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

MSP 304: Digestive system, Nutrition
& Metabolic disorders
Dr. G. K. Maiyoh
Department of Medical Biochemistry,
School of Medicine, MU
1GKM/MUSOM/MSP304:NUT.MET.DIS.2014
Lecturer:
TOPICS;
1) Gout
2) Orotic aciduria
3) 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”
08/03/14 2GKM/CLINCHEM/MMED.SURG/2013

What is a metabolic disease?
• Garrod’s hypothesis
product deficiency
substrate excess
toxic metabolite
A
D
B C

General mechanism of problems
I. Substrate accumulates to toxic levels
II. Toxic byproducts produced from shunting
of accumulated substrate
III. Deficiency of end product
IV. 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. Cytosine
2. Thymine
3. 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 Pathway

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)
X

How is Pyrimidine Biosynthesis regulated?
• Regulation occurs at first step in the pathway
(committed step)
• 2ATP + CO2 + Glutamine = carbamoyl phosphate
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;
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
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
19August 3, 2014 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.

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
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.
To be discussed further - Lesch-Nyhan syndrome
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).
Page1097
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 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;
X

How does UMP Cure
Orotic Aciduria?
UMP
Synthetase
X
Carbamoyl
Phosphate Orotate
Feedback
Inhibition
• 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
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)
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 pattern

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

Behavioral Abnormalities
self-mutilation of the lips by biting

Behavioral Abnormalities
self-mutilation of the fingers by biting 53GKM/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)

-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)

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

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