Gout,a cuduria les
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Gout,a cuduria les Gout,a cuduria les Presentation Transcript

  • Metabolic disorders TOPICS; •Glycogen storage disorders •Gout and Orotic aciduria •Lesh-nyhan syndrome Lecturer: Dr. G. K. Maiyoh Department of Medical Biochemistry, School of Medicine, MU GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 1 3
  • Carbohydrate Disorders • Enzyme defects in metabolism of glycogen, galactose, and fructose • Present in infancy, result in; – Hypoglycemia with ketosis – Encephalopathy – Lethargy or coma – Enlarged liver – Mental Retardation GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 2 3
  • Glycogen Storage Diseases • Collection of enzyme deficits of glycogen production or break-down • Most result in hepatomegaly and hypoglycemia (some seizures), and muscle weakness • Prognosis varies widely GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 3 3
  • GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 4 3
  • Glycogen storage disease type I• Glycogen storage disease (GSD) type I is also known as von Gierke disease or hepatorenal glycogenosis.• Von Gierke described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica.• In 1952, Cori and Cori demonstrated that glucose-6- phosphatase (G6Pase) deficiency was a cause of GSD type I.• In 1978, Narisawa et al proposed that a transport defect of glucose-6-phosphate (G6P) into the microsomal compartment may be present in some patients with GSD type I. GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 5 3
  • Classes• Thus, GSD type I is divided into GSD type Ia caused by G6Pase deficiency and GSD type Ib resulting from deficiency of a specific translocase T1.• Apart from the substrate translocation defect, patients with GSD type Ib have altered neutrophil functions predisposing them to gram-positive bacterial infections. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 6 3
  • Glycogen storage disease type II • GSD type II, also known as acid maltase deficiency or Pompe disease, is a lysosomal disease. • Its clinical presentation clearly differs from other forms of GSD. Deficiency of a lysosomal enzyme, alpha-1,4-glucosidase, causes GSD type II. • Pompe initially described the disease in 1932. • An essential pathologic finding is the accumulation of normally structured glycogen in most tissues. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 7 3
  • Classes • Three forms of the disease exist: infantile, juvenile, and adult. In the classic infantile form, the main clinical signs are cardiomyopathy and muscular hypotonia. • In the juvenile and adult forms, the involvement of skeletal muscles dominates the clinical presentation. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 8 3
  • Glycogen storage disease type III • GSD type III is also known as Forbes-Cori disease or limit dextrinosis. • In contrast to GSD type I, liver and skeletal muscles are involved . • Glycogen deposited in these organs has an abnormal structure. • Differentiating patients with GSD type III from those with GSD type I solely on the basis of physical findings is not easy. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 9 3
  • Glycogen storage disease type IV• GSD type IV, also known as amylopectinosis or Andersen disease, is a rare disease that leads to early death.• In 1956, Andersen reported the first patient with progressive hepatosplenomegaly and accumulation of abnormal polysaccharides.• The main clinical features are liver insufficiency and abnormalities of the heart and nervous system. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 10 3
  • Glycogen storage disease type V• GSD type V, also known as McArdle disease, affects the skeletal muscles.• McArdle reported the first patient in 1951.• Initial signs of the disease usually develop in adolescents or adults.• Due to muscle phosphorylase deficiency which adversely affects the glycolytic pathway in skeletal musculature. GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 11 3
  • Glycogen storage disease type VI • GSD type VI, also known as Hers disease, belongs to the group of hepatic glycogenoses and represents a heterogenous disease. Hepatic phosphorylase deficiency or deficiency of other enzymes that form a cascade necessary for liver phosphorylase activation cause the disease. • In 1959, Hers described the first patients with proven phosphorylase deficiency. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 12 3
  • Glycogen storage disease type VII• GSD type VII, also known as Tarui disease, arises as a result of phosphofructokinase (PFK) deficiency.• The enzyme is located in skeletal muscles and erythrocytes.• Tarui reported the first patients in 1965.• The clinical and laboratory features are similar to those of GSD type V. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 13 3
