TITLE: Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. AUTHOR(S): Yeh-J; Zheng-S; Howard-BD
ADDRESS OF AUTHOR: Department of Biological Chemistry, School of Medicine, University of California, Los Angeles 90095, USA. SOURCE (BIBLIOGRAPHIC CITATION): J-Neurosci-Res. 1998 Jul 1; 53(1): 78-85 INTERNATIONAL STANDARD SERIAL NUMBER: 0360-4012 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: 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. MINOR MESH HEADINGS: Antimetabolites,-Antineoplastic-pharmacology; Azaserine-pharmacology; Blotting,-Northern; Cell-Differentiation-physiology; Cell-Survival-drug-effects; Hypoxanthine-Phosphoribosyltransferase-genetics; Neurites-drug-effects; Neurites-ultrastructure; Proto-Oncogene-Proteins-c-bcl-2-biosynthesis; Purines-biosynthesis; PC12-Cells; Rats-; Tyrosine-3-Monooxygenase-metabolism MAJOR MeSH HEADINGS: *Dopamine-physiology; *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Lesch-Nyhan-Syndrome-enzymology; *Lesch-Nyhan-Syndrome-pathology; *Neurons-enzymology; *Neurons-parasitology CHECKTAGS: Animal; Human; Support,-U.S.-Gov't,-P.H.S. PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: RO1MH38633MHNIMH CAS REGISTRY NUMBER OR EC NUMBER: EC 1.14.16.2; EC 2.4.2.8; 0; 0; 0; 115-02-6; 51-61-6 NAME OF SUBSTANCE: Tyrosine-3-Monooxygenase; Hypoxanthine-Phosphoribosyltransferase; Antimetabolites,-Antineoplastic; Proto-Oncogene-Proteins-c-bcl-2; Purines; Azaserine; Dopamine MEDLINE ACCESSION NUMBER: 98334069
UPDATE CODE: 9811
Record 2 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Prenatal diagnosis of HPRT mutant genes in Lesch-Nyhan syndrome. AUTHOR(S): Yamada-Y; Goto-H; Suzumori-K; Ogasawara-N ADDRESS OF AUTHOR: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Japan. SOURCE (BIBLIOGRAPHIC CITATION): Adv-Exp-Med-Biol. 1998; 431: 211-4 INTERNATIONAL STANDARD SERIAL NUMBER: 0065-2598 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
MINOR MESH HEADINGS: Exons-; Family-; Heterozygote-Detection; Introns-; Lesch-Nyhan-Syndrome-embryology; Lesch-Nyhan-Syndrome-genetics; Polymerase-Chain-Reaction; Polymorphism,-Restriction-Fragment-Length; Pregnancy- MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-diagnosis; *Point-Mutation; *Prenatal-Diagnosis CHECKTAGS: Female; Human; Male; Support,-Non-U.S.-Gov't PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8 NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase MEDLINE ACCESSION NUMBER: 98260423
UPDATE CODE: 9809
Record 3 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. AUTHOR(S): Harris-JC; Lee-RR; Jinnah-HA; Wong-DF; Yaster-M; Bryan-RN ADDRESS OF AUTHOR: Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamesharris@erols.com SOURCE (BIBLIOGRAPHIC CITATION): Arch-Neurol. 1998 Apr; 55(4): 547-53 INTERNATIONAL STANDARD SERIAL NUMBER: 0003-9942 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: OBJECTIVE: To provide the first comprehensive magnetic resonance imaging (MRI) assessment of brain in a series of patients with Lesch-Nyhan syndrome (LNS), with emphasis on basal ganglia measurements. DESIGN: Routine readings of MRI studies, repeated reading in random order blinded to subject diagnosis, and 3-dimensional volumetric measures of basal ganglia regions. