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NUcleotide Metabolism Disorders

The document discusses disorders of nucleotide metabolism, focusing on purine and pyrimidine metabolism disorders, including enzyme deficiencies and their clinical implications such as gout and Lesch-Nyhan syndrome. It outlines the causes, pathophysiology, diagnosis, and management strategies for these conditions, emphasizing the role of uric acid levels in gout and the importance of dietary factors. Additionally, it covers specific disorders like orotic aciduria and highlights treatment options including urate-lowering therapies and supportive care.

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0% found this document useful (0 votes)
14 views50 pages

NUcleotide Metabolism Disorders

The document discusses disorders of nucleotide metabolism, focusing on purine and pyrimidine metabolism disorders, including enzyme deficiencies and their clinical implications such as gout and Lesch-Nyhan syndrome. It outlines the causes, pathophysiology, diagnosis, and management strategies for these conditions, emphasizing the role of uric acid levels in gout and the importance of dietary factors. Additionally, it covers specific disorders like orotic aciduria and highlights treatment options including urate-lowering therapies and supportive care.

Uploaded by

parajulibibek451
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPTX, PDF, TXT or read online on Scribd
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DISORDERS OF

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

Increases Uric Acid Levels Decreases Uric Acid Levels


in Blood in Blood
DISORDERS OF PYRIMIDINE METABOLISM
• Orotic Aciduria
Type I
Type II
Secondary orotic aciduria
GOUT
• Caused by the deposition of
monosodium urate (MSU) crystals in
articular and non-articular structures.

• Once known as “disease of kings and


king of diseases”.

• Most common form of inflammatory


arthritis that affects adults.
Can be due to NOTE:
Uric Acid mainly excreted
through kidneys, & some
through gut

Increased Uric Acid Decreased Uric Acid


Production Excretion

More common

Both lead to increased uric acid levels.

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

Sardines Mackerel Crab Oyster


Is presence of hyperuricemia sufficient for gout?

• Not really.
• Why this occurs only in some people with hyperuricemia is not known.

• But, hyperuricemia is required for the formation of MSU crystals.

• The major contributor for hyperuricemia is under-excretion of urate by


kidney or gut rather than overproduction.
Pathophysiology
Hyperuricemia

Monosodium Urate (MSU) crystallization

Acute inflammatory response to MSU crystallization


(Gouty flare)

Asymptomatic phase after or between flares


(Inter-critical gout)

Chronic gouty arthritis with or without tophi


(Advanced gout)
I & II. Hyperuricemia & MSU crystallization
• Risk factors for hyperuricemia are same as that of gout.

• Under secretion is more important than over secretion.

• Genetic studies suggest various forms of polymorphisms


associated with variations in serum urate concentrations:
o URAT 1 & ABCG2 transporters are most commonly associated.
Urate transporters in intestine and kidney

Much better understood in kidney than intestine


Over production of uric acids occurs in...

Clinical disorders Drugs, diets, toxins


Malignancies, Cytotoxic drugs,
Hemolytic disorders, Ethanol,
Hypoxia,
Fructose,
Down’s syndrome,
Purine rich diets etc.
Von Gierke’s disease,
Obesity,
HGPRTase deficiency,
PRPP synthetase deficiency etc.

Biochemical basis of important causes will be dealt during practical session


Under secretion of uric acid occurs in...

Metabolic syndrome, Dyslipidemia, Obesity,


DKA, Starvation ketoacidosis,
Lactic acidosis,
Alcoholism,
Chronic renal insufficiency,
Genetic (esp. URAT1 and ABCG2 polymorphisms),
Fluid loss,
Heart failure,
Hypothyroidism, Hyperparathyroidism etc

Biochemical basis of important causes will be dealt during practical session


III. Gouty Flare/Acute Gouty Arthritis
• Is an acute inflammatory response to MSU deposition.
• Pronounced neutrophilic infiltration in synovial tissue & fluid.
• Many inflammatory mediators have been said to be responsible.
• Of typical importance is:
 NLRP3 inflammasome activation leading to release of bioactive IL 1β

• Typically mono-articular (involving foot, ankle, knees).

