Nucleotide Metabolism: Clinical Aspects Flashcards
Discuss the etiology of ARTS syndrome.
🩺 ARTS syndrome stands for Ataxia, Retardation, Tremor and Seizures syndrome. It is caused by mutations in the PRPS1 gene, which is responsible for producing the enzyme phosphoribosyl pyrophosphate synthetase 1 (PRPP synthetase 1). This disorder is X-linked and is hence more serious in affected males than females.
[Symptoms: profound sensorineural hearing loss, weak muscle tone, imparied muscle coordination, developmental delay, intellectual disability, vision loss due to optic nerve atrophy, peripheral neuropathy]
Discuss the etiology and symptoms of Lesch-Nyhan syndrome.
🩺 This is a syndrome caused by severe or complete deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRTase), thus the salvage pathway for purine biosynthesis is affected. It is inherited in an X-linked recessive manner hence primarily affects males.
🩺 LNS is characterized by three major hallmarks: neurological dysfunction, cognitive and behavioral disturbances (including self-mutilation), and overproduction of uric acid (hyperuricemia). The latter often results in gout, kidney stones, and bladder stones.
🩺 People with LNS usually cannot walk and generally use a wheelchair.
🩺 Treatment focuses on managing symptoms and improving quality of life.
🩺 Affected people often do not survive past the first or second decade of life due to renal failure.
🩺 [6-minute video]
🩺 [Image 1] [Image 2] [Image 3]
Discuss the etiology of Gout.
🩺 This is a type of arthritis that causes intense pain, swelling, and stiffness in a joint; classically, it affects the joint in the big toe.
🩺 It is caused by elevated levels of uric acid and deposition of sodium urate crystals in the joints and kidneys. It may be caused by genetic deficiency in some enzymes in the purine biosynthetic pathway.
🩺 [6-minute video]
[Diagram] [Image 1] [Image 2] [Image 3]
What are three inherited defects that may lead to early development of severe hyperuricemia and gout?
(1) Glucose-6-phosphatase deficiency
(2) Severe and partial hypoxanthine-guanine phosphoribosyl transferase (HGPRase) deficiency
(3) phosphoribosyl-1’-pyrophosphate synthetase (PRPP synthetase) overactivity
Explain the link between glucose-6-phosphatase deficiency and gout.
◾ Glucose-6-phosphatase catalyses the final step in both glycogenolysis and gluconeogenesis.
◾ A deficiency in this enzyme leads to impaired glucose release from the liver, resulting in hypoglycemia and glycogen accumulation in the liver and kidneys.
◾ The impaired glucose release leads to increased production of lactate, which competes with uric acid for excretion in the kidneys, hence reduced uric acid clearance and subsequent hyperuricemia.
Discuss risk factors associated with Gout.
(1) Age and Gender: Men produce more uric acid than women, though women’s levels of uric acid approach those of men after menopause.
(2) Genetics: A family history of gout increases the likelihood of the condition developing.
(3) Lifestyle choices: Alcohol consumption interferes with the removal of uric acid from the body. Eating a high-purine diet also increases the amount of uric acid in the body.
(4) Lead exposure: Chronic lead exposure has been linked to some cases of gout.
(5) Medications: Certain medications can increase the levels of uric acid in the body; these include some diuretics and drugs containing salicylate.
(6) Weight: Being overweight increases the risk of gout as there is more turnover of body tissue, which means more production of uric acid as a metabolic waste product. Higher levels of body fat also increase levels of systemic inflammation as fat cells produce pro-inflammatory cytokines.
(7) Recent trauma or surgery: increases risk
(8) Other health problems: renal insufficiency and other kidney problems can reduce the body’s ability to efficiently remove waste products, leading to elevated uric acid levels.
Discuss treatment and prevention of Gout.
Treatment
🩺 Allupurinol: It is a hypoxanthine analog and binds tightly to xanthine oxidase, thereby inhibiting the enzyme’s activity. As a result, products of purine catabolism i.e. xanthine and hypoxanthine, which are more soluble are excreted and are less likely to form crystals than uric acid.
🩺 Other medications e.g. NSAIDs, colchicine and corticosteroids may be administered to reduce pain and inflammation.
Prevention
🩺 Diet control: Avoiding foods high in purines, such as red meat, organ meats, and certain seafoods. Limit alcohol intake, especially beer, and avoid sugary beverages.
🩺 Adequate hydration
🩺 Weight management
2 uricosuric agents that increases the renal excretion of uric acid
probenecid, benzbromarone
medications that convert uric acid to allantoin
pegloticase, rasburicase
Which of the following is not associated with Lesch-Nyhan Syndrome?
(a) Urine with maple smell
(b) Self-mutilation
(c) Severe mental retardation
(d) Excess uric acid in urine
(e) Build-up of hypoxanthine and guanine in the body
(a) Urine with maple smell
Explanation:
Maple Syrup Urine Disease is a rare inherited metabolic disorder that prevents the body from properly breaking down certain amino acids.
Specifically, it affects the breakdown of leucine, isoleucine, and valine, which are branched-chain amino acids.
Lesch-Nyhan syndrome is due to deficiency of which of the following enzymes?
(a) Hypoxanthine-Guanine phosphoribosyl transferase
(b) 5’ Nucleotidase
(c) Adenine phosphoribosyl transferase
(d) Adenosine deaminase
(e) Purine nucleoside phosphorylase
(a) Hypoxanthine-Guanine phosphoribosyl transferase
Neurological disorders in Lesch-Nyhan syndrome occur due to ________.
