Purine & Pyrimidine Disorders: Dietary Aspects Tony Marinaki Purine Research Laboratory.
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Transcript of Purine & Pyrimidine Disorders: Dietary Aspects Tony Marinaki Purine Research Laboratory.
Purine & Pyrimidine Disorders: Dietary Aspects
Tony Marinaki
Purine Research Laboratory
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
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 oxidase2.Xanthine dehydrogenase3.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
• 1-1.7 g/kg/day restricted natural protein
• Rest as X MET CYS Analog
Methionine, Cystine and Sulphocysteine levels on Prospective dietary therapy
0
5
10
15
20
25
30
35
40
05/0
9/20
00
05/1
0/20
00
05/1
1/20
00
05/1
2/20
00
05/0
1/20
01
05/0
2/20
01
05/0
3/20
01
05/0
4/20
01
05/0
5/20
01
05/0
6/20
01
05/0
7/20
01
05/0
8/20
01
05/0
9/20
01
05/1
0/20
01
05/1
1/20
01
05/1
2/20
01
05/0
1/20
02
Date
Mic
rom
ol/L
Sulphocysteine
Methionine
Cystine
Urine Sulphite negative
LOWER LIMIT OF NORMAL
Clinical Course
• Growth appropriate on 3rd centile
• Intractable seizures - worsening EEG
• Neurodevelopmental regression
• Recurrent admissions with aspiration pneumonia and respiratory failure
Purine salvage pathway DNADNA ribose-5-P ribose-5-P PRPP PRPP DNA DNA
dGTPdGTP RNA RNA SAICAR SAICAR dATP dATP
dGDPdGDP GTP GTP AICAR AICAR dADP dADP ATP ATP
GDPGDP ADP ADP
XMPXMP S-AMP S-AMP
GMPGMP IMPIMP AMPAMP
guanosineguanosine inosineinosine adenosineadenosine
PRPPPRPP PRPPPRPP
guanineguanine hypoxanthine hypoxanthine adenine adenine
xanthinexanthine
uric aciduric acid
HPRT
HPRT: Clinical
Lesch Nyhan syndrome neuro
renal
LNS variants milder neuro
Partial HPRT no neuro
HPRT ManagementSeating & posture MxRelaxation techniquesOT + aidsAllopurinol + citrate + fluidsSelf injury communication skills
+ consistent handling + relaxation techniques + protective devices
DietL-Dopa
Uric acid, dietary purines and allopurinol
Neutraceuticals
S-adenosyl methionineS-adenosyl methionine
• Treatment of liver disease• Depression• Osteoarthritis• Treatment of Alzheimer’s disease
S-Adenosyl methionineS-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 NHS Innovations London award November 2008