Gout,a cuduria les
-
Upload
dr-geoffrey-maiyoh -
Category
Documents
-
view
195 -
download
2
Transcript of Gout,a cuduria les
Metabolic disorders
Dr. G. K. MaiyohDepartment of Medical Biochemistry,
School of Medicine, MU
April 13, 2023 1GKM/MUSOM/MSP302:MET.DIS.2012.2013
Lecturer:
TOPICS;
•Glycogen storage disorders•Gout and Orotic aciduria•Lesh-nyhan syndrome
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
April 13, 2023 2GKM/MUSOM/MSP302:MET.DIS.2012.2013
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
April 13, 2023 3GKM/MUSOM/MSP302:MET.DIS.2012.2013
April 13, 2023 4GKM/MUSOM/MSP302:MET.DIS.2012.2013
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 5
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 6
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 7
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 8
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 9
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 10
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 11
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 12
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.
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 13
GSD SUMMARYName Enzyme Symptoms
Type O Glycogen synthetase Enlarged, fatty liver; hypoglycemia when fasting von Gierke (Type IA)
Glucose-6-phosphatase Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia
Type IB G-6-P translocase Same as in von Gierke's disease but may be less severe; neutropenia Pompe
(Type II) Acid maltase Enlarged liver and heart, muscle weakness
Forbe (Cori) (Type III)
Glycogen debrancher Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people
Andersen (Type IV)
Glycogen branching enzyme Cirrhosis in juvenile type; muscle damage and CHF
McArdle's (Type V)
Muscle glycogen phosphorylase
Muscle cramps or weakness during physical activity
Her (Type VI)
Liver glycogen phosphorlyase Enlarged liver; often no symptoms
Tarui (Type VII)
Muscle phosphofructokinase Muscle cramps during physical activity; hemolysis
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
April 13, 2023 14GKM/MUSOM/MSP302:MET.DIS.2012.2013
Hyperuricemia GoutOrotic aciduriaLesh-nayhan syndrome
April 13, 2023 15GKM/MUSOM/MSP302:MET.DIS.2012.2013
PURINES and PYRIMIDINES
• Purines are heterocyclic compound consisting of a pyrimidine ring fused to an imidazole Ring
April 13, 2023 16GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
Salvage Pathwayde novo PathwayApril 13, 2023 17GKM/MUSOM/
MSP302:MET.DIS.2012.2013
Many Steps Require an Activated Ribose Sugar (PRPP)
5’
April 13, 2023 18GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
XApril 13, 2023 19GKM/MUSOM/
MSP302:MET.DIS.2012.2013
Raw materials for biosynthesis
• Pyrimidine rings are synthesized independent of the ribose and transferred to the PRPP (ribose)
• Generated as UMP (uridine 5’-monophosphate)
• Synthesized from:– Glutamine
– CO2
– Aspartic acid
– Requires ATP
April 13, 2023 20GKM/MUSOM/MSP302:MET.DIS.2012.2013
How is Pyrimidine Biosynthesis regulated?
• Regulation occurs at first step in the pathway (committed step)
• 2ATP + CO2 + Glutamine = carbamoyl phosphate
Inhibited by UTPIf you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as;
X
April 13, 2023 21GKM/MUSOM/MSP302:MET.DIS.2012.2013
Biosynthesis: Purine vs Pyrimidine
• Synthesized on PRPP
• Regulated by GTP/ATP• Generates IMP• Requires Energy
• Synthesized then added to PRPP
• Regulated by UTP• Generates UMP/CMP• Requires Energy
April 13, 2023 22GKM/MUSOM/MSP302:MET.DIS.2012.2013
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.
Nucleoside + H2O base + ribose
Nucleoside + Pi base + ribose-1-P
Nucleoside phosphorylase
nucleosidase
April 13, 2023 23GKM/MUSOM/MSP302:MET.DIS.2012.2013
Major pathways of purine catabolism in animals.
ADA
April 13, 2023 24GKM/MUSOM/MSP302:MET.DIS.2012.2013
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).
April 13, 2023 25GKM/MUSOM/MSP302:MET.DIS.2012.2013
•Purine nucleotide degradation refers to a regulated series of reactions by which purine ribonucleotides and deoxyribonucleotides are 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.
April 13, 2023 26GKM/MUSOM/MSP302:MET.DIS.2012.2013
Disorders of purines Catabolism
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
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 27
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
April 13, 2023 28GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
April 13, 2023 29GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
April 13, 2023 30GKM/MUSOM/MSP302:MET.DIS.2012.2013
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
April 13, 2023 31GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
April 13, 2023 32GKM/MUSOM/MSP302:MET.DIS.2012.2013
Other causes may include:
• Eclampsia• Lead toxicity• Chronic alcohol ingestion
• NOTE Hypouricaemia is not an important chemical disorder in itself
April 13, 2023 33GKM/MUSOM/MSP302:MET.DIS.2012.2013
Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.
Management of disorders
April 13, 2023 34GKM/MUSOM/MSP302:MET.DIS.2012.2013
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.
