Partial Hypoxanthine-guanine Phosphoribosyltransferase Research Articles

Prolonged fasting increases purine recycling in postweaned northern elephant seals

Northern elephant seals are naturally adapted to prolonged periods (1–2 months) of absolute food and water deprivation (fasting). In terrestrial mammals, fasting stimulates ATP degradation and decreases ATP synthesis. Hypoxanthine‐guanine phosphoribosyl transferase (HGPRT) salvages ATP by recycling the purine degradation products derived from xanthine oxidase (XO) metabolism. The contributions of HGPRT to purine recycling during prolonged fasting in marine mammals are not well defined. In the present study, complete and partial HGPRT and XO cDNA sequences were obtained. Also, HGPRT and XO mRNA and protein expression was quantified in tissue from fasting elephant seals, along with the plasma levels of hypoxanthine (HX) and xanthine and activities of HGPRT and XO. Blood and tissue samples were collected from animals during the 1, 3, 5 and 7 week of their natural post‐weaning fast. The HGPRT and XO cDNA sequences encode proteins with conserved domains important for their function and regulation. HGPRT and XO mRNA and protein expression increased during the 7 wk in adipose tissue and muscle, respectively. Plasma xanthine and HX levels, and XO and HGPRT activities increased during the last two weeks of fasting. Results suggest that prolonged fasting in elephant seal pups is associated with increased capacity to recycle purines, which may contribute to enhancing the supply of ATP.

Molecular Analysis of Two Enzyme Genes, HPRT1 and PRPS1, Causing X-Linked Inborn Errors of Purine Metabolism

Inherited mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome or HPRT-related gout. On the other hand, PRPS1 mutations cause PRPP synthetase superactivity associated with hyperuricemia and gout, sometimes including neurodevelopmental abnormalities. We have identified two mutations in two Lesch-Nyhan families after our last report. One of them, a new single nucleotide substitution (130G>T) resulting in a missense mutation D44Y was detected in exon 2 of HPRT1. RT-PCR amplification showed not only a cDNA fragment with normal size, but also a small amount of shorter fragment skipping exons 2 and 3. The other missense mutation F74L (222C > A) was detected in a Japanese patient but has been reported previously in European families. In four hyperuricemic patients with mild neurological abnormality, no mutations responsible for partial HPRT deficiency were identified in HPRT1. In these four patients, we also performed molecular analysis of PRPS1, but no mutations in PRPP synthetase were found.

Partial HPRT Deficiency Phenotype and Incomplete Splicing Mutation

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of enzyme deficiency. The complete deficiency causes Lesch-Nyhan syndrome (LNS). Partial HPRT-deficient patients can show a variable degree of neurological manifestations. Both diseases have been associated with mutations in the HPRT1 gene. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene. In fact, more than 300 disease-associated mutations have been described. Splice mutations accounts for more that 16% of HPRT mutations and in most cases cause a complete LNS phenotype. A 16 year-old boy consulted to La Paz University Hospital because of hyperuricemia (9.4 mg/dL). At age one year he was given a diagnosis of dystonic cerebral palsy. Although he usually employs a wheelchair, under certain circumstances, he is able to stand up and walk by himself. He has never showed self injurious behavior. This patient presented a splice mutation (NM_000194.2: c.552 -2 A > G) causing exon 5 exclusion. An exon-5 specific PCR was designed, and a minor amount of normally spliced HPRT mRNA was found. Normally spliced HPRT mRNA was quantified by real-time PCR in this patient, in control subjects, and in two Lesch Nyhan patient with splice mutations excluding exon 4 (patient B) and exon 8 (patient C) who had clinically a Lesch Nyhan disease phenotype. A minor amount of normally spliced HPRT mRNA was found in all the patients. No correlation was found between the percentage of the normally spliced HPRT mRNA and the phenotype. We conclude that the partial HPRT deficient phenotype of this patient can not be explained by the finding of a minor amount of normally splice HPRT mRNA. It is possible that the amount of normally splice mRNA vary among different tissues.

