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Discussion Starter · #1 ·
A 56 year old Female patient presents to the ER with a chief complaint of shortness of breath. She says that she noticed the shortness of breath initially about a month ago when climbing up the stairs at the stadium during college football game. However, the shortness of breath has gotten worse over the past couple weeks and she has recently been waking up at night out of breath. Her physical exam shows pitting edema in her ankles and bilateral basilar rales. Diagnostic studies confirmed the diagnosis of heart failure due to a dilated cardiomyopathy. She is begun on diuretics plus ACE inhibitors and Beta-blockers. A month later, she visits her primary care doctor because she has some joint pain and swelling on the big toe of her right foot. An aspriation of the joint showed an accumulation of sodium urate crystals. Her primary care doctor recognized this as a side effect of her diuretic use and immediately stopped this treatment. A deficiency in which of the following enzymes could lead to this same condition?

A. Xanthine Oxidase
B. Adenine Phosphoribosyl Transferase
C. Hypoxanthine-Guanine Phosphoribosyl Transferase
D. PRPP Synthase
E. Adenosine Deaminase
 

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yeah...the sodium crystals was the key concept so i looked it up in FA and was under the gout section and mentioned HGPRT.
 

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C.

I'll go with C as well - HGPRT salvages the precursors of uric acid, so impaired HGPRT could lead to this patient's gout. The other choices are all enzymes in the synthetic pathway of uric acid, so their impairment would mean less uric acid.
 

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Discussion Starter · #10 ·
Answer is C

Great job everyone! Here is a detailed explanation of the other answer choices:

This patient presents with gout secondary to her diuretic use. Diuretics can increase retention of uric acid, which can then accumulate in the joint (sodium urate crystals) causing erythema, swelling, and pain. Hyperuricemia can occur by a number of mechanisms, not just diuretic use. The two enzymes to know for the pathogenesis of gout are Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) and PRPP Synthase. HGPRT converts Hypoxanthine and Guanine to IMP/GMP, respectively. If there is a deficiency in HGPRT, then the increased Hypoxanthine levels leads to increased uric acid formation, thus hyperuricemia which can lead to gout (Hypoxanthine --> Xanthine --> Uric Acid by Xanthine oxidase). PRPP synthase is required to form PRPP, which is used in the salvage pathway to create nucleotides. If the activity of PRPP is increased, there is a significant rise in purine nucleotides. When these purines are broken down, one of the major products is Uric Acid (ex/ AMP --> IMP --> Hypoxanthine --> Xanthine --> Uric Acid) so increased PRPP synthase activity can also lead to gout.

Choice A would cause decreased conversion of Hypoxanthine to uric acid. Choice B: deficiency in APRT would caused decreased AMP, thus decreased breakdown to IMP, so again decreased uric acid. Choice D: an INCREASE in PRPP Synthase would lead to hyperuricemia, not a decrease. Choice E: this is the enzyme that is absent in SCID --> buildup of ATP and dATP leads to inhibition of DNA synthesis and somehow specifically leads to lack of lymphocytes (mechanism not clear).

Diagnosis: Gout
Common Causes: Drug toxicity (alcohol, diuretics), HGPRT deficiency (Lesch-Nyhan), Increased PRPP activity, others
Treatment: Allopurinol (inhibits Xanthine Oxidase) + NSAIDs for pain

Reference First Aid 2010 pg 69
 

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Great job everyone! Here is a detailed explanation of the other answer choices:

This patient presents with gout secondary to her diuretic use. Diuretics can increase retention of uric acid, which can then accumulate in the joint (sodium urate crystals) causing erythema, swelling, and pain. Hyperuricemia can occur by a number of mechanisms, not just diuretic use. The two enzymes to know for the pathogenesis of gout are Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) and PRPP Synthase. HGPRT converts Hypoxanthine and Guanine to IMP/GMP, respectively. If there is a deficiency in HGPRT, then the increased Hypoxanthine levels leads to increased uric acid formation, thus hyperuricemia which can lead to gout (Hypoxanthine --> Xanthine --> Uric Acid by Xanthine oxidase). PRPP synthase is required to form PRPP, which is used in the salvage pathway to create nucleotides. If the activity of PRPP is increased, there is a significant rise in purine nucleotides. When these purines are broken down, one of the major products is Uric Acid (ex/ AMP --> IMP --> Hypoxanthine --> Xanthine --> Uric Acid) so increased PRPP synthase activity can also lead to gout.

Choice A would cause decreased conversion of Hypoxanthine to uric acid. Choice B: deficiency in APRT would caused decreased AMP, thus decreased breakdown to IMP, so again decreased uric acid. Choice D: an INCREASE in PRPP Synthase would lead to hyperuricemia, not a decrease. Choice E: this is the enzyme that is absent in SCID --> buildup of ATP and dATP leads to inhibition of DNA synthesis and somehow specifically leads to lack of lymphocytes (mechanism not clear).

Diagnosis: Gout
Common Causes: Drug toxicity (alcohol, diuretics), HGPRT deficiency (Lesch-Nyhan), Increased PRPP activity, others
Treatment: Allopurinol (inhibits Xanthine Oxidase) + NSAIDs for pain

Reference First Aid 2010 pg 69
I still dont understand. I would have chose HGPRT because I know it causes gout but not because it makes sense to me. I mean, PRPP is needed to form GMP and IMP, otherwise Guanine and Hypoxanthine levels would increase leading to gout. On the other hand HGPRT makes GMP and IMP from Guanine and Hypoxanthine, if there is no HGPRT my Guanine and Hypoxanthine levels would increase as well. If you go to FA graphic, PRPP and HGPRT are put together meaning they have the "same function". You say INCREASE in PRPP would lead to Hyperuricemia because there is more activity of GMP and IMP BUT if you INCREASE HGPRT also increases GMP and IMP activity leading to more Hyperuricemia. So I think the answer could be either HGPRT or PRPP synthetase deficiency. Besides this patients has no Lesch-Nyhan symptoms but hyperuricemia and gout. =/ Im lost

Hyperuricemia
Gout
Pissed off (aggression)
Retardation (intellectual disability)
DysTonia
 
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