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Seven patients with LNS who have hypoxanthine guanine phosphoribosyltransferase levels less than 1.6% and characteristic clinical features of the disorder, which include hyperuricemia, cognitive impairment, and dystonic movement disorder, were compared with 7 age-matched control subjects. Five of the 7 patients demonstrated self-injurious behavior. MRI studies were performed using general anesthesia because of the severity of the movement disorder. MAIN OUTCOME MEASURES: Measurement of brain regions from MRI-obtained images. RESULTS: Routine readings described mild cerebral atrophy in 2 of 7 patients, but no caudate or putamen abnormalities were reported. However, on the directed blinded rereading, small caudates were suspected in 5 of 7 cases, and abnormalities in cerebral size and cranium were identified. Volumetric studies of the patients with LNS confirmed a 34% decrease in caudate volume (P<.001), a 17% decrease in total cerebral volume (P<.03), and a 12% decrease in putamen volume (P=.19). CONCLUSIONS: To our knowledge, this is the first demonstration of consistent neuroanatomic abnormalities in LNS. The findings of reduced basal ganglia volume are consistent with the dystonic movement disorder. MINOR MESH HEADINGS: Adult-; Atrophy-; Caudate-Nucleus-pathology; Putamen-pathology; Single-Blind-Method MAJOR MeSH HEADINGS: *Basal-Ganglia-pathology; *Brain-pathology; *Lesch-Nyhan-Syndrome-diagnosis; *Magnetic-Resonance-Imaging CHECKTAGS: Female; Human; Male; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S. PUBLICATION TYPE: CLINICAL-TRIAL; JOURNAL-ARTICLE; RANDOMIZED-CONTROLLED-TRIAL CONTRACT OR GRANT NUMBERS: HD23042HDNICHD; HD24061HDNICHD; HD33095HDNICHD MEDLINE ACCESSION NUMBER: 98220451
UPDATE CODE: 9807
SUBSET: AIM
Record 4 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Cross-sensitization between footshock stress and apomorphine on self-injurious behavior and neostriatal catecholamines in a rat model of Lesch-Nyhan syndrome. AUTHOR(S): Stodgell-CJ; Loupe-PS; Schroeder-SR; Tessel-RE ADDRESS OF AUTHOR: Department of Pharmacology and Toxicology, 5036A Malott, School of Pharmacy, University of Kansas, Lawrence, KS 66045-2505, USA. SOURCE (BIBLIOGRAPHIC CITATION): Brain-Res. 1998 Feb 2; 783(1): 10-8 INTERNATIONAL STANDARD SERIAL NUMBER: 0006-8993 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: The effects of footshock sensitization (priming), apomorphine (APO) priming and their combination on behavior and neostriatal and cortical catecholamines were examined in adult rats which had neonatally received bilateral intracerebroventricular injections with 6-hydroxydopamine (6-OHDA; a model of Lesch-Nyhan syndrome (LNS)) or vehicle (unlesioned rats). Lesioned (6-OHDA-treated) rats displayed self-biting (SB; 7/20 rats) and self-injurious behavior (SIB; 1/20 rats) during APO priming, but not during footshock priming. During subsequent acute cumulative APO dosing, 20-30% of lesioned rats primed with APO alone or footshock alone displayed SB and SIB. However, SB and SIB incidence in APO+footshock-primed lesioned rats was nearly tripled. Dopamine (DA) synthesis, metabolism and extracellular concentrations (disposition) in unlesioned rats and in cortices of lesioned animals were unaffected by priming. In lesioned rats primed with APO alone or footshock alone, only neostriatal 3-methoxytyramine (3-MT) was significantly increased. However, neostriatal DA and metabolite concentrations (and norepinephrine (NE)) were all significantly elevated in lesioned rats primed with both APO and footshock. These results confirm that neonatal 6-OHDA-induced neostriatal catecholamine depletion can be antagonized by experiential change, suggest that behavioral and neurochemical cross-sensitization between APO and footshock in such rats is unidirectional and support the view that stress can exacerbate the incidence of SIB in LNS. MINOR MESH HEADINGS: Animals,-Newborn; Disease-Models,-Animal; Electroshock-; Injections,-Intraventricular; Lesch-Nyhan-Syndrome-chemically-induced; Lesch-Nyhan-Syndrome-metabolism; Neostriatum-metabolism; Neurotoxins-; Oxidopamine-; Rats-; Rats,-Sprague-Dawley; Self-Injurious-Behavior; Stress-metabolism MAJOR MeSH HEADINGS: *Apomorphine-pharmacology; *Catecholamines-metabolism; *Dopamine-Agonists-pharmacology; *Lesch-Nyhan-Syndrome-psychology; *Neostriatum-drug-effects; *Stress-psychology CHECKTAGS: Animal; Male; Support,-U.S.-Gov't,-P.H.S. PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: POHD26927HDNICHD; RO1HD33896HDNICHD CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 1199-18-4; 58-00-4 NAME OF SUBSTANCE: Catecholamines; Dopamine-Agonists; Neurotoxins; Oxidopamine; Apomorphine MEDLINE ACCESSION NUMBER: 98147968
