Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior. Mutations in the same gene also cause less severe clinical phenotypes with only some portions of the full syndrome. A large database of 271 mutations associated with both full and partial clinical phenotypes was recently compiled. Since the original database was assembled, 31 additional mutations have been identified, bringing the new total to 302. The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes. The differences between LND and the partial phenotypes cannot be explained by differences in the locations of mutations, but the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function. The reasons for some apparent exceptions to this proposal are addressed.
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PMID:The spectrum of mutations causing HPRT deficiency: an update. 1557 Dec 20

Lesch-Nyhan syndrome is a rare X-linked recessive disorder of purine metabolism, caused by complete absence of the enzyme hypoxanthine-guanine phosphoribosyl transferase. Persons affected with this incurable disease are developmentally and physically delayed, and suffer from self-injurious behavior. The most typical feature results in partial or total destruction of perioral tissues. The purpose of this paper was to discuss a case of Lesch-Nyhan syndrome with self-mutilative behavior and lip injuries, including some suggestions of a preventive approach avoiding the extraction of teeth. A soft mouthguard fabricated to prevent the destruction of perioral soft tissues and combined psychiatric pharmacologic therapy proved to have satisfactory results.
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PMID:A preventive approach to oral self-mutilation in Lesch-Nyhan syndrome: a case report. 1690 43

Lesch-Nyhan syndrome (LNS) is an X-linked genetic disorder resulting in hyperuricemia, choreoathetosis, mental retardation, and self-injurious behavior. It is caused by loss of activity of the ubiquitous enzyme hypoxanthine-guanine-phosphoribosyltransferase (HPRT). The biochemical analysis of residual HPRT activity in patients' red blood cells is the first step in LNS diagnosis, and it precedes molecular study to discover the specific mutation. Unfortunately, biochemical diagnosis of healthy carriers is difficult because HPRT enzymatic activity in blood cells is similar in LNS carriers and in healthy people; genetic tests can help reveal mutations at the genomic or cDNA level, whereas gross deletions involving the first or last exons of HPRT gene are not detectable. Until now, a test based on 6-thioguanine-resistant phenotype of HPRT mutant cells from LNS patients is the only method accepted for the diagnosis of any kind of mutation in carriers. In this work, we introduce a new approach to identify carriers of large deletions in HPRT gene using real-time PCR. Results were validated in a blinded manner with a linkage study and with results obtained in Italian families previously analyzed with selective medium test. Real-time PCR analysis clearly confirmed the results obtained by selective medium; linkage data strengthened real time results, allowing us to follow the allele with the mutated HPRT through the family pedigree. We hope that the real-time PCR approach will provide a useful and reliable method to diagnose LNS carriers of large deletions in HPRT gene.
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PMID:Real-time PCR and linkage studies to identify carriers presenting HPRT deleted gene. 1722 73

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 the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15-18 weeks' gestation, or chorionic villus cells obtained at about 10-12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments.
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PMID:Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. 1806 74

Lesch-Nyhan syndrome (LNS) is a rare X-linked recessive disorder involving purine metabolism caused by the congenital absence of hypoxanthine guanine phosphoribosyl transferase. A characteristic feature of LNS is the appearance of intractable self-injurious behavior, usually in the form of severe lip and finger biting. The mechanism behind this severe self-mutilating behavior is unknown, and is one of the main challenges in the management of this condition. We here report the case of a 30-year-old man with a confirmed diagnosis of LNS who was successfully treated for self-mutilation of his lips with repeated botulinum toxin A (BTX-A) injections in the facial perioral muscles. Our findings suggest that treatment with BTX-A helped reduce self-abusive behavior in this patient. Our case illustrates that BTX-A injections can be a useful therapeutic approach in patients with self-abusive behavior.
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PMID:Botulinum toxin: treatment of self-mutilation in patients with Lesch-Nyhan syndrome. 1852 Sep 86

Neurobehavioral manifestations of complete HPRT deficiency include severe action dystonia, choreathetosis, alteration of executive functions, and self-injurious behavior. Dystonic manifestations are also present in patients with partial HPRT deficiency. Pathophysiology of these manifestations is unknown. Guanidinoacetate is a neurotoxin implicated in certain dystonic syndromes. We have examined guanidinoacetate and creatine levels in urine from 11 HPRT deficient patients (9 with Lesch-Nyhan syndrome and 2 with partial deficiency). Urinary guanidinoacetate and creatine levels in HPRT deficient patients were within the normal range. Guanidinoactetate alteration does not seem to be implicated in the pathogenesis of the neurological disease associated with HPRT deficiency.
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PMID:Urinary guanidinoacetate and creatine levels in patients with HPRT deficiency. 1860 May 7

Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.
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PMID:Abnormal adenosine and dopamine receptor expression in lymphocytes of Lesch-Nyhan patients. 1963 51

We previously reported a male patient with an 18q21.3 deletion, hyperuricemia and typical symptoms of the Lesch-Nyhan syndrome who lacked hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) deficiency. The patient developed progressive peripheral neuropathy in additon to his profound mental retardation and self-injurious behavior. At the age of 23 years MR imaging revealed globally delayed myelination with relative sparing of the corpus callosum and frontal lobes. They were focal hyperintensities suggestive of gliosis. Multimodality evoked potentials found evidence of impaired central and peripheral conduction. Single photon emission computed tomographic (SPECT) imaging demonstrated left frontal hyperperfusion and under it a temporoparietal hypoperfusion.
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PMID:Myelination disturbance in a patient with hyperuricemia and hyperserotoninemia combined with 18q deletion syndrome. 2002 32

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.
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PMID:Partial HPRT deficiency phenotype and incomplete splicing mutation. 2054 10

Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND.
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PMID:PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse. 2181 16


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