  • GSD SUMMARY Name Enzyme Symptoms Type O Glycogen synthetase Enlarged, fatty liver; hypoglycemia when fasting von Gierke Glucose-6-phosphatase Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia (Type IA) Type IB G-6-P translocase Same as in von Gierkes disease but may be less severe; neutropenia Pompe Acid maltase Enlarged liver and heart, muscle weakness (Type II)Forbe (Cori) Glycogen debrancher Enlarged liver or cirrhosis; low blood sugar levels; muscle damage (Type III) and heart damage in some people Andersen Glycogen branching enzyme Cirrhosis in juvenile type; muscle damage and CHF (Type IV) McArdles Muscle glycogen Muscle cramps or weakness during physical activity (Type V) phosphorylase Her Liver glycogen phosphorlyase Enlarged liver; often no symptoms (Type VI) Tarui Muscle phosphofructokinase Muscle cramps during physical activity; hemolysis (Type VII) Type VIII Unknown Hepatomegaly; ataxia, nystagmus Type IX Liver phosphorylase kinase Hepatomegaly; Often no symptoms Type X Cyclic 3-5 dependent kinase Hepatomegaly, muscle pain (1 patient) Type XI Unknown Hepatomegaly. Stunted growth, acidosis, Rickets GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 14 3
  • HyperuricemiaGoutOrotic aciduriaLesh-nayhan syndrome GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 15 3
  • PURINES and PYRIMIDINES• Purines are heterocyclic compound consisting of a pyrimidine ring fused to an imidazole Ring GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 16 3
  • Synthesis Pathways • For both purines and pyrimidines there are two means of synthesis (often regulate one another) – de novo (from bits and parts) – salvage (recycle from pre-existing nucleotides) de novo Pathway Salvage Pathway GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 17 3
  • Many Steps Require an Activated Ribose Sugar (PRPP) 5’ GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 18 3
  • de novo Synthesis • Committed step: This is the point of no return – Occurs early in the biosynthetic pathway – Often regulated by final product (feedback inhibition) X GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 19 3
  • Raw materials for biosynthesis • Synthesized from: – Glutamine – CO2 – Aspartic acid – Requires ATP • Pyrimidine rings are synthesized independent of the ribose and transferred to the PRPP (ribose) • Generated as UMP (uridine 5’-monophosphate) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 20 3
  • How is Pyrimidine Biosynthesis regulated? • Regulation occurs at first step in the pathway (committed step) • 2ATP + CO2 + Glutamine = carbamoyl phosphate X Inhibited by UTP If you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as; GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 21 3
  • Biosynthesis: Purine vs Pyrimidine• Synthesized on PRPP • Synthesized then added to PRPP• Regulated by GTP/ATP • Regulated by UTP• Generates IMP • Generates UMP/CMP• Requires Energy • Requires Energy GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 22 3
  • Nucleotide degradation• Nucleic acids can survive the acid of the stomach• They are degraded into nucleotides by pancreatic nucleases and intestinal phosphodiesterases in the duodenum.• Components cannot pass through cell membranes, so they are further hydrolyzed to nucleosides.• Nucleosides may be directly absorbed by the intestine or undergo further degradation to free bases and ribose or ribose-1-phosphate by nucleosidases and nucloside phosphorylase. nucleosidase Nucleoside + H2O Nucleoside base + ribose phosphorylase Nucleoside + PGKM/MUSOM/MSP302:MET.DIS.2012.201 base + ribose-1-P 23March 21, 2013 i 3
  • ADAMajor pathways of purine catabolism in animals. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 24 3
  • Catabolism of pyrimidines • Animal cells degrade pyrimidines to their component bases. • Happen through dephosphorylation, deamination, and glycosidic bond cleavage. • Uracil and thymine broken down by reduction (vs. oxidation in purine catabolism). GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 25 3
  • Disorders of purines Catabolism•Purine nucleotide degradation refers to a regulated series ofreactions by which purine ribonucleotides and deoxyribonucleotidesare degraded to uric acid in humans.•Two major types of disorders occur in this pathway; • A block of degradation occurs with syndromes involving;- • immune deficiency. •myopathy or •renal calculi. •Increased degradation of nucleotides occurs with syndromes characterized by;- • hyperuricemia and gout, •renal calculi, •anemia or acute hypoxia. GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 26 3
  • 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 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 27 3
  • 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.g probenecid or sulfinpyrazone),which block tubular urate reabsorption GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 28 3
  • 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) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 29 3
  • HYPERURICAEMIA• This is increase in blood levels of uric acid that is greater than 0.42 mmol/l in men and more than 0.36mmol/l in women• It can occur by two mechanisms:• 1 Increased production(Over Production)• 2 Decreased Excretion (under excretors) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 30 3