• Elbows, wrists, and hand joints involved usually only in patients


with long-standing, poorly controlled disease.
IV. Inter-critical gout
• Resolution of gouty flares leading to asymptomatic period (at least until
another gouty flare appears).

• The gout flare is a self limiting inflammation.


• The redness, joint swelling & severe pain usually disappear after 7- 10 days.

• Various mechanisms proposed.

• Role of neutrophil is said to be substantial (+ production of anti-inflammatory


factors in the joint)

[Neutrophils have role in both flare production & resolution]


V. Chronic Gout/ Advanced Gout

• Chronic gouty arthritis, joint damage &


erosion, tophi.
• Tophi may not be present in all.

• The tophus represents a chronic, foreign-


body granulomatous inflammatory
response to monosodium urate crystals
DIAGNOSIS
• Gold standard:
- Microscopic confirmation of
MSU crystals.
- Needle shaped crystals with
negative birefringent under
polarizing microscopy confirms
MSU crystals
• Negative birefringence of urate crystals in gout.mp4

• Live Synovial Gout phagocyte Showing Negative Birefringent Characteristic


MSU Crystal.mp4
Other diagnostic tools:
• Hyperuricemia + Typical signs and symptoms (e.g. podagra)
• Other helpful features to consider:
o Male sex,
o Previously reported arthritic attack,
o Acute onset,
o Presence of co morbidities like HTN, CVDs etc.

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

MANAGING GOUTY FLARES LONG TERM MANAGEMENT


MANAGING GOUTY FLARES
• Major priority:

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

No studies comparing canakinumab with more commonly used first‐line


therapies for acute gout flares such as NSAIDs or colchicine.

Low‐quality evidence indicated that compared with maximum doses of


indomethacin (50 mg three times a day), 320 mg of rilonacept may
provide less pain relief with a similar rate of adverse events.
2. Long term management
I. Urate lowering therapies(ULTs)
• First line: Xanthine oxidase inhibitors (Allopurinol);
• Second line: Uricosurics (probenecid);
• Third line: Recombinant uricase (pegloticase)

II. Prevent Future flares


Anti inflammatory prophylaxis (NSAIDs/ colchicine 0.5 mg)

III. Patient education


IV. Diet and lifestyle modification

V. Management of co-morbidities
VI. Target uric acid levels : Regular monitoring
DISORDERS
CONT’D
Lesch-Nyhan Syndrome

• Inherited disorder of purine metabolism


• X linked recessive
• Incidence is 1 in 1000 males
• Complete def. of HGPRTase
HGPRTase deficiency

salvage pathway blocked

Purines accumulated

More purine degradation

Hyperuricemia
• Characterized by motor dysfunction that resembles cerebral palsy, cognitive
& behavioral disturbances.

• Uric acid overproduction (hyperuricemia).

• Persistent self-injurious behavior (biting fingers, hands, lips, & cheeks;


banging head or limbs) is a hallmark of disease.

• Overproduction of uric acid may lead to deposition of uric acid crystals or


calculi in kidneys, ureters, or bladder.
• Bloody diaper with crystals of uric acid (sand).
Persistent self-mutilating behavior (biting the fingers, hands,
lips, and cheeks; banging the head or limbs) is a hallmark of
disease
HYPOURICEMIA

• Enzyme Deficiencies
ADA deficiency
Xanthine oxidase deficiency (Xanthinuria)

• Purine Nucleoside phosphorylase deficiency

• Fanconi syndrome

• Familial renal hypouricemia


ADENOSINE DEAMINASE (ADA) DEFICIENCY
• ADA catalyses deamination of adenosine to inosine, & of deoxyadenosine
to deoxyinosine

Def. of ADA

Accumulation of adenosine & deoxy
adenosine

Toxic to lymphocytes

Suppresses immune function
• Accumulated deoxyadenosine → dAMP, dADP & dATP

• dATP: powerful inhibitor of Ribonucleotide reductase (an enzyme


required for conversion of ribonucleotide to deoxyribonucleotide)

• This deprives the cell of precursor deoxyribonucleotide molecules for DNA


synthesis

• The enzyme depletion is associated with:

SEVERE COMBINED IMMONODEFICIENCY DISEASE (SCID)

• In this inherited disease, B-cells as well as T-cells are defective

• First gene therapy was attempted for this disease.