Methylation Status of HPRT1 Promoter in HPRT Deficiency with Normal Coding Region

Lesch-Nyhan syndrome is an X-linked recessive inborn error of metabolism due to a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity (OMIM 300322). Partial deficiency of HPRT (OMIM 300323) is characterized by the effects of excess uric acid synthesis and a continuum spectrum of neurological manifestations, without the manifestations of full-blown Lesch-Nyhan syndrome. Both diseases have been associated with mutations in the HPRT1 gene. We have described one Lesch-Nyhan patient and four partial HPRT deficient patients with a normal HPRT1 coding region. These patients showed markedly decreased HPRT mRNA expression, but no mutation in their genomic regulatory sequences from HPRT1 gene. In this study, we analyzed the promoter region methylation status of the HPRT1 gene in these five HPRT deficient patients. Methods: DNA was bisulphite modified and a 620 bp fragment including 320 bp 5′ to start codon was amplified and sequenced. The methylation status of 35 CpG island 5′ to start codon and 28 CpG island 3′ to start codon were investigated in male controls, female controls, patients, and the patient's mothers. Primer pairs were designed for methylated-specific and unmethylated-specific amplification and PCR was performed employing DNA bisulphite treated as template. Results: No alterations in the methylation pattern of the HPRT1 promoter were found in the five HPRT deficient patients. Conclusions: The promoter region methylation status of these five HPRT deficient patients was similar to that of normal subjects. Thus, some other genetic alteration must explain a reduced enzyme activity with a normal gene coding region.

Hyperuricemia and Gout: A Review Article

Hyperuricemia and Gout: A Review Article

Gouty Synovitis of the Knee with Partial Hypoxanthine-guanine Phosphoribosyl Transferase Deficiency (Kelley-Seegmiller Syndrome): A Case Report

We present here a case of gouty synovitis of the knee in a patient with partial hypoxanthine-guanine phosphoribosyl transferase deficiency (Kelley-Seegmiller syndrome), which is an inherited purine metabolic disorder. Magnetic resonance images and computed tomography showed a diffuse mass with stippled calcification around the posterior cruciate ligament (PCL) in the posterior intercondylar notch. Arthroscopic examination revealed that the articular surfaces and menisci in the affected knee were almost completely covered with white chalky monosodium urate (MSU) crystals. The diffuse mass around the PCL was composed of proliferative synovial villi covered with MSU crystals that looked like snow covered trees. Arthroscopic total synovectomy was performed. The posterior trans-septal portal was especially useful for removal of the proliferative villi around the PCL. To our knowledge, this is the first report of arthroscopic examination in a patient with Kelley-Seegmiller syndrome.

Normal HPRT coding region in complete and partial HPRT deficiency

Lesch–Nyhan syndrome is an X-linked recessive inborn error of metabolism due to a virtually complete lack of hypoxanthine–guanine phosphoribosyltransferase (HPRT) activity (OMIM 300322). Partial deficiency of HPRT (OMIM 300323) is characterized by the effects of excess uric acid synthesis and a continuum spectrum of neurological manifestations, without the manifestations of full-blown Lesch–Nyhan syndrome. Both diseases have been associated with mutations in the HPRT gene. These mutations are heterogeneous and disperse throughout the entire HPRT gene. In 2005 Dawson et al. described, for the first time, an individual with gout in whom HPRT deficiency appeared to be due to a defect in gene regulation. In the present study we present four patients with partial HPRT deficiency and one patient with Lesch–Nyhan syndrome who showed a normal HPRT coding sequence and markedly decreased HPRT mRNA expression. This is the first report of a patient with Lesch–Nyhan syndrome due to a defect in HPRT gene expression regulation.

Partial hypoxanthine-guanine phosphoribosyltransferase deficiency due to a newly recognized mutation presenting with renal failure in a one-year-old boy

We describe the case of a 1-year-old boy with partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. At his first visit to the hospital, he was diagnosed with hyperuricemia and irreversible renal failure. The misssense mutation Asp185Gly (554A>G) was identified in exon 8 of his HPRT gene, and this mutation was inherited from the mother.

Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose.

Partial hypoxanthine–guanine phosphoribosyl transferase deficiency without elevated urinary hypoxanthine excretion

Partial hypoxanthine–guanine phosphoribosyl transferase (HGPRT) deficiency, also known as the Kelley–Seegmiller syndrome, can give rise to a wide range of neurological symptoms, and renal insufficiency. Biochemically, it is characterized by high uric acid concentrations in blood, high uric acid and hypoxanthine excretion in urine, and decreased activity of hypoxanthine–guanine phosphoribosyl transferase activity (HGPRT). However, normal uric acid concentrations in blood and uric acid excretions in urine have been reported. Here, a boy is presented with normal development and suffering from recurrent attacks of acute renal failure with slightly to clearly increased urinary uric acid excretion. Between these attacks, episodes of elevated urinary excretion of uric acid were observed with normal blood concentrations of uric acid and normal urinary excretion of hypoxanthine. HGPRT activity in erythrocytes, leukocytes, and fibroblasts was found to be strongly decreased. This case shows that not only normal blood uric acid but also normal urinary hypoxanthine concentrations do not exclude the diagnosis of partial HGPRT deficiency.

