Gout,a cuduria les

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.2012.201
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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

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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

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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
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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.

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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.
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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.

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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.
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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.

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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.

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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.
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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.
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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 Gierke's 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)
McArdle's 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

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Hyperuricemia
Gout
Orotic aciduria
Lesh-nayhan syndrome

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PURINES and PYRIMIDINES

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

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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)

de novo Pathway Salvage Pathway
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Many Steps Require an Activated
Ribose Sugar (PRPP)

5’

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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
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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)

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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;

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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

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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.
nucleosidase

Nucleoside + H2O Nucleoside
base + ribose
phosphorylase

Nucleoside + PGKM/MUSOM/MSP302:MET.DIS.2012.201 base + ribose-1-P 23
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ADA

Major pathways of purine
catabolism in animals.

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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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Disorders of purines 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.
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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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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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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 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)

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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

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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)
• 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)

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Other causes may include:
• Eclampsia
• Lead toxicity
• Chronic alcohol ingestion

• NOTE Hypouricaemia is not an important
chemical disorder in itself

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

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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.

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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
March 21, 2013and permanent kidney damage. 36
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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
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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).
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.
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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;
Also;
• Malignancy therapy •Excessive purine intake
• Dehydration •Alcohol intake
• Lactic acidosis •Carbohydrate ingestion
• Ketoacidosis
• Stavation
• Diuretic therapy
• Renal failure
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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
1. Superactivity of PP-ribose-p synthetase
2. Glucose -6-phosphatase defficiency (glycogen
storage disease type 1)
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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

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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
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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
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).

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)
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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

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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 common
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This condition is inherited in an X-linked recessive pattern57
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PODAGRA

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

March 21, 2013 self-mutilation of the lips by biting
3
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Behavioral Abnormalities

March 21, 2013
self-mutilation of the fingers by biting
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Overproduction and accumulation of uric acid
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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)

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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
-To help reduce some of the problem behaviors and
neurological effects of LNS :
Diazepam (Diastat, Valium)
Haloperidol (Haldol)
Phenobarbital (Luminal)
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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.

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