U01.01.004 Purine salvage deficiencies

Nucleic acids, including DNA and RNA, are fundamental for storing and transmitting genetic information. They are composed of nucleotides, which include purines and pyrimidines.

Nucleotides Involved

GMP (Guanosine Monophosphate)
IMP (Inosine Monophosphate)
AMP (Adenosine Monophosphate)

De Novo Synthesis and Salvage Pathways

De Novo Synthesis

De Novo Pathway: Synthesizes purines from simpler molecules, involving ribose-5-phosphate as a key intermediate.

Salvage Pathway

Salvage Pathway: Recycles purines from degraded nucleotides to form nucleotides like GMP, IMP, and AMP.

Degradation

Purine Degradation: Results in the production of uric acid, which is excreted in urine.

Excretion

End Products: Uric acid is the primary excretory product of purine metabolism.

Key Enzymes and Substrates

Enzyme	Function	Deficiency Effects
PRPP synthetase	Converts ribose-5-phosphate to PRPP	Affects nucleotide synthesis
ADA (Adenosine Deaminase)	Degrades adenosine and deoxyadenosine	Leads to dATP accumulation, affecting lymphocytes
APRT (Adenine Phosphoribosyltransferase)	Converts adenine to AMP	Deficiency causes adenine accumulation
HGPRT (Hypoxanthine Guanine Phosphoribosyltransferase)	Converts hypoxanthine to IMP and guanine to GMP	Deficiency leads to Lesch-Nyhan syndrome
XO (Xanthine Oxidase)	Converts hypoxanthine and xanthine to uric acid	Affects uric acid levels
Urate Oxidase (Rasburicase)	Converts uric acid to allantoin	Used in hyperuricemia treatment

Purine Metabolism Products

Ribose-5-phosphate: Precursor in purine synthesis.
Inosine: Intermediate in purine salvage.
Hypoxanthine: Precursor for IMP synthesis.
Adenine: Precursor for AMP synthesis.
Xanthine: Intermediate in purine degradation.
Uric Acid: Final product of purine degradation.
Allantoin: Product of uric acid oxidation (via urate oxidase).

Purine Salvage Deficiencies

Adenosine Deaminase (ADA) Deficiency

Function: ADA is essential for degrading adenosine and deoxyadenosine.
Consequences:
- Accumulation of dATP
- Inhibition of ribonucleotide reductase activity
- Lymphotoxicity
Clinical Relevance: One of the major causes of autosomal recessive Severe Combined Immunodeficiency (SCID).

Lesch-Nyhan Syndrome

Cause: Defective purine salvage due to absent HGPRT.
Function: HGPRT converts hypoxanthine to IMP and guanine to GMP.
Consequences:
- Excess uric acid production
- Increased de novo purine synthesis
Clinical Features:
- Intellectual disability
- Self-mutilation
- Aggression
- Hyperuricemia (orange “sand” in diaper)
- Gout
- Dystonia
- Macrocytosis
Treatment: Allopurinol or febuxostat (second-line).

Points to Remember

Purine Salvage Pathway: Vital for recycling purines to avoid excessive de novo synthesis.
Deficiencies in Key Enzymes: This can lead to significant clinical conditions such as SCID and Lesch-Nyhan syndrome.
Management: Involves understanding the role of each enzyme and the impact of its deficiency on purine metabolism and associated symptoms.

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