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


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



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.


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.


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.


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.


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.


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.


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.


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.


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


Hyperuricemia GoutOrotic aciduriaLesh-nayhan syndrome


PURINES and PYRIMIDINES

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


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/

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Many Steps Require an Activated Ribose Sugar (PRPP)

5’


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)

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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


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


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


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


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).


•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.


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


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


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 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)


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


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)


Other causes may include:

• Eclampsia• 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 is an analogue of hypoxanthine that strongly inhibits xanthine oxidase. Xanthine and hypoxanthine, which are soluble, are accumulated and excreted.


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.


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).

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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 excretionor 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 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)


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


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


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).

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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 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)


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



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 patternApril 13, 2023 57GKM/MUSOM/

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

PODAGRA



self-mutilation of the lips by biting



self-mutilation of the fingers by bitingApril 13, 2023 61GKM/MUSOM/

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Overproduction and accumulation of uric acid


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)


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 -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/

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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.


Gout,a cuduria les

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