  • Factors contributing to Hyperuraecimia• Increased synthesis of purines (primary Gout)• Secondary GOUT (Other disorder in which there is rapid tissue break down or rapid cellular turnover)• Increase intake of purines• Increase turnover of Nucleic Acids• Increased rate of urate formation• Reduced rate of Excretion GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 31 3
  • Factors contributing to Hyperuraecimia• Sex(plasma uric acid is higher in male than females)• Obesity (Obese people tends to have high plasma level of urate)• Diet (subject with high protein diet ,which is also rich in NUCLIEC acids and who do have high alcohol consumption have high levels of plasma urate• Genetic factor(These are very important factor in high plasma urate levels) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 32 3
  • Other causes may include:• Eclampsia• Lead toxicity• Chronic alcohol ingestion• NOTE Hypouricaemia is not an important chemical disorder in itself GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 33 3
  • Management of disorders Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 34 3
  • 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. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 35 3
  • 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;I. Hypoxanthine guanige phosphorybosyltransferase (HPRT) defficiency – May be total (Lesch-Nyhan syndrome ) or partal defficiency 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.I. 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 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013and permanent kidney damage. 36 3
  • 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 March 21, 2013 grimacing, involuntary writhing and repetitive facial GKM/MUSOM/MSP302:MET.DIS.2012.201 37 3
  • 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 GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 38 3
  • Gout• Commonly monoarticular (Affecting the metatarsophalangeal joint of the big toe.• However deposits of sodium urates may also occur in; – The elbows – Knees – Feet – Helix of the ear GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 39 3
  • Figure 28-29 The Gout, a cartoon by James Gilroy (1799).Page 1097 Gout is a disease characterized by elevated levels of uric acid in body fluids. Caused by deposition of nearly insoluble crystals of sodium urate or uric acid. GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 40 3
  • 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 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 41 3
  • 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 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 42 3
  • Other conditions that could lead togout• Any other condition that may lead to either; – Decreased uric acid clearance or – Increase in production These may include; Also; • Malignancy therapy •Excessive purine intake • Dehydration •Alcohol intake • Lactic acidosis •Carbohydrate ingestion • Ketoacidosis • Stavation • Diuretic therapy • Renal failure GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 43 3
  • Hereditary disorders associatedwith gout• These include 3 key enzymes resulting in hyperuricemia• These are; 1. Severe HPRT defficiency (Lesch-Nyhan syndrome) • Also Partial HPRT defficiency 1. Superactivity of PP-ribose-p synthetase 2. Glucose -6-phosphatase defficiency (glycogen storage disease type 1) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 44 3
  • Hereditary disorders associatedwith 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 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 45 3
  • Familial Juvenile Gout (Familial Juvenile Hyperuricemic Nephropathy (FJHN)• Due to severe renal hypoexcretion of uric acid• Presentation usually occurs at puberty to the 3rd decade – Has also been reported in infancy Characteristics – Hyperuricemia – Gout – Familial renal disease – Low urate clearance relative to GFR GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 46 3
  • Hereditary Orotic Aciduria• Is a defect in de novo synthesis of pyrimidines• Loss of functional UMP synthetase – Gene located on chromosome III• Characterized by excretion of orotic acid• Results in severe anemia and growth retardation• Extremely rare (15 cases worldwide)• Treated by feeding UMP
  • How is Pyrimidine Biosynthesisregulated? • Regulation occurs at first step in the pathway (committed step) • 2ATP + CO2 + Glutamine = carbamoyl phosphate X Inhibited by UTP If you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as;
  • How does UMP Cure Orotic Aciduria? Carbamoyl Phosphate Orotate XUMP Synthetase Feedback• Disease (-UMP) Inhibition – No UMP/excess orotate• Disease (+UMP) – Restore depleted UMP – Downregulate pathway via feedback inhibition (Less orotate)
  • Catabolism of pyrimidines• Animal cells degrade pyrimidines to their component bases.• Happen through dephosphorylation, deamination, and glycosidic bond cleavage.• Uracil and thymine broken down by reduction (vs. oxidation in purine catabolism).
