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