msp 304. gsd,gout,a cuduria and lesh.2014
DESCRIPTION
Lecture presentation - Disorders of NA metabolismTRANSCRIPT
MSP 304: Digestive system, Nutrition & Metabolic disorders
Dr. G. K. MaiyohDepartment of Medical Biochemistry,
School of Medicine, MU
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Lecturer:
TOPICS;1) Gout2) Orotic aciduria3) Lesh-nyhan syndrome
What is a metabolic disease?
• “Inborn errors of metabolism”• inborn error : an inherited (i.e. genetic)
disorder• Metabolism : chemical or physical changes
undergone by substances in a biological system
• “any disease originating in our chemical individuality”
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What is a metabolic disease?
• Garrod’s hypothesis
product deficiencysubstrate excess
toxic metabolite
A
D
B C
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General mechanism of problemsI. Substrate accumulates to toxic levelsII. Toxic byproducts produced from shunting
of accumulated substrateIII. Deficiency of end productIV. Poor regulation results in overproduction
of intermediates to toxic level
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Effects• Clinical effects range from none (polymorphims) to
lethal• Diagnosis
– Neonatal screening– Non-specific signs: vomiting, failure to thrive, seizures, lab
abnormalities• Treatment (not many!)
– Avoid precursors– Get rid of accumulating metabolites– Prevent shunting– ?Genetic engineering (under investigation)
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Categories of metabolic diseases• Small molecule
disease– Carbohydrate– Protein– Lipid– Nucleic Acids
• Purines• Pyrimidines
• Organelle disease
– Lysosomes– Mitochondria– Peroxisomes– Cytoplasm
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- Gout- Orotic aciduria- Lesh-nayhan syndrome
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Disorders of purine and pyrimidine metabolism
PURINES and PYRIMIDINES• Purines are heterocyclic
compound consisting of a pyrimidine ring fused to an imidazole Ring
• Adenine and Guanine are the major purine bases
• While the major pyrimidine bases are:1. Cytosine2. Thymine3. Uracil
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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 Pathway9GKM/MUSOM/MSP304:NUT.MET.DIS.2014
Raw materials for de novo biosynthesis
• Synthesized from:– Glutamine
– CO2
– Aspartic acid– Requires ATP
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de novo Synthesis and regulation• Committed step: This is the point of no
return– Occurs early in the biosynthetic pathway– Often regulated by final product (feedback
inhibition)
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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
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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
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Major pathways of purine catabolism in animals.
ADA
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•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;
•Either blockage or Increased degradation
1. A block of degradation occurs with syndromes involving;-
• Immune deficiency. • Myopathy or • Renal calculi.
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Disorders of purines degradation
2. Increased degradation of nucleotides occurs with syndromes characterized by;-
– Hyperuricemia and gout, –Renal calculi, –Anemia or acute hypoxia.
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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
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Male: 4.0 - 8.5 mg/dL. Female: 2.5 - 7.5 mg/dL
Normal values
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
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The Nephron
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• Functional unit of the kidney;
– Filtration – Tubular
reabsorption – Tubular secretion
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)
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HYPERURICAEMIA• This is increase in blood levels of uric acid
that is greater than 8.5 mg/dl in men and more than 7.5 mg/dl in women
• It can occur by two mechanisms:
1) Increased production (Over Production) 2 ) Decreased Excretion (Under excretion)
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Factors contributing to Hyperuraecimia• Increased synthesis of purines - Primary GOUT • Other disorder in which there is rapid tissue break
down or rapid cellular turnover - Secondary GOUT
• They are due to;– Increase intake of purines– Increase turnover of Nucleic Acids– Increased rate of urate formation– Reduced rate of Excretion
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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) (through xanthine oxidoreductase (XOR) ??
• 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 factors (These are very important factor in high plasma urate levels)
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Other causes may include:
• Eclampsia - is an acute and life-threatening complication of pregnancy
• Lead toxicity• Chronic alcohol ingestion
• NOTE: Hypouricaemia is not an important chemical disorder in itself
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Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.
Management of disorders
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Common treatment for gout: Allopurinol
• Allopurinol ( and its active metabolite, oxypurinol) is an analogue of hypoxanthine that strongly inhibits xanthine oxidase. • Xanthine and hypoxanthine, which are soluble, are accumulated and excreted. 26GKM/MUSOM/MSP304:NUT.MET.DIS.2014
Major pathways of purine catabolism in animals.
ADA
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Disorders due to salvage pathway
There are two critical enzyme deficiencies;I. Hypoxanthine guanine 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.
To be discussed further - Lesch-Nyhan syndrome GKM/MUSOM/MSP304:NUT.MET.DIS.2014 28
A salvage pathway is a pathway in which nucleotides (Purine and pyrimidine) are synthesized from intermediates in the degradative their pathway
Disorders of the salvage pathway - CNT
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.
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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
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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
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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.
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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
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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
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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
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Also;•Excessive purine intake•Alcohol intake•Carbohydrate ingestion
Hereditary Orotic Aciduria• Is a defect in de novo synthesis of pyrimidines• Due to 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
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Pattern of inheritance of orotic aciduria
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Two copies of an abnormal gene must be present in order for the disease or trait to develop.
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
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How does UMP Cure Orotic Aciduria?
UMPSynthetase
XCarbamoylPhosphate Orotate
FeedbackInhibition
• Disease (-UMP)– No UMP/excess orotate
• Disease (+UMP)– Restore depleted UMP– Downregulate pathway via feedback inhibition (Less orotate)
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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).
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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 Phosphoribosyl-1-pyrophosphate (PRPP)– Catalyzed by Pyrimidine
phosphoribosyltransferaseDegradation pathways are quite distinct for
purines and pyrimidines, but salvage pathways are quite
similar44GKM/MUSOM/MSP304:NUT.MET.DIS.2014
•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)
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Lesch-Nyhan syndrome
Total Aside on X-linked Diseases• Why are X-linked diseases
generally found only in males?
• Females have two X chromosomes - would need to mutate both copies to see a recessive phenotype
• Males have a single X chromosome
XY XX
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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
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Signs and symptoms
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
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This condition is inherited in an X-linked recessive patternThis condition is inherited in an X-linked recessive pattern49GKM/MUSOM/MSP304:NUT.MET.DIS.2014
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Gout causes sudden, yet severe attacks of pain, redness, and tenderness and inflammation of the joints
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Behavioral Abnormalities
self-mutilation of the lips by biting 52GKM/MUSOM/MSP304:NUT.MET.DIS.2014
Behavioral Abnormalities
self-mutilation of the fingers by biting53GKM/MUSOM/MSP304:NUT.MET.DIS.2014
Overproduction and accumulation of uric acid
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Diagnostic Exams and Tests There may be a family history of this condition. The doctor will perform a physical exam. The exam
may show: Over exaggerated reflexes Spacity Blood and urine tests may reveal high uric acid levels. A
skin biopsy may show decreased levels of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme.
Prenatal diagnosis is possible by DNA testing of fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS)
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-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 (procedure that uses shock waves to break up stones in the kidney)
-To help reduce some of the problems with behaviors and neurological effects of LNS :
Diazepam (Diastat, Valium) Haloperidol (Haldol)
Phenobarbital (Luminal)56GKM/MUSOM/MSP304:NUT.MET.DIS.2014
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.
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