  • Page 1098
  • Pyrimidine Degradation/Salvage• Pyrimindine rings can be fully degraded to soluble structures (Compare to purines that make uric acid)• Can also be salvaged by reactions with PRPP – Catalyzed by Pyrimidine phosphoribosyltransferaseDegradation pathways are quite distinct for purines and pyrimidines, but salvage pathways are quite similar
  • •Also known as Nyhans syndrome, Kelley- Seegmiller syndrome and Juvenile gout•It is a hereditary disorder of purine metabolism, characterized by mental retardation, self-mutilation of the fingers and lips by biting, impaired renal function, and abnormal physical development.• It is a recessive disease that is linked to the X chromosome• It is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 53 3
  • Overproduction of uric acid Behavioral• Urate crystal Abnormalities formations, which look • Impaired cognitive like orange sand, are functon deposited in diapers of • Self-mutilation the babies• Kidney stones • Aggression/Impulsion• Blood in the urine• Dysphagia (difficulty swallowing)• Swelling of the joints• Vomiting GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 54 3
  • GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 55 3
  • Pathogenesis Neurological disability Overproduction of - includes dystonia Uric Acid (abnormal firmness - associated with hyperuricernia of tissue or muscle), - can produce choreoathetosis Nephrolithiasis (kidney (abnormal stones) with renal failure movement of body), and solid subcutaneous and occasional deposits (tophi) ballismus (jerky movement of arms Behavioral Elements or legs) - cognative disfunction and aggressive and - other signs include impulsive behaviors spasticity and -severe self injurious hyperreflexia behavior is commonMarch 21, 2013 GKM/MUSOM/MSP302:MET.DIS.2012.201 56 3
  • This condition is inherited in an X-linked recessive pattern57 GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 3
  • GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 58 3
  • PODAGRA Gout causes sudden, yet severe attacks of pain, redness, and tenderness and inflammation of the joints GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 59 3
  • Behavioral AbnormalitiesMarch 21, 2013 self-mutilation of the lips by biting GKM/MUSOM/MSP302:MET.DIS.2012.201 3 60
  • Behavioral AbnormalitiesMarch 21, 2013 self-mutilation of the fingers by biting GKM/MUSOM/MSP302:MET.DIS.2012.201 61 3
  • Overproduction and accumulation of uric acid GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 62 3
  • Exams and Tests There may be a family history of this condition. The doctor will perform a physical exam. The exam may show:  Overexaggerated reflexes  Spacity  Blood and urine tests may reveal high uric acid levels. A skin biopsy may show decreased levels of the HGP enzyme.  Prenatal diagnosis is possible by DNA testing of fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS) GKM/MUSOM/MSP302:MET.DIS.2012.201 March 21, 2013 63 3
  • -LNS itself cannot be treated -Only the symptoms of LNS can be treated. -The drug allopurinol may be used to control excessive amounts of uric acid. -Kidney stones can be treated with lithotripsy -To help reduce some of the problem behaviors and neurological effects of LNS : Diazepam (Diastat, Valium) Haloperidol (Haldol) Phenobarbital (Luminal) GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 64 3
  • Prognosis: -The prognosis for LNS is poor because there are no treatments for the neurological effects of the syndrome. -Persons with this syndrome usually require assistance walking and sitting and generally need a wheelchair to get around. -The build-up of excessive uric acid in the body causes painful episodes of self-mutilation and may result in severe retardation and death. GKM/MUSOM/MSP302:MET.DIS.2012.201March 21, 2013 65 3