Xanthinuria Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase. Orotic aciduria Orotic aciduria is a disease caused by an enzyme deficiency resulting in a decreased ability to synthesize pyrimidines. It is the only known enzyme deficiency of the de novo pyrimidine synthesis pathway. Gout Gout is caused by a condition known as hyperuricemia, where there is too much uric acid in the body.

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IMMUNODEFICIENCY DISEASES
ASSOCIATED WITH DEFECTS IN
PURINE NUCLEOTIDE
METABOLISM
Dr. V. MAGENDIRA MANI
Assistant Professor of Biochemistry
Islamiah College (Autonomous),
Vaniyambadi
magivbio@gmail.com

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1
Xanthinuria, also known as
xanthine oxidase deficiency, is
a rare genetic disorder
causing the accumulation of
xanthine. It is caused by a
deficiency of the enzyme
xanthine oxidase.
0
2
Orotic aciduria is a disease
caused by an enzyme
deficiency resulting in a
decreased ability to
synthesize pyrimidines. It is
the only known enzyme
deficiency of the de novo
pyrimidine synthesis pathway.
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3
Gout is caused by a condition
known as hyperuricemia,
where there is too much uric
acid in the body.
Xanthinuria Orotic aciduria Gout

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Xanthinuria
Xanthinuria, is a rare genetic disorder causing the
accumulation of xanthine.
It is caused by a deficiency of the enzyme xanthine
oxidase.
It was first formally characterized in 1954.

5. Overview
Hereditary xanthinuria is a purine metabolic disorder due to
inherited deficiency of the xanthine dehydrogenase/oxidase
enzyme and is characterized by very low (or undetectable)
concentrations of uric acid in blood and urine and very high
concentration of xanthine in urine, leading to urolithiasis.
Urolithiasis - A small, hard deposit (stones) that forms in the kidneys and
is often painful when passed

7. Causes
1 Type I xanthinuria can be caused by
a deficiency of xanthine
dehydrogenase, which is an
enzyme necessary for converting
xanthine to uric acid
2 Type II xanthinuria caused by
molybdenum cofactor deficiency
lack one or two other enzyme
activities in addition to xanthine
3 Xanthinuria can be caused by
mutations in the xanthine
dehydrogenase gene,
aldehyde oxidase gene, or
the molybdenum cofactor
gene.
4
Xanthinuria may also
be caused by
treatment of uric acid
excretion with
allopurinol therapy.

8. Symptoms
➔ Haematuria,
➔ Nausea,
➔ Vomiting,
➔ Abdominal pain,
➔ Joint pain,
➔ Failure to thrive,
➔ Fever,
➔ Flank pain,
➔ Dysuria,
➔ Urinary tract infection,
➔ Renal colic,
➔ Acute renal failure,
➔ Crystalluria / urolithiasis.
➔ Kidney stones
In some rare patients, renal disease may evolve to renal failure, or may
even induce arthropathy, myopathy or duodenal ulcer
Flank pain - upper abdominal pain, Dysuria - painful or difficult urination. Renal colic - pain you
get when urinary stones block part of your urinary tract. Haematuria - blood in urine

9. Diagnosis
➔ Diagnosis is based on estimation of uric acid in blood and urine
If hypouricemia is confirmed, detailed purine metabolic
investigation follows, and includes measurement of xanthine
and hypoxanthine in urine and plasma.
➔ Ultrasonography - reveals the presence of xanthine
urolithiasis
➔ Allopurinol loading test, xanthine oxidase assay and molecular
analysis.

10. Treatment
There is no specific treatment beyond maintaining a high fluid
intake and avoiding foods that are high in purine, avoiding foods
and drinks that contain xanthine derivatives, such as coffee, tea,
and cola

11. OROTIC ACIDURIA

12. Orotic aciduria
Orotic aciduria refers to an excessive excretion of orotic acid in urine.
Orotic acid is an intermediate product in pyrimidine synthesis pathway, a
subsequent product of which plays a role in conversion between dihydrofolate
and tetrahydrofolate.
Orotic aciduria is associated with megaloblastic anemia due to decreased
pyrimidine synthesis, which leads to decreased nucleotide-lipid cofactors
needed for erythrocyte membrane synthesis in the bone marrow.

13. Signs and symptoms
➔ It causes a characteristic form of anemia and may be associated with
mental and physical retardation.
➔ In addition to the characteristic excessive orotic acid in the urine, patients
typically have megaloblastic anemia which cannot be cured by
administration of vitamin B12 or folic acid
➔ It also can cause inhibition of RNA and DNA synthesis and failure to thrive.
This can lead to mental and physical retardation

14. Genetics
Orotic aciduria has an autosomal recessive of
inheritance.
Its can be caused by a deficiency in the enzyme
Uridine Monophosphate Synthetase, a
bifunctional protein that includes the enzyme
activities of orotate phosphoribosyltransferase and
orotidine 5'-phosphate decarboxylase.
It can also arise secondary to blockage of the urea
cycle, particularly in ornithine transcarbamylase
deficiency (or OTC deficiency).