An Unusual Cause of Renal Amyloidosis Secondary to Gout—the First Description of Familial Occurrence

Background: AA amyloidosis caused by the chronic inflammation accompanying gouty arthritis is extremely rare and familial occurrence has not been described so far. Case report: We present the case of two brothers (47 and 44 years old) with 7- and 10-year history of hyperuricaemia and chronic tophaceous gout with polyarticular involvement. The enzymatic assay performed in their erythrocytes proved the partial hypoxanthine-guanine phosphoribosyl transferase deficiency (Kelley-Seegmiller syndrome), the genetic defect of purine metabolism. Later on they developed proteinuria and chronic renal insufficiency /CRI/. Renal biopsy disclosed the combination of AA amyloidosis and gouty nephropathy in both the cases. Despite the standard treatment the older brother progressed to chronic renal failure. On the contrary, the younger one being longterm treated with oral colchicin have stabilized CRI. Conclusions: Only several cases of AA renal amyloidosis until recently, secondary to gout have been reported. Our case represents the first report of familial occurrence of this extremely rare disease.

Partial hypoxanthine-guanine phosphoribosyltransferase deficiency presenting as acute renal failure

Hyperuricemia and secondary urate nephropathy are uncommon in the paediatric setting outside of tumour lysis syndrome. We describe the case of a 12-year-old boy who presented at 3 years of age with acute renal failure. The cause of this remained unknown until the development of uric acid renal calculi 9 years later. This, and the availability of the previously unknown family history, provided the subsequent diagnosis of partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Detailed family history is important for early detection of this heterogeneous group of disorders. Early treatment may minimise long-term renal morbidity and mortality from renal insufficiency.

Clinical and Biochemical Manifestations and Molecular Characterization of the Mutation HPRT Jerusalem

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Clinical and Biochemical Manifestations and Molecular Characterization of the Mutation HPRT Jerusalem

A novel point mutation (I137T) was identified in the hypoxanthine‐guanine phosphoribosyltransferase (HPRT) encoding gene, in a patient with partial deficiency of the enzyme. The mutation, ATT to ACT (substitution of isoleucine to threonine), occurred at codon 137, which is within the region encoding the binding site for 5‐phosphoribosyl‐1‐pyrophosphate (PRPP). The mutation caused decreased affinity for PRPP, manifested clinically as a Lesch–Nyhan variant (excessive purine production and delayed acquisition of language skills). The partial HPRT deficiency could be detected only by measuring HPRT activity in intact fibroblasts (uptake of hypoxanthine into nucleotides).

The biochemical basis of the neurobehavioral abnormalities in the Lesch–Nyhan syndrome: a hypothesis

Lesch–Nyhan syndrome (LNS) is a rare X-recessive disorder that leads to virtually complete deficiency of the purine salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT). Partial HPRT deficiency results in uric acid overproduction with subsequent hyperuricemia, nephrolithiasis, renal failure and gouty arthritis. In contrast, at complete HPRT deficiency, besides overproduction of uric acid neurological problems appear including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The cause for the uric acid overproduction has been clarified, but the connection between the enzyme deficiency and the neurological manifestations in LNS remains unclear. A hypothesis, which explains this relation, is proposed in the paper. The hypothesis has several important points most substantial of which is the accelerated biosynthesis of semiessential amino acid histidine that against the background of accelerated purine de novo biosynthesis results in 5-aminoimidazole-4-carboxamideribotide (AICAR) and histamine accumulation. The histamine and AICAR were determined to be the compounds that cause the neurobehavioral symptoms of LNS for several reasons. First, in the basal ganglia a balance between the direct (activating) and the indirect (inhibiting) pathways arising on the basis of the antagonistic and reciprocal dopamine–adenosine interactions normally exists. This balance can tonically regulate smooth voluntary movements and the activity of the thalamus, which, in turn, processes the afferent sensorimotor signals from the whole body to the all areas of the cerebral cortex and is concerned to modulate mental development and bring sensory information into awareness. Second, histamine is known to induce a selective damage in dopaminergic neurons inhibiting the direct dopaminergic pathway, which could lead to muscular rigidity, and slowness in initiating movements as well as tremor that are characteristic of Parkinsonism in LNS. Third, AICAribosid (AICAR breakdown product) is a potent adenosine A2a receptor antagonist inhibiting the indirect dopamine–adenosinergic pathway and, therefore, could be responsible for the choreoathetosis, dystonia and ballismus found in LNS. The excitatory–inhibitory disbalance in the basal ganglia could result in inadequate modification of the thalamus activity with subsequent mental retardation and symptoms that include the patients not being aware for their own bodies that could give rise to self-mutilation. Finally, a possibility for the creation of a new animal model that could exactly match the human LNS is proposed in the paper.