April 13, 2023 35GKM/MUSOM/MSP302:MET.DIS.2012.2013
Disorders due to salvage pathway
There are two critical enzyme defficiencies;I. Hypoxanthine guanige phosphorybosyltransferase (HPRT)
defficiency– May be total (Lesch-Nyhan syndrome )
or partal defficiencyPartial HPRT-deficient patients present with symptoms similar to total but with a reduced intensity, and in the least severe forms symptoms may be unapparent.
II. 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.April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 36
A salvage pathway is a pathway in which nucleotides (Purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides.
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.
April 13, 2023 37GKM/MUSOM/MSP302:MET.DIS.2012.2013
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
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 38
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
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 39
Figure 28-29 The Gout, a cartoon by James Gilroy (1799).
Pag
e 10
97
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.
April 13, 2023 40GKM/MUSOM/MSP302:MET.DIS.2012.2013
Types of Gout
• Primary Gout– Occurrence: Middle aged men (mostly)– Cause: Overproduction of Uric Acid
Decreased renal excretionor both
Biochemical Etiology: Not clearly known and is considered a polygenic disease
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 41
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
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 42
Other conditions that could lead to gout• Any other condition that may lead to
either;– Decreased uric acid clearance or – Increase in production
These may include;• Malignancy therapy• Dehydration• Lactic acidosis• Ketoacidosis• Stavation• Diuretic therapy• Renal failure
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 43
Also;•Excessive purine intake•Alcohol intake•Carbohydrate ingestion
Hereditary disorders associated with gout• These include 3 key enzymes resulting in
hyperuricemia• These are;
1. Severe HPRT defficiency (Lesch-Nyhan syndrome)• Also Partial HPRT defficiency
2. Superactivity of PP-ribose-p synthetase3. Glucose -6-phosphatase defficiency (glycogen
storage disease type 1)
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 44
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
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 45
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 infancyCharacteristics– Hyperuricemia– Gout– Familial renal disease– Low urate clearance relative to GFR
April 13, 2023 GKM/MUSOM/MSP302:MET.DIS.2012.2013 46
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 Biosynthesis regulated?
• Regulation occurs at first step in the pathway (committed step)
• 2ATP + CO2 + Glutamine = carbamoyl phosphate
Inhibited by UTPIf you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as;
X
How does UMP Cure Orotic Aciduria?
CarbamoylPhosphate Orotate
UMPSynthetase
X
FeedbackInhibition• Disease (-UMP)
– 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).
Pag
e 10
98
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 phosphoribosyltransferase
Degradation pathways are quite distinct for purines and
pyrimidines, but salvage pathways are quite similar
•Also known as Nyhan's 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)
April 13, 2023 53GKM/MUSOM/MSP302:MET.DIS.2012.2013
Overproduction of uric acid
• Urate crystal formations, which look like orange sand, are deposited in diapers of the babies
• Kidney stones• Blood in the urine• Dysphagia (difficulty
swallowing)• Swelling of the joints• Vomiting
Behavioral Abnormalities
• Impaired cognitive functon
• Self-mutilation• Aggression/Impulsion
April 13, 2023 54GKM/MUSOM/MSP302:MET.DIS.2012.2013
April 13, 2023 55GKM/MUSOM/MSP302:MET.DIS.2012.2013
Pathogenesis Overproduction of
Uric Acid- associated with hyperuricernia- can produce Nephrolithiasis (kidney stones) with renal failure and solid subcutaneous deposits (tophi)
Behavioral Elements- cognative disfunction and aggressive and impulsive behaviors-severe self injurious behavior is common
Neurological disability- includes dystonia (abnormal firmness of tissue or muscle), choreoathetosis (abnormal movement of body), and occasional ballismus (jerky movement of arms or legs)- other signs include spasticity and hyperreflexia
April 13, 2023 56GKM/MUSOM/MSP302:MET.DIS.2012.2013
This condition is inherited in an X-linked recessive patternThis condition is inherited in an X-linked recessive patternApril 13, 2023 57GKM/MUSOM/
MSP302:MET.DIS.2012.2013
April 13, 2023 58GKM/MUSOM/MSP302:MET.DIS.2012.2013
Gout causes sudden, yet severe attacks of pain, redness, and tenderness and inflammation of the joints
PODAGRA
April 13, 2023 59GKM/MUSOM/MSP302:MET.DIS.2012.2013
Behavioral Abnormalities
self-mutilation of the lips by biting
April 13, 2023 60GKM/MUSOM/MSP302:MET.DIS.2012.2013
Behavioral Abnormalities
self-mutilation of the fingers by bitingApril 13, 2023 61GKM/MUSOM/
MSP302:MET.DIS.2012.2013
Overproduction and accumulation of uric acid
April 13, 2023 62GKM/MUSOM/MSP302:MET.DIS.2012.2013
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)
April 13, 2023 63GKM/MUSOM/MSP302:MET.DIS.2012.2013
-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)April 13, 2023 64GKM/MUSOM/
MSP302:MET.DIS.2012.2013
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.
April 13, 2023 65GKM/MUSOM/MSP302:MET.DIS.2012.2013