Italian Lesch-Nyhan patient Treated with intrathecal injection of buffy coat on a two week cycle. Significant residual enzyme activity = 1.7Completely 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
18Warning. Dietary supplements can seriously damage your health Warning! Dietary supplements can seriously damage your health! There are side effects and the long term consequences are not known!
19Our thanks to PUMPA for agreeing to fund our research on 5-fluoruracil pharmacogeneticsNHS Innovations London award November 2008