PNP – Purine Nucleoside Phosphorylase Deficiency

Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive metabolic disorder characterized by profound T-cell immunodeficiency often presenting as severe combined immunodeficiency (SCID) and a range of neurological manifestations including developmental delay and ataxia. Hypouricemia is a common biochemical clue. Early diagnosis is critical as hematopoietic stem cell transplantation (HSCT) offers curative potential.

Genetic evidence for PNP deficiency is robust. Over 67 probands from 49 unrelated families have been reported (PMID:22132981), with segregation of biallelic pathogenic variants in multiple pedigrees including demonstration of homozygosity for p.Arg24Ter and p.Arg234Pro alleles in affected siblings (PMID:9737781). Inheritance is autosomal recessive with documented co-segregation in at least two affected siblings (affected_relatives = 2).

The variant spectrum includes missense, nonsense, splice-site, frameshift, and recurrent hotspot alleles. A notable example is c.383A>G (p.Asp128Gly), which abolishes enzymatic activity in vitro (PMID:1384322). Recurrent founder and hot-spot variants such as p.Arg234Pro have been identified across diverse populations, and deep-intronic or hypomorphic alleles have also been described.

Functional studies confirm that missense substitutions such as p.Asp128Gly and p.Arg234Pro lead to loss of PNP function in COS cells, while Gly56 variants may be neutral or deleterious depending on context (PMID:1384322). Murine PNP knockout models replicate the T-cell immunodeficiency via mitochondrial DNA repair defects, supporting a loss-of-function mechanism (PMID:10859343).

Clinically, PNP deficiency manifests with recurrent infections, failure to thrive, neurologic impairment (global developmental delay, ataxia), and autoimmune phenomena. HSCT restores immune function and can stabilize or improve neurological outcomes when performed early, although neurodevelopmental sequelae may persist if treatment is delayed.

Key Take-Home

PNP deficiency is a definitive autosomal recessive immunodeficiency with >67 probands, confirmed by biallelic loss-of-function variants and concordant functional assays; early recognition via genetic and enzymatic testing enables HSCT before irreversible neurologic injury.

References

• American journal of human genetics • 1992 • Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. PMID:1384322
• Nucleosides, nucleotides & nucleic acids • 2011 • Purine nucleoside phosphorylase deficiency: a mutation update. PMID:22132981
• The Journal of experimental medicine • 2000 • Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice. PMID:10859343

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