Disorders of Purine Metabolism

1. Disorders of Purine Metabolism

2. Purines are heterocyclic compound consisting of a pyrimidine ring fused to an imidazole Ring

3. Functions Key functions include; • Provision of Energy e.g. ATP, GTP • Building blocks for DNA and RNA (along side pyrimidines) • Basic conenzymes i.e. NAD and NADH • Play role in signal transduction e.g GTP, cAMP, cGMP

4. Purine Related Disorders • Gout • Other hyper-uricemias • Lesch – Nyhan Syndrome • Von Gierke’s disease • Hypo-uricemia • Adenosine deaminase and • Purine nucleoside phosphorylase deficiency

5. Uric Acid (2,6,8-trioxypurine) • This is the end product of purine metabolism in humans • Accumulation of uric acid in blood is reffered to as hyperuricemia • Uric acid is highly insoluble therefore a very slight alteration in the production or solubility will increase levels in blood. • Due to poor solubility, levels in blood are usually near the maximal tolerable limits

6. Excretion of uric acid • Uric acid is filtered through the glomeruli and most is reabsorbed in the proximal tubules. • More than 80% of uric acid formed in the urine is derived from distal tubular secretion • Urinary excretion is slightly lower in males than females,which may contribute to the higher incidence of hyperuricaemia in men • Renal secretion may be enhanced by uricosonic drugs(e.gprobenecid or sulfinpyrazone),which block tubular uratereabsorption

7. Excretion of uric acid • 75% urate leaving the body is in urine • The remaining 25% passes into the intestinal lumen,where it is broken down by intestinal bacteria(URICOLYCIS)

8. HYPERURICAEMIA • This is increase in blood levels of uric acid • It can occur by two mechanisms: • Increased production(Over Production) • Decreased Excretion (under excretors)

9. Gout • Uric Acid = 3 – 9 mg/dl or 0.18 – 0.54 mmol/L(Men)(Serum / plasma) 2.5 – 7.5 mg/dl or 0.15 – 0.45 mmol/L (Women) • A group of disorders of purine metabolism due to over production & hence over-excretion of uric acid • PRPP synthetase is abnormal and is not responsive to feedback inhibition by ADP & GDP

11. Gout • Characterised by the accumulation of monosodium urate crystal deposits which result in inflamation in joints and surrounding tissues. • Presentation • Hyperuricemia • Uric acid nephrolithiasis • Acute inflamatory arthritis

12. Gout • Commonly monoarticular (Affecting the metatarsophalangeal joint of the big toe. • However deposits of sodium urates may aslo occur in; • The elbows • Knees • Feet • Helix of the ear

13. Types of Gout • Primary Gout • Occurrence: Middle aged men (mostly) • Cause: Overproduction of Uric Acid Decreased renal excretion or both Biochemical Etiology: Not clearly known and is considered a polygenic disease

14. Types of Gout • Secondary Gout • Occurrence: Children • Cause: other condition in which there is rapid tissue breakdown or cellular turnover • Such condition leads to either; • Increased production of Uric acid • Decreased clearance of Uric acid

15. Hereditary disorders associated with gout • These include 3 key enzymes resulting in hyperuricemia • These are; • Severe HPRT defficiency (Lesch-Nyhan syndrome) • Also Partial HPRT defficiency • Superactivity of PP-ribose-p synthetase • Glucose -6-phosphatase defficiency (glycogen storage disease type 1)

16. Hereditary disorders associated with gout - cnt • 1st two are caused by hyperuricemia due to purine nucleotide and uric acid overproduction • The 3rd due to excess uric acid production and impaired uric acid secretion

18. Common treatment for gout: allopurinol Allopurinol is an analogue of hypoxanthine that strongly inhibits xanthine oxidase. Xanthine and hypoxanthine, which are soluble, are accumulated and excreted.

19. Diet and drugs that may promote gout • too much food, too rich in purines • excessive fructose or sucrose • alcoholic beverages • anorexia nervosa • drugs that interfere with uric acid secretion: pyrazinamide, salicylic acid • drugs that contain purines: dideoxyadenosine

20. Advanced GoutClinically Apparent Tophi 2 1 3 1 1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida. 3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.

