Transcript Purine & Pyrimidine Disorders: Clinical Aspects

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