U01.01.004 Purine salvage deficiencies

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Learning Objectives

Understand the Purine Salvage Pathway and its role in recycling nucleic acids.
Identify the biochemical consequences of Adenosine Deaminase (ADA) deficiency.
Master the clinical presentation and pathophysiology of Lesch-Nyhan Syndrome.
Recognize the mechanisms of treatment for hyperuricemia (Allopurinol, Febuxostat, Rasburicase).

1. The Purine Salvage & Degradation Pathway

The body recycles free bases (Guanine, Hypoxanthine, Adenine) back into nucleotides (GMP, IMP, AMP) to save energy. When salvage fails, bases are diverted into the Uric Acid pathway.

HGPRT: Converts Hypoxanthine to IMP and Guanine to GMP.
APRT: Converts Adenine to AMP.
Xanthine Oxidase (XO): Converts Hypoxanthine and Guanine (via Xanthine) into Uric Acid.

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2. Adenosine Deaminase (ADA) Deficiency

ADA is required to degrade Adenosine and Deoxyadenosine. Its deficiency is a major cause of Autosomal Recessive SCID.

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Pathophysiology:
$\downarrow$ ADA $\rightarrow$ $\uparrow$ dATP $\rightarrow$ Inhibition of Ribonucleotide Reductase $\rightarrow$ $\downarrow$ DNA precursors $\rightarrow$ $\downarrow$ Lymphocytes.

3. Lesch-Nyhan Syndrome

An X-linked recessive disorder caused by a complete deficiency of HGPRT. This leads to an inability to salvage Hypoxanthine or Guanine.

Biochemical Profile: $\uparrow$ Uric acid production and a compensatory $\uparrow$ in de novo purine synthesis ( $\uparrow$ PRPP amidotransferase activity).
Clinical Mnemonic (HGPRT):
- Hyperuricemia
- Gout
- Pissed off (Self-mutilation, aggression)
- Red/orange crystals in urine (Sodium urate “sand” in diaper)
- Tense muscles (Dystonia)

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4. Pharmacology of Uric Acid

Drug	Mechanism
Allopurinol / Febuxostat	Inhibits Xanthine Oxidase (decreases uric acid production).
Rasburicase	Recombinant uricase; catalyzes the metabolism of uric acid to Allantoin (more soluble).