(a) the salvage of guanine and hypoxanthine
(b) partial deficiency of HGPRTase activity
(c) lack of tetrahydrobiopterin required is biosynthesis of neurotransmitters
(d) proper regulation of de novo synthesis of purine nucleotides
(e) increased levels of intracellular GTP
(b) partial deficiency of HGPRTase activity
Further notes:
While some individuals with less severe HGPRTase deficiency may have milder symptoms, the neurological issues in classic Lesch-Nyhan are associated with near-complete deficiency.
Which of the following is not true regarding Lesch-Nyhan syndrome?
(a) It is characterized by neurological disorders
(b) Occurs due to severe deficiency of HGPRTase activity
(c) Limited to males
(d) It is characterized by decreased production of uric acid
(e) Occur due to defective purine metabolism
(d) It is characterized by decreased production of uric acid
Further notes:
Regarding choice (c): Lesch-Nyhan is X-linked recessive, so it technically can also affect females, though this is rare.
Lesch-Nyhan syndrome occurs due to:
(a) Increased levels of intracellular GTP
(b) High levels of tetrahydrobiopterin required in biosynthesis of neurotransmitters
(c) Complete deficiency of HGPRTase activity
(d) Partial decrease in HGPRTase activity
(e) None of the choices is correct
(c) Complete deficiency of HGPRTase activity
Further notes:
Regarding choice (d): Though possibly correct, it does not seem to adequately highlight the severity of the deficiency of the enzyme; it’s mildly ambiguous.
The importance of purine salvage pathway in humans is clearly exemplified in ________.
(a) severe combined immunodeficiency disease (SCID)
(b) orotate aciduria
(c) gout
(d) Lesch-Nyhan syndrome
(e) none of the above
(d) Lesch-Nyhan syndrome
Deficiency of which one of the following enzymes can cause gout or glycogen storage disease type I (GSD 1)?
(a) glucose-6-phosphate dehydrogenase
(b) xanthine oxidase
(c) aldolase
(d) PRPP synthetase
(e) glucose-6-phosphatase
(e) glucose-6-phosphatase
Which of the following is a dietary cause of gout?
(a) Excessive fructose or sucrose
(b) Anorexia nervosa
(c) Drugs that contain purines
(d) All of the choices are correct
(e) None of the choices is correct
(a) Excessive fructose or sucrose
Which of the following drugs used in gout treatment have the same mode of action?
(a) Allopurinol and Rasburicase
(b) Benzbromarone and Rasburicase
(c) Rasburicase and Pegloticase
(d) Allopurinol and Colchicine
(e) Probenecid and Allopurinol
(c) Rasburicase and Pegloticase
Which of the following would not be expected to contribute to hyperuricemia (gout)?
(a) Inhibition of xanthine oxidase
(b) High activity of adenosine deaminase
(c) Unusually high turnover of nucleic acids
(d) Unusually high levels of PRPP
(e) Deficiency of HG-PRT
(a) Inhibition of xanthine oxidase
An administration of allopurinol, an inhibitor of xanthine oxidase, to a patient with gout and normal HG-PRT levels would be expected to lead to all of the following, EXCEPT
(a) Increased levels of PRPP
(b) An increase of hypoxanthine in the blood
(c) Increased xanthine in the blood
(d) Decreased de novo synthesis of IMP
(e) Decreased urate in the urine
(a) Increased levels of PRPP
Which of the following is used in the treatment of gout?
(a) Allopurinol
(b) Benzbromarone
(c) Rasburicase
(d) All of the above
(e) None of the above
(d) All of the above
Which of the following pairs of drugs used in gout treatment have the same mechanisms of action?
(a) Benzbromarone and Rasburicase
(b) Probenecid and Benzbromarone
(c) Allopurinol and Colchicine
(d) Allopurinol and Pegloticase
(e) Allopurinol and Rasburicase
(b) Probenecid and Benzbromarone
Which one of the following agents is used in the treatment of gout?
(a) Allopurinol
(b) Puromycin
(c) Rifampicin
(d) Levamisole
(e) None of the choices is correct
(a) Allopurinol
Which of the following is true with regards to gout?
(a) It is characterized by high uric acid in urine.
(b) It is characterized by high uric acid in blood.
(c) It can be characterized as primary and secondary gout.
(d) Primary gout is managed by the administration of allopurinol.
(e) All of the above are true.
(e) All of the above are true.
Benzbromarone is a uricosuric drug whose mode of action is to ________.
(a) maintain the levels of uric acid in the body
(b) decrease renal elimination of uric acid
(c) increase the levels of uric acid in the body
(d) inhibit the tubular reputake of uric acid
(e) activate the tubular reputake of uric acid
(d) inhibit the tubular reputake of uric acid
Elevated uric acid levels in human blood and urine may be due to ________.
(a) increased PRPP synthetase activity
(b) partial decrease in HGPRTase activity
(c) glucose-6-phosphatase deficiency
(d) all of the above
(e) none of the above
(d) all of the above
Uricosuric drugs ________.
(a) inhibit the tubular reuptake of uric acid
(b) decrease renal elimination of uric acid
(c) include Benzbromarone and Probenecid
(d) A and C are correct
(e) don’t change the levels of uric acid in the body
(d) A and C are correct
Probenecid is a uricosuric drug whose mode of action is to ________.
(a) maintain the levels of uric acid in the body
(b) increase the levels of uric acid in the body
(c) inhibit the tubular reuptake of uric acid
(d) decrease renal elimination of uric acid
(e) activate the tubular reuptake of uric acid
(c) inhibit the tubular reuptake of uric acid