Biochemical and molecular study of mentally retarded patient with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase

Nucleotide metabolism was studied in erythrocytes of a mentally retarded child and family members. Partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency was found in the propositus and an asymptomatic maternal uncle. Studies in crude lysates demonstrated decreased apparent V max and slightly decreased apparent K m for hypoxanthine in both HPRT-deficient subjects . Genomic DNA analysis revealed a single nucleotide change with leucine-147 to phenylalanine substitution in both subjects; mother and grandmother were heterozygous carriers of the same defect. This new variant has been termed HPRT Potenza. Increased erythrocyte concentration of NAD and rate of synthesis by intact erythrocytes were found in the patient; increased activities of nicotinic acid phosphoribosyltransferase (NAPRT) and NAD synthetase (NADs) were demonstrated in erythrocyte lysates, with normal apparent K m for their substrates and increased V max. These alterations were not found in any member of the family, including the HPRT-deficient uncle. These findings show multiple derangement of nucleotide metabolism associated with partial HPRT deficiency. The enzyme alteration was presumably not the cause of neurological impairment since no neurological symptoms were found in the HPRT-deficient uncle, whereas they were present in the propositus' elder brother who had normal HPRT activity.

Partial Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency as the Unsuspected Cause of Renal Disease Spanning Three Generations: A Cautionary Tale

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked defect of purine metabolism. Clinical manifestations are usually related to the degree of enzyme deficiency: complete HPRT deficiency (Lesch-Nyhan syndrome) presenting with severe neurologic or renal symptoms, or partial HPRT deficiency (Kelley-Seegmiller syndrome) manifesting as a gout-urolithiasis syndrome. A 3-generation kindred is described in which the recognition of partial HPRT deficiency in 2 adolescent male siblings presenting with uric acid lithiasis led to the diagnosis in 2 maternal uncles already in renal failure of unknown cause. This report highlights the importance of clinical awareness leading to early diagnosis, appropriate diagnostic methodology, and therapy of a treatable inherited disorder of purine metabolism for the prevention of renal failure.

Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency.

Lesch-Nyhan disease (LND) is a rare, X-linked genetic disorder that involves the nearly complete absence of an enzyme (hypoxanthine-guanine phosphoribosyltransferase, or HPRT) that is essential for purine salvage. In addition to hyperuricemia, all patients with classic LND suffer from movement disorder and compulsive self-injury, and most have mental retardation. Patients with partial HPRT deficiency (variants) always have hyperuricemia and often have neurologic abnormalities, but do not self-injure and usually are described as having normal intelligence. Here we compare 15 patients with LND to 9 variants and 13 normal adolescents and adults. Testing revealed unambiguous and qualitatively similar cognitive deficits in both patient groups. The variants produced scores that were intermediate between those of patients with LND and normal participants on nearly every cognitive measure. We discuss these findings in terms of what is known about the neuropathology of LND.

Cytosolic 5'-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients.

Lesch-Nyhan syndrome is a metabolic-neurological syndrome caused by the X-linked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Metabolic consequences of HGPRT deficiency have been clarified, but the connection with the neurological manifestations is still unknown. Much effort has been directed to finding other alterations in purine nucleotides in different cells of Lesch-Nyhan patients. A peculiar finding was the measure of appreciable amount of Z-nucleotides in red cells. We found significantly higher IMP-GMP-specific 5'-nucleotidase activity in the erythrocytes of seven patients with Lesch-Nyhan syndrome than in healthy controls. The same alteration was found in one individual with partial HGPRT deficiency displaying a severe neurological syndrome, and in two slightly hyperuricemic patients with a psychomotor delay. Since ZMP was a good substrate of 5'-nucleotidase producing Z-riboside, we incubated murine and human cultured neuronal cells with this nucleoside and found that it is toxic for our models, promoting apoptosis. This finding suggests an involvement of the toxicity of the Z-riboside in the pathogenesis of neurological disorders in Lesch-Nyhan syndrome and possibly in other pediatric neurological syndromes of uncertain origin.

Novel initiation codon mutation Met1Thr identified in a patient with partial hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency: HPRT Heidelberg

Novel initiation codon mutation Met1Thr identified in a patient with partial hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency: HPRT Heidelberg