The gene therapy
treatment for ADA-SCID
showed remarkable clinical
success, and UCLA licensed
the therapy to a biotech
company, Orchard
Therapeutics, for
commercial development.
XANTHINURIA
• Cause: Def. of xanthine oxidase
• Xanthine oxidase: Involved in production of urate
• Def. causes purine catabolism to stop at xanthine & hypoxanthine → Urate
level in blood & urine are exceedingly low
• Xanthine & hypoxanthine become major end products.
• In most cases this condition isn’t associated with any clinical symptoms &
goes unnoticed
• Diagnosis is made after incidental finding of low serum urate

ASSIGNMENT
PNP deficiency
• Solubility of xanthine is low in acidic pH of urine

• In xanthinuria, (at high concentration), xanthine is prone to precipitation

• Thus, urinary tract stones composed of xanthine are common

• Crystalline deposits of xanthine & hypoxanthine in skeletal muscles may


lead to myopathy
FAMILIAL RENAL HYPOURICAEMIA

• Inadequate reabsorption uric acid by renal tubules → ↑ed urinary


elimination of uric acid → Hypouricemia
FANCONI SYNDROME
DO not confuse
• Inadequate reabsorption in the PCT. with Fanconi
anemia
• Various small molecules of metabolism passed into the
urine instead of being reabsorbed:
o glucose,
o amino acids,
o uric acid,
o phosphate, and
o bicarbonate
• Causes:
1. Congenital:
cystinosis, Wilson’s disease, tyrosinemia type 1 etc.

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

Orotic Aciduria Disorders of pyrimidine metabolism are


Type I not only rare but are also less severe as
Type II compared to disorders of purine
Secondary causes metabolism
 Overproduction of pyrimidines is
harmless as their catabolites are easily
excreted
OROTIC ACIDURIA TYPE I
• Autosomal recessive disorder

• Results from absence the enzymes OPRT (Orotate phosphoribosyl


transferase) & OMP decarboxylase.

• Orotate accumulation, which is excreted in urine.

• Decreased pyrimidine de novo synthesis


• Excessive urinary level of this substance(> 1 gm/day; normal=1.4 mg/day)
leads to its crystallization & consequent obstruction to urine flow.

• Characterized by retarded growth & megaloblastic anemia.

• Oral administration of uridine controls the disease as all the pyrimidine


nucleotides can be synthesized from uridine.
OROTIC ACIDURIA TYPE II
• Extremely rare
• There is deficiency of OMP decarboxylase only.

• OMP and orotic acid are excreted in urine.

• Megaloblastic anemia is the only clinical abnormality which is


controlled by oral administration of uridine.
Secondary Causes of Orotic aciduria

• Defect in ornithine transcarbamylase ( of urea cycle) causes


accumulation of carbamoyl phosphate.

• This is then diverted for increased synthesis and excretion of


orotic acid.
Towards pyrimidine
synthesis
ASSIGNMENT: SHORT NOTES

• Purine and pyrimidine analog drugs


Pyrimidine analogs: - 5 FU - cytosine arabinoside - 5-azacytidine
- 5-fluorocytosdine - Floxuridine
Pyrimidine Nucleoside analogs: - Gemcitabine - Cytarabine
Purine analogs: - Azathioprine - Mercaptopurine - Thioguanine
Purine nucleoside analog: -Clofarabine - Pentostatin - Cladribine
Purine nucleotide analogs: - Fludarabine

• Other drugs related to purine and pyrimidine metabolism.


- Methotrexate, Allopurinol, Uricosurics etc.

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