Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Lesch-Nyhan disease (LND) is an inborn error of purine metabolism caused by defective activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT, EC 2.4.2.8), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classic phenotype occurs almost exclusively in males and is characterized by hyperuricemia, mental retardation, severe dystonia, and self-injurious behavior. Heterozygous carrier females are usually clinically normal. However, a small number of clinically affected females have been described. In all previous cases there was a mutation in one HPRT allele and non-random inactivation of the X chromosome carrying the normal HPRT gene. We have analyzed a female MZ twin pair discordant for Lesch-Nyhan disease. The mother and both twins are heterozygous carriers of a HPRT splicing mutation (IVS8 + 4A > G; c.609 + 4A > G) and all three express the mutant allele at similar frequencies in peripheral blood T cells. The mother and one sister are clinically normal. In the affected twin, the clinical phenotype is classical for Lesch-Nyhan disease, despite the fact that HPRT activity in the blood was also normal. X inactivation analysis showed a skewed pattern in the fibroblasts of the affected twin sister, with the X chromosome carrying the normal HPRT allele preferentially inactivated. As in many other reported cases of X-linked diseases, the discordant phenotype of the two monozygous twin sisters suggests that the process responsible for monozygotic twinning can trigger skewed X inactivation.
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PMID:Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. 1586 83

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder resulting from a deficiency of the metabolic enzyme hypozanthine-guanine phosphoribosyltransferase (HPRT). This syndrome presents with abnormal metabolic and neurological manifestations including hyperuricemia, mental retardation*, spastic cerebral palsy (CP), dystonia, and self-mutilation. The mechanism behind the severe self-mutilating behavior exhibited by patients with LNS is unknown and remains one of the greatest obstacles in providing care to these patients. This report describes a 10-year-old male child with confirmed LNS who was treated for self-mutilation of his hands, tongue, and lips with repeated botulinum toxin A (BTX-A) injections into the bilateral masseters. Our findings suggest that treatment with BTX-A affects both the central and peripheral nervous systems, resulting in reduced self-abusive behavior in this patient.
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PMID:Botulinum toxin as a novel treatment for self-mutilation in Lesch-Nyhan syndrome. 1613 73

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.
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PMID:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency presenting as acute renal failure. 1624 Jan 58

A 24-year-old male with end-stage renal disease (ESRD) and disproportionately high uric acid plasma concentration was admitted to our unit. After studying the patient's medical history, as well as that of the entire family, hyperuricemia was discovered in his brother, while microscopic examination of his brother's and mother's urine revealed abundant uric acid crystals. After performing purine metabolic studies, it was determined that the two siblings suffered from partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Kelley-Seegmiller syndrome). This report highlights the importance of clinical awareness and a thorough examination of the patient's medical history for establishing an early diagnosis and commencing treatment for such rare inherited metabolic disorders to prevent renal failure.
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PMID:HPRT deficiency as the cause of ESRD in a 24-year-old patient: a very rare presentation of the disorder. 1624 52

Azathioprine, a purine analogue, significantly suppressed the purine synthesis de novo of two gouty patients manifesting overproduction of uric acid, as well as three of four gouty patients who showed normal uric acid production. This suppression is taken as evidence that phosphoribosyl-pyrophosphate amidotransferase, the rate-controlling step in purine synthesis de novo, has a normal sensitivity to feedback inhibitors in the patients who responded to the drug.Two children afflicted with the familial disorder of hyperuricemia, choreo-athetosis, and self-mutilation described by Lesch and Nyhan showed no reduction in the activity of the biosynthetic pathway in response to azathioprine. This inability to respond to azathioprine can be directly related to the absence in these patients of the enzyme hypoxanthine-guanine phosphoribosyltransferase which is required for conversion of the drug or its metabolites to the biochemically active ribonucleotide form.
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PMID:The effects of azathioprine (imuran) on purine synthesis in clinical disorders of purine metabolism. 1669 29

Inherited mutations of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8), give rise to Lesch-Nyhan syndrome or HPRT-related gout. We have identified a number of HPRT mutations in Asian patients manifesting different clinical phenotypes, by analyzing all nine exons of the HPRT gene (HPRT1) from genomic DNA and reverse-transcribed mRNA using the PCR technique coupled with direct sequencing. In this study, we update the spectrum of mutations with nine novel mutations. Two missense mutations (T124P and D185G) were detected in patients with HRH (HPRT-related hyperuricemia). In a patient having a severe partial deficiency of HPRT with neurological dysfunction (HRND: HPRT-related neurological dysfunction), a single nucleotide substitution (27+5G > A) causing a splicing error was found in intron 1. The mutation resulted in a remarkably decreased level of normal mRNA, and production of an abnormal mRNA with a 49-bp insert at the 5'-end of intron 1, which caused the frame-shift of an amino acid codon (10fs27X). In six typical Lesch-Nyhan families, we found two 3-bp deletions responsible for single amino acid deletions (V8del and Y28del), two 1-bp deletions (440delA and 635delG) generating a frame-shift, an insertion of two amino acids (159insKV), and a 4,131-bp deletion from introns 4 to 6 resulting in two types of abnormal mRNA. Including these nine mutations, 42 HPRT1 mutations have been identified among 47 Asian families with deficiency of HPRT.
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PMID:Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations. 1702 11

We have used the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme-deficient mouse model of human Lesch-Nyhan disease (LND) to examine the tissue-specificity of altered global gene expression in a genetically "simple" monogenic human disease. We have identified a number of genes and gene families whose expression is aberrant in the mouse knockout model of the LND, and we have identified different patterns of aberrant gene expression in two principal target tissues associated with the disease phenotype, i.e., the central nervous system and the liver. The major neurological phenotype reflects dysfunction of the dopamine neurotransmitter system in the basal ganglia, and we have now identified aberrant expression of a small number of genes in HPRT-deficient striata. The abnormal metabolic phenotype of hyperuricemia in HPRT-deficient mice is also reflected in an aberrant gene expression in the liver. We interpret these findings to suggest that the genetic consequences of a primary HPRT knockout in the mouse produces transcriptional aberrations in a number of other genes that may play a role in the disease phenotype. Knowledge of these secondary genetic defects may help in the identification of targets for drug- and gene-based therapy.
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PMID:Tissue-specific aberrations of gene expression in HPRT-deficient mice: functional complexity in a monogenic disease? 1750 72

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.
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PMID:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency due to a newly recognized mutation presenting with renal failure in a one-year-old boy. 1789 42

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 is a rare genetic disorder, caused by a mutation in the gene coding for the enzyme hypoxanthine-guanine phosphoribosyltransferase, which is characterized by hyperuricemia and its associated symptoms along with motor disorders and compulsive self-mutilation. We show that the temporal difference learning algorithm that has been often used to interpret dopaminergic activity in the basal ganglia offers an explanation for the self-mutilation behaviors. We propose that a dysfunctional dopamine signal inadvertently reinforces early, accidental injurious behavior that is initially caused by clumsiness owing to the motor disorders. Simulations of this model reproduce findings on the results of behavioral treatments for dealing with self-mutilation behaviors.
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PMID:A model of behavioral treatments for self-mutilation behavior in Lesch-Nyhan syndrome. 1828 46


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