Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The patient, H.Chr.B., was among the first reported with hyperuricemia and central nervous system symptoms. He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E.C.2.4.2.8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome. The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia. However, his intelligence was normal and he had no evidence of self-mutilation. There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner. Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides. In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides. The patient's fibroblasts were even more efficient in the metabolism of 8-14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides. The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally. Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patient's cells was intermediate between normal and Lesch-Nyhan cells. These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene. They document that this famous patient did not have the Lesch-Nyhan syndrome.
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PMID:Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. 52 96

The Lesch-Nyhan syndrome is a rare inborn error of purine metabolism caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which results in mental retardation with characteristic self-mutilation, spasticity, extrapyramidal signs and hyperuricaemia. The clinical and biochemical findings in an 18-month-old boy, who presented with renal calculi and was shown to have less than 1% of normal HGPRT activity, are reported. The obvious neurological abnormalities had previously been thought to be due to hypoxic-ischaemic encephalopathy. The expected incidence of this disease is much higher than the known number of cases diagnosed.
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PMID:The Lesch-Nyhan syndrome--an under-recognised condition in South Africa? A case report. 156 65

We studied 5 boys, 2 to 10 years old, with marked or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and Lesch-Nyhan syndrome with varying degrees of mental retardation, dysarthria, chorea, dystonia, spasticity, and ataxia. Four patients had marked reduction of homovanillic acid in the cerebrospinal fluid (CSF) and all showed low CSF 3-methoxy-4-hydroxy phenylethylene glycol, indicating reduced dopamine and norepinephrine turnover. Three patients showed high CSF 5-hydroxyindoleacetic acid, suggesting increased serotonin turnover. Some patients improved with carbidopa-levodopa, but others benefited from tetrabenazine, a monoamine-depleting agent. This study provides support for the theory of abnormal central monoamine metabolism in Lesch-Nyhan syndrome.
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PMID:Lesch-Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters. 245 72

Dopaminergic mechanisms involved in self-inflicting biting behavior (SBB) were investigated in two animal models: monkeys with unilateral ventromedial tegmental (VMT) lesions of the brainstem and rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) neurons. The administration of mixed D1/D2 DA agonists to some monkeys with unilateral VMT lesions of the brainstem elicits SBB of the forelimb digits contralateral to the lesion and spasticity of the contralateral hindlimb. This behavior is prevented by pretreatment with the selective D1 antagonist SCH 23390 and with the D1/D2 antagonist fluphenazine. The combined administration of the D1 DA agonist SKF 38393 with the D2 DA agonist quinpirole produces SBB at doses that were ineffective when these drugs were administered individually. The intrastriatal (middle ventrolateral area [MVL]) microinjection of the D1/D2 DA agonist apomorphine (Apo) to rats with unilateral 6-OHDA lesions elicits SBB. This behavior is not prevented by systemic administration of SCH 23390 and partially prevented by the selective D2 antagonist raclopride. However, the combined administration of SCH 23390 and raclopride completely prevents the Apo-induced SBB. Thus, the pharmacological characteristics of the DA agonist-induced SBB in monkeys with unilateral VMT lesions of the brainstem seem to differ from those induced by intrastriatal (MVL area) administration of DA agonists into rats with 6-OHDA lesions of the nigrostriatal DA neurons. The role of DA neuronal systems in the expression of SBB in Lesch-Nyhan syndrome and in some patients with mental retardation, as well as the link between hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and abnormal dopaminergic function in Lesch-Nyhan syndrome, is discussed.
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PMID:Dopaminergic mechanisms in self-inflicting biting behavior. 269 8

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10-14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2-4 years old. The administration of mixed DA agonists, such as L-DOPA, apomorphine (Apo) and abeorphine 201-678, elicit a self-mutilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D1, but not D2 DA receptors, and was prevented or abolished by the D1 DA antagonist SCH 23390 or by the D1 and D2 DA antagonist fluphenazine (Flu), but not by the D2 antagonist (+/-)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D1 and/or by both D1 and D2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.
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PMID:Dopamine agonist induced self-mutilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: possible pharmacological model for Lesch-Nyhan syndrome. 293 64

