msp 304. gsd,gout,a cuduria and lesh.2014

MSP 304: Digestive system, Nutrition & Metabolic disorders

Dr. G. K. MaiyohDepartment of Medical Biochemistry,

School of Medicine, MU

1GKM/MUSOM/MSP304:NUT.MET.DIS.2014

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”

04/12/23 2GKM/CLINCHEM/MMED.SURG/2013

What is a metabolic disease?

• Garrod’s hypothesis

product deficiencysubstrate excess

toxic metabolite

A

D

B C


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


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)


Categories of metabolic diseases• Small molecule

disease– Carbohydrate– Protein– Lipid– Nucleic Acids

• Purines• Pyrimidines

• Organelle disease

– Lysosomes– Mitochondria– Peroxisomes– Cytoplasm


- Gout- Orotic aciduria- Lesh-nayhan syndrome


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


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


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)

X11GKM/MUSOM/MSP304:NUT.MET.DIS.2014

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


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


Major pathways of purine catabolism in animals.

ADA


•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.


Disorders of purines degradation

2. Increased degradation of nucleotides occurs with syndromes characterized by;-

– Hyperuricemia and gout, –Renal calculi, –Anemia or acute hypoxia.

GKM/MUSOM/MSP304:NUT.MET.DIS.2014 16

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


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


The Nephron

19April 12, 2023 GKM/M.MEDSURG/LECT 01/2014

• 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)


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)


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


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)


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


Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.

Management of disorders


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


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.


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


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


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.


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


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


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


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


Pattern of inheritance of orotic aciduria


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


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)


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).


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)


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


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


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


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

Gout causes sudden, yet severe attacks of pain, redness, and tenderness and inflammation of the joints



self-mutilation of the lips by biting 52GKM/MUSOM/MSP304:NUT.MET.DIS.2014


self-mutilation of the fingers by biting53GKM/MUSOM/MSP304:NUT.MET.DIS.2014

Overproduction and accumulation of uric acid


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)


http://health.nytimes.com/health/guides/test/skin-lesion-biopsy/overview.html

-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.


msp 304. gsd,gout,a cuduria and lesh.2014

Health & Medicine

hyperuricemia uric acid

purine nucleotide degradation

block of degradation

major purine bases

pyrimidines purines

pyrimidine metabolism

major pyrimidine bases

purine ribonucleotides