15. Diagnosis
➔ A diagnosis of hereditary orotic aciduria is based upon identification
of characteristic symptoms, a detailed patient and family history, a
thorough clinical evaluation and examination of the urine.
➔ Examination of the urine (urinalysis) can reveal elevated levels of
orotic acid.
➔ Orotic aciduria can be diagnosed through genetic sequencing of the
UMPS gene.
➔ Hereditary orotic aciduria by assessing blood ammonia levels and
blood urea nitrogen (BUN).

16. ➔ Treat with feeding diet rich in Uridine /Cytidine
➔ This provide Pyrimidine nucleotides through Salvage Pathway.
➔ Promotes DNA and RNA synthesis.
➔ Also the introduced Pyrimidine bases inhibits CPS II enzyme by
feed back mechanism and block synthesis of Oroticaciduria.
Treatment

17. Administration of uridine, which is converted to
UMP, will bypass the metabolic block and provide

18. GOUT

19. Gout is a common metabolic disorder of Purine
metabolism characterized by :
● Persistent Hyperuricemia
● Hyperuricaciduria and
● Joint pain

20. ➔ Gout, is a disease of the joints, usually in males, caused by an
elevated concentration of uric acid in the blood and tissues.
➔ The joints become inflamed, painful, and arthritic, owing to
the abnormal deposition of crystals of sodium urate.
➔ The kidneys are also affected, because excess uric acid is
deposited in the kidney tubules.
● Primary Gout (Genetic Cause)
● Secondary Gout
Types of Gout

22. Basic cause of primary Gout is genetic
cause.
It has Enzyme defects concerned with:
➔ Over Production Of Purine
Nucleotides
➔ Over catabolism of Purine
Nucleotides
➔ Results in Hyperuricemia
1. Ribose-phosphate diphosphokinase
(Increased Activity))
2. PRPP Glutamyl Amido Transferase
(Increased Activity)
3. Hypoxanthine-guanine
phosphoribosyltransferase
(Decreased Activity)
4. Glucose 6 Phosphatase
(Decreased Activity)
5. Glutathione Reductase
(Decreased Activity)’
5 Enzyme Defects
Causing Primary Gout

23. ● The defect of above 5 Enzymes in primary Gout
● Directly or indirectly increases the Denovo Biosynthesis of Purine
nucleotides.
● There is overproduction of Purine Nucleotides more than their
functional use
● Which further catabolizes them to produce increased Uric acid
levels (Hyperuricemia)

24. ● It is an acquired cause:
● In some pathological states where there is abnormal and excessive
breakdown of cells releases Nucleic acids and Nucleotides.
● Whose catabolism produces increased Uric acid levels
(Hyperuricemia)
Conditions Of Secondary Gout

25. Renal Gout
➔ Type of Gout caused due to insufficiency of Renal System.
➔ Where there is reduced excretion of Uric acid through Urine.
➔ Retention of the Uric acid in blood leading to Hyperuricemia.
➔ Renal Failure
➔ Use of Thiazide diuretics (Drug increase urine flow)
➔ Metabolic Acidosis
➔ Ketoacidosis and Lacticacidosis affects the excretion of Uric
acid through Urine.
Conditions Of Renal Gout

26. ➔ The increased Uric acid levels
➔ Decreases the solubility of Uric acid
and
➔ Get crystallized to form Mono Sodium
Urate Crystals.
➔ The Mono Sodium Urate Crystals get
deposited in the synovial spaces of
joints form Tophi (Hard Mass/
Swelling)

27. —Deposition of Urate crystals in synovial
spaces affects the movements of joints.
—Leads to pain , inflammation, stiffness and
redness of joints known as Gouty Arthritis.

28. Symptoms

29. ● Obesity (High BMI)
● Hypertension (HTN )
● Use of Thiazide diuretics
● Diet high in meat &
seafood
● Excess Alcohol use
Highest with Beer
● Male Gender
● Postmenopausal female
● Older Persons
● Pharmaceuticals:
Cyclosporine

30. The normal serum Uric acid level in adults is 2-7 mg%
—0.5-1 g of uric acid is formed daily in the organism.
—In Gout the serum Uric acid levels rises above 8 mg%.
● History taking & physical examination
● Family history of Gout
● Clinical symptoms alone are sufficient to make accurate diagnosis
in most cases
● Performing Diagnostic studies may help in knowing the stage and
progression of Gout.
Diagnosis

31. ➔ Examination of joint fluid (Arthrocentesis extraction of joint fluid).
➔ X-rays of joint
➔ Blood Examination
➔ Serum Uric acid levels usually elevated.
➔ 24 hour urine Uric acid levels increased.
➔ WBC Count elevated during acute attacks.
➔ ESR (elevated)

32. Treatment
➔ Bed rest : No much movements of joints.
➔ Bed rest : With a position for comfort
➔ Local application of heat or cold around the joint area.
➔ Restrict intake of diet rich in Purine content.
➔ Restrict Alcohol consumption
➔ Avoid dehydration
➔ Drink lots of Water
➔ Allopurinol (Zyloprim) is a drug of choice for Treatment of Gouty
arthritis.
➔ Allopurinol is a structural analog of Hypoxanthine.

34. Thank you...
Dr. V. MAGENDIRA MANI
Assistant Professor of Biochemistry
Islamiah College (Autonomous),
Vaniyambadi
magivbio@gmail.com