Ten cases of Lesch-Nyhan syndrome have been followed for 3-19 years (mean, 11 years and four months). Criteria of Lesch-Nyhan syndrome were restricted to the following: complete absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in hemolysate and fibroblast, spasticity, choreoathetosis, mental retardation, self-mutilation, and occurrence in males. Two patients have died of pneumonia and two died suddenly. However, autopsies produced no positive findings. Hyperuricemia has been controlled by benzbromarone in nine patients. One patient did not take any medical treatment and died suddenly when he was 19 years old, but showed no gouty signs. Patients with Lesch-Nyhan syndrome indicated no change or aggravation of choreoathetosis or spasticity. Self-mutilation was difficult to control by any treatment with continuing effect. After the age of ten, self-mutilation declined in seven cases, and in one patient disappeared completely. Mental delay was remarkable and suspected developmental age (DA) was 7 months - four years and 10 months (chronological age, 7 years and five months - 19 years and 6 months). Mean DQ score was 15.6. Physical development was severely delayed, and weight age was 28.9-46.4%, mean 37.4% of chronological age. Future investigations will evolve clarification of CNS signs and its treatment, and etiological research of sudden death.
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PMID:Long-term follow-up of ten patients with Lesch-Nyhan syndrome. 376 72

The Lesch-Nyhan syndrome is characterized clinically by choreoathetosis, spasticity, selfmutilation, and mental and growth retardation. Biochemically, there is a striking reduction of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in affected individuals. We have examined erythrocytes from 14 patients with the Lesch-Nyhan syndrome for the presence of hypoxanthine-guanine phosphoribosyltransferase activity and enzyme protein. In contrast to the usual finding of no detectable hypoxanthine-guanine phosphoribosyltransferase activity, we have found low levels (0.002-0.79 nmoles/mg protein per hr) of hypoxanthine-guanine phosphoribosyltransferase activity in erythrocyte lysates from five of these patients. In three of the five patients, hypoxanthine-guanine phosphoribosyltransferase activity appeared to be substantially more labile in vivo than normal using erythrocytes which had been separated according to their density (age). Immunochemical studies using a monospecific antiserum prepared from a homogeneous preparation of normal human erythrocyte hypoxanthine-guanine phosphoribosyltransferase revealed immunoreactive protein (CRM) in hemolysate from all 14 patients with the Lesch-Nyhan syndrome. The immunoreactive protein from each patient gave a reaction of complete identity with normal erythrocyte hypoxanthine-guanine phosphoribosyltransferase and was present in quantities equal to those observed in normal erythrocytes. In addition, a constant amount of CRM was found in erythrocytes of increasing density (age) from patients with the Lesch-Nyhan syndrome despite the decreasing hypoxanthine-guanine phosphoribosyltransferase activity. These studies confirm previous data which indicate that the mutations leading to the Lesch-Nyhan syndrome are usually, if not always on the structural gene coding for hypoxanthine-guanine phosphoribosyltransferase. In addition, although the mutant proteins appear to be present in normal amounts, they are often very labile in vivo with respect to enzymatic activity. These observations suggest that therapy directed at stabilization or activation of enzyme activity in vivo may be of potential benefit.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase: characteristics of the mutant enzyme in erythrocytes from patients with the Lesch-Nyhan syndrome. 462 52

