APRT – Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT; HGNC:626) deficiency (MONDO:0013869) is a rare autosomal recessive purine salvage disorder resulting in accumulation of insoluble 2,8-dihydroxyadenine (DHA) crystals, leading to urolithiasis and progressive renal impairment. The condition is confirmed by undetectable APRT enzymatic activity in erythrocytes and by identification of biallelic pathogenic APRT variants.

Inheritance is autosomal recessive, with 21 pediatric cases from 18 families reported (median diagnosis age 3 y) and confirmed by APRT sequencing showing homozygous or compound heterozygous mutations (PMID:22212387). Family screening identified 3 asymptomatic affected siblings, demonstrating segregation of pathogenic alleles within kindreds (PMID:11532677).

The variant spectrum includes frameshift, nonsense, splice-site, and missense mutations. A single T insertion at the intron 4 splice donor (IVS4+2insT) accounts for ~40% of alleles in white cohorts (PMID:20150536), while the APRT*J founder allele c.407T>C (p.Met136Thr) occurs in ~79% of Japanese patients (PMID:2227951). Recurrent hypomorphic alleles and private splice variants contribute to geographic and familial clustering.

Clinically, >80% of patients present with radiolucent nephrolithiasis (HP:0000787) often in childhood, and up to 50% have reduced renal function (HP:0012622) at diagnosis (PMID:22212387). Untreated, crystalline nephropathy leads to chronic kidney disease and end-stage renal disease.

Functional assays demonstrate absent APRT activity in red cell lysates and, in stop-codon or splicing mutants, reduced mRNA abundance (~25% of normal) with absent protein on Western blot (PMID:9521589). Cell-based and enzymatic studies confirm haploinsufficiency of APRT and the pathogenic mechanism of DHA overproduction.

Misdiagnosis is common: Fourier transform infrared stone analysis alone misidentified DHA in 50% of cases, emphasizing the need for enzyme assay or genetic confirmation (PMID:32399606).

APRT deficiency is a clinically actionable disorder: early recognition and xanthine oxidoreductase inhibition (e.g., allopurinol) prevent stone formation and preserve renal function. Genetic testing allows cascade screening of at-risk relatives.

Key Take-home: APRT deficiency is a definitive autosomal recessive cause of DHA urolithiasis and nephropathy with well-characterized genotype–phenotype correlations and effective treatment to prevent irreversible renal damage.

References

• Pediatric Nephrology • 2012 • APRT deficiency in children PMID:22212387
  
• American Journal of Kidney Diseases • 2001 • Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland PMID:11532677
  
• Journal of the American Society of Nephrology • 2010 • Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency PMID:20150536
  
• Human Genetics • 1990 • Crossovers within a short DNA sequence indicate a long evolutionary history of the APRT*J mutation PMID:2227951
  
• Human Genetics • 1998 • A germline mutation abolishing the original stop codon of the human APRT gene leads to complete loss of the enzyme protein PMID:9521589
  
• Urolithiasis • 2020 • Are conventional stone analysis techniques reliable for the identification of 2,8-dihydroxyadenine kidney stones? A case series PMID:32399606

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