21. Other Hyper-uricemias Lesch-Nyhan Syndrome • A severe deficiency or complete absence of enzyme of salvage pathway (hypo-xanthine-guanine phospho-ribosyl transferase) • Purine bases cannot be salvaged • More hypo-xanthine available   uric acid • Severe gout, renal failure & neurological problems

22. Other Hyper-uricemias Von Gierke’s Disease • Deficiency of Glucose-6-Phosphatase • Glucose-6-Phosphate cannot be converted to glucose • Glucose-6-Phosphate will enter HMP shunt   ribose-5-P   PRPP   purines   uric acid • In addition, G-6-P  Lactic acid, which competes with uric acid for excretion resulting in uric acid retention

23. Lesch-Nyhan syndrome

24. Hypo-uricemia • Xanthine oxidase deficiency • Decreased xanthine degradation  accumulation • Increased hypoxanthine excretion • Decreased uric acid formation and excretion

25. Xanthine Oxidase Deficiency (XANTHINURIA) • This is a rare hereditary disorder in which there is a deficiency of liver xanthine oxidase • The catabolism of purine stops with xanthine-hypoxanthine stones. • The blood uric acid is very low and there is a high level of urinary excretion of xanthine • There is reduced excretion of urinary uric acid

26. Immunodeficiency Disorders 1. Adenosine deaminase deficiency • Due to this deficiency adenosine & deoxy-adenosine cannot be degraded  concentration increases  converted into nucleotides (ATP & dATP) in WBC • dATP inhibits ribonucleotidereductase thus inhibiting DNA synthesis, therefore WBCs cannot proliferate (T-Cell, B-Cell functions are defective)

27. Adenosine Deaminase Deficiency • This is a genetic disorder that impairs the immune system and is the basis of severe combined immunodeficiency, or SCID. • Children diagnosed with SCID are typically deficient in almost all immune protection from pathogens and are vulnerable to chronic infections caused by "opportunistic" organisms that ordinarily do not cause disease in healthy people with a normal immune response. • Symptoms of SCID include pneumonia and chronic diarrhea, with impeded growth compared to healthy children. • Additionally, neurological problems such as developmental delay, motor function disorders and hearing loss often occur. • Left untreated, children with SCID usually survive only a year or two.

28. Immunodeficiency Disorders 2. Purine nucleoside phosphorylase (PNP) deficiency • Inability to metabolize guanosine and deoxy-guanosine  Accumulation  Conversion to nucleotides (GTP & dGTP)  which also inhibit ribonucleotide reductase (but not to the degree of ATP & dATP)  only T-lymphocyte function is affected (i.e. symptoms not so severe)

29. Disorders due to salvage pathway A salvage pathway is a pathway in which nucleotides (Purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides. There are two critical enzyme defficiencies; • Hypoxanthine guanigephosphorybosyltransferase (HPRT) defficiency • May be total (Lesch-Nyhan syndrome ) or partaldefficiency Partial HPRT-deficient patients present with symptoms similar to total but with a reduced intensity, and in the least severe forms symptoms may be unapparent. • Adenine phosphorybosyltransferase (APRT) defficiency • The disorder results in accumulation of the insoluble Purine 2,8-dihydroxyadenine. • It can result in nephrolithiasis (kidney stones), acute renal failure and permanent kidney damage.

30. Lesch-Nyhan Syndrome • Lesch-Nyhan syndrome is a metabolic disorder caused by a deficiency of an enzyme (HPRT) produced by mutations in a gene located on the X chromosome. • The disease is marked by a buildup of uric acid in all body fluids that results in conditions known as hyperuricemia and hyperuricosuria. • Symptoms often include severe gout, impaired muscular control, moderate mental retardation and kidney problems. • These complications frequently emerge in the first year of life. Neurological symptoms can include facial grimacing, involuntary writhing and repetitive movements. • The mental deficits and behavior do not react well to therapy. There is no known cure, but many patients can survive to adulthood.