UPDATE CODE: 9807
Record 5 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model. AUTHOR(S): Van-Keuren-KR; Stodgell-CJ; Schroeder-SR; Tessel-RE ADDRESS OF AUTHOR: Department of Pharmacology, Schiefelbusch Institute for Life Span Studies, School of Pharmacy, University of Kansas, Lawrence 66045-2505, USA. SOURCE (BIBLIOGRAPHIC CITATION): Brain-Res. 1998 Jan 5; 780(1): 56-66 INTERNATIONAL STANDARD SERIAL NUMBER: 0006-8993 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some central DA receptors, FR discrimination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-treated rats depend on the age at which 6-OHDA is administered. MINOR MESH HEADINGS: Apomorphine-pharmacology; Corpus-Striatum-drug-effects; Corpus-Striatum-metabolism; Disease-Models,-Animal; Dopamine-metabolism; Motor-Activity-drug-effects; Neurotoxins-; Parkinson-Disease,-Symptomatic-chemically-induced; Parkinson-Disease,-Symptomatic-psychology; Rats-; Rats,-Sprague-Dawley MAJOR MeSH HEADINGS: *Amphetamine-pharmacology; *Conditioning,-Operant-drug-effects; *Discrimination-Learning-physiology; *Dopamine-Agents-pharmacology; *Oxidopamine-toxicity; *Parkinson-Disease,-Symptomatic-drug-therapy; *Reinforcement-Schedule CHECKTAGS: Animal; Male; Support,-U.S.-Gov't,-P.H.S. PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: POHD26927HDNICHD; RO1HD33896HDNICHD CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 1199-18-4; 300-62-9; 51-61-6; 58-00-4 NAME OF SUBSTANCE: Dopamine-Agents; Neurotoxins; Oxidopamine; Amphetamine; Dopamine; Apomorphine MEDLINE ACCESSION NUMBER: 98156811
UPDATE CODE: 9807
Record 6 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Self-mutilation in the Lesch-Nyhan syndrome: a corporal consciousness problem?--a new hypothesis. AUTHOR(S): Pellicer-F; Buendia-Roldan-I; Pallares-Trujillo-VC ADDRESS OF AUTHOR: Laboratorio de Neurofisiologia, Instituto Mexicano de Psiquiatria, Tlalpan, Mexico DF. SOURCE (BIBLIOGRAPHIC CITATION): Med-Hypotheses. 1998 Jan; 50(1): 43-7 INTERNATIONAL STANDARD SERIAL NUMBER: 0306-9877 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: ENGLAND
ABSTRACT: The Lesch-Nyhan syndrome (LNS) has been extensively studied from the genetic and biochemical point of view. The main characteristic of the syndrome is the self-mutilation feature, which has been poorly studied and understood. We propose a new hypothesis about the self-mutilation physiopathology, which is related to the supersensitivity of the dopaminergic D1 receptors in the neuromatrix found in the cingulum cortex region. The LNS shows an increase of uric acid levels as a result of the deficiency of hypoxanthine phosphoribosyltransferase enzyme. This increase could induce damage to dopaminergic neurons. As a consequence, a decrease in dopamine synthesis during gestation and the early postnatal period could occur, producing a functional dopaminergic denervation of the D1 receptors, located on the prefrontal cortex, specifically in the cingulum bundle projections. This phenomenon could induce a codification disturbance in the 'genetic body' of the neuromatrix, that could be expressed functionally as anosognosia, giving rise to self-mutilation. We suggest that this self-mutilation is a pain consciousness problem. MINOR MESH HEