NUcleotide Metabolism Disorders
NUcleotide Metabolism Disorders
NECLEOTIDE
METABOLISM
DISORDERS OF PURINE METABOLISM
• Enzyme Deficiencies
• Gout/Gouty Arthritis
- ADA deficiency
- Primary
- Xanthine oxidase deficiency (xanthinuria)
- Secondary
- Purine Nucleoside phosphorylase deficiency
• Lesch-Nyhan syndrome
• Fanconi syndrome
• Familial renal hypouricemia
More common
When uric acid is precipitated in joints in the form of MSU crystals, it is called
gout
Risk factors for Gouty arthritis:
• Hyperuricemia
(present in virtually everyone with gout).
Modifiable risk factors:
- Hypertension/Obesity/dyslipidemia/DM/Cardiovascular diseases Non-modifiable
- Alcohol risk factors:
- Chronic kidney disease - Age
- Acidosis - Various genetic
- Dietary factors variants
o purine and protein rich diet.
o High fructose contents etc.
- Medications altering urate balance
o e.g. diuretics, low-dose aspirin, ethambutol,
pyrazinamide, cyclosporine
When there is hyperuricemia, what are the precipitating
factors that might cause deposition of MSU crystals?
• Alcohol
• Low pH
• High purine and protein rich diets
o Red meat, liver, kidney.
o Sea foods (several)
o Beans, spinach, cabbage, Broccoli,
• Low temperature
• High fructose diet
Sea foods rich in purines
Quite High purine Moderately high purine
Lobster Shrimp
Mussels Anchovies
• Not really.
• Why this occurs only in some people with hyperuricemia is not known.
Clinical features + hyperuricemia diagnose the gout correctly most of the time.
Scoring systems have been developed based on these, but not mandated.
Other diagnostic tools CONT’D
• USG, Dual energy CT.
o Only employed if diagnostic uncertainty and joint aspiration not feasible or available.
MANAGEMENT
pain suppression
inflammation suppression.
• Oral steroids (prednisolone)
• NSAIDs
• Low dose Colchicine
• IL-1 inhibitors (Anakinra, Canakinumab, Rilonacept )
• Intra-articular corticosteroid (triamcinolone )
o Preferred for single inflamed joint.
• Non-pharmacological therapies
o e.g., application of ice packs on the inflamed joints can provide some analgesia.
• Supportive care including the following are important:
o rest,
o mobility assistance, and
o adequate nutrition & hydration
Are IL-1 inhibitors better than other
commonly used therapies for gouty flare?
Single dose 150 mg Canakinumab
Vs.
Single suboptimal dose 40 mg Overall Quality of
(subcutaneous) Triamcinolone acetonide (IM)
Evidence = Moderate
Canakinumab: Better pain relief and joint swelling in people with gouty flare
Canakinumab:
Canakinumab costs 5000 times more than triamcinolone acetonide $16,000 per 150-
Canakinumab probably related with increased risk of adverse events mg vial
V. Management of co-morbidities
VI. Target uric acid levels : Regular monitoring
DISORDERS
CONT’D
Lesch-Nyhan Syndrome
Purines accumulated
Hyperuricemia
• Characterized by motor dysfunction that resembles cerebral palsy, cognitive
& behavioral disturbances.
• Enzyme Deficiencies
ADA deficiency
Xanthine oxidase deficiency (Xanthinuria)
• Fanconi syndrome
Def. of ADA
↓
Accumulation of adenosine & deoxy
adenosine
↓
Toxic to lymphocytes
↓
Suppresses immune function
• Accumulated deoxyadenosine → dAMP, dADP & dATP
ASSIGNMENT
PNP deficiency
• Solubility of xanthine is low in acidic pH of urine
2. Acquired:
heavy metal toxicity, adverse drug reactions (e.g. expired tetracycline),
Vitamin D deficiency, kidney transplantation, amyloidosis, multiple
myeloma etc
• Treatment:
- Replacement of substances lost in urine
- Identify the cause if acquired and treat accordingly.
DISORDERS OF PYRIMIDINE METABOLISM