Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients

Abstract

Uric acid (UA) is the end product of purine nucleotide degradation. Abnormal levels of UA in serum/urine can guide the detection of some metabolic errors such as deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT-d), xanthine oxidase and molybdenum cofactor (MoCo-d). HPRT-d, with X-linked inheritance, causes Lesch-Nyhan disease (LND) and its variants (LNV) characterized by hyperuricemia/hyperuricosuria, self-mutilation (LND), gout, nephrolithiasis, kidney failure, and variable neurological involvement. MoCo-d is a rare autosomal recessive neurodegenerative disorder characterized by combined deficiency of molybdenum cofactor-dependent enzymes, such as xanthine oxidase, and presents with hypouricemia/hypouricosuria, microcephaly, intractable seizures, and severe developmental delay. The objective of this work is to characterize Argentine paediatric patients with defects in purine metabolism in which the value of UA together with the phenotype data allowed to guide the biochemical/molecular studies for the exact diagnosis.

Twenty-nine patients with HPRT-d and 2 MoCo-d, first/main clinical manifestations, onset and diagnosis ages were included. UA concentrations in serum/urine, urinary hypoxanthine and xanthine, enzyme activity and genotype were determined. The quantification of metabolites and enzyme activity assays were performed by liquid chromatography and genetic studies by PCR and sequencing.

All patients with HPRT-d presented hyperuricemia (range 7.7-17 mg/dl; normal 3.7-7); increased urinary UA (range 1400-2300 μmol/mmol creatinine; normal >1300), hypoxanthine (range 55-778; normal >45) and xanthine (range 23-200; normal >43). Deficient HPRT activity and identification of pathogenic genetic variants (private to each family) allowed the diagnostic confirmation; there was high phenotypic variability, being able to classify the cases in LND and LNV. The two patients with MoCo-d had a similar clinical presentation and fatal outcome; laboratory findings included hypouricemia (AU >0.5 mg/dl), hypouricosuria (AU >30 μmol/mmol creatinine), increased urinary xanthine/hypoxanthine, and mutations in the MOCS2 gene.

Purine metabolic defects comprise a group of diseases with highly variable clinical manifestations. Altered levels of UA and clinical suspicion are indicative for its detection, biochemical-enzymatic and genetic studies allow the exact nosological definition. Early diagnosis is beneficial for the patient and allows genetic counseling for these diseases considered rare or infrequent.