A large Arab family affected with the rare X-linked Lesch-Nyhan syndrome is reported on. Two hemizygous boys, two and nine years of age, had the classical biochemical and clinical-neurological syndrome. The activity of erythrocyte hypoxanthine-guanine phosphoribosyltransferase (HGPRT) was below the detectable limit (greater than 0.1% of normal). They were mentally and physically retarded and exhibited spasticity and choreoathetosis; the older of the two also exhibited self-mutilation. The mother and three of her seven daughters, all clinically asymptomatic, were proven to be heterozygous for HGPRT deficiency, by demonstration of an increased rate of de novo purine synthesis in cultured skin fibroblasts. Erythrocyte HGPRT activity was normal in the three heterozygous daughters, but was significantly reduced in the mother. However, in all four heterozygotes, erythrocyte HGPRT/adenine phosphoribosyltransferase ratio was lower than in all other family members. All heterozygotes had blood uric acid levels within the normal range, although higher than in the normal women in the family. The ratio uric acid/creatinine concentration in the urine was significantly elevated in one of the heterozygotes, and in the upper normal limit in two others, indicating excessive purine production.
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PMID:Lesch-Nyhan syndrome in an Arab family. Detection and biochemical manifestation of heterozygosity. 732 17

Lesch-Nyhan syndrome is associated with complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), characterized by hyperuricemia and severe neurological signs. The HPRT gene has been mapped to the q26 region on the long arm of the X-chromosome. We are taking care of a family of Lesch-Nyhan syndrome. A 14-year-old male was noted the growth disturbance at the age of 7 months and self-mutilation behavior characterized by compulsive biting of his lip and fingers at the age of 18 months. In 1987, at the age of 4, he was diagnosed as Lesch-Nyhan syndrome from neurologic signs and hyperuricemia (9.8 mg/dl). Neurological examination revealed mild mental and growth retardation, spasticity and hyperreflexia of lower extremities, choreoathetoid movements of extremities, and compulsive self-mutilation. The HPRT activity in erythrocytes of this patient was 0.02 nmol/min/mg hemoglobin (control value 1.76 +/- 0.06), and adenine phosphoribosyltransferase (APRT) activity was 1.08 nmol/min/mg hemoglobin (control value 0.43 +/- 0.06). Using polymerase chain reaction (PCR) method coupled with direct sequencing, we analyzed the nucleotide sequences of each exon from the genomic DNA as well as the entire HPRT coding region of the cDNA by RT-PCR method. In the HPRT gene from the patient, a guanine to adenine substitution at base position 209 in exon 3 was identified, which resulted in a single amino acid substitution of glycine with glutamic acid at codon 70. The family studies indicated that his mother, sister and grandmother were heterozygotes. PCR-restriction fragment length polymorphism (RFLP) utilizing Mnl I site which created by the mutation, was useful for detection of the mutant gene. We have identified a new missense mutation of the HPRT gene in a Japanese patient. This mutation was reported at the same codon as foreign mutants and mighty be indicative of a location of mutation activity in the HPRT gene.
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PMID:[A Japanese family with Lesch-Nyhan syndrome resulting from a new point mutation in hypoxanthine-guanine phosphoribosyltransferase gene]. 939 32

Lesch-Nyhan syndrome is a hereditary disorder of purine metabolism causing overproduction of uric acid and neurological problems including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The syndrome is caused by a defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which converts guanine and hypoxanthine to the nucleotides GMP and IMP. There is evidence that the neurological problems are due to an adverse effect of the HPRT deficiency on the survival and/or development of dopaminergic neurons, specifically. Here we report that HPRT-deficient PC12 mutants that have a normal or near normal dopamine content (55-97% of that of wild-type cells) fail to undergo neuronal differentiation induced by nerve growth factor (NGF) when the de novo pathway of purine synthesis is partially inhibited. However, nerve growth factor-induced differentiation is near normal under these conditions in PC12 HPRT-deficient mutants containing much lower dopamine levels (<8% of that of wild type cells), indicating a neurotoxic effect of the endogenous dopamine in the mutants. The degree of inhibition of the de novo pathway of purine synthesis was the same in both classes of HPRT-deficient mutants. Expression of BCl-2 in a PC12 mutant that has a normal dopamine content allowed partial NGF-induced differentiation suggesting that the apoptotic pathway might be involved in the failure of differentiation when the de novo pathway of purine synthesis is partially inhibited.
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PMID:Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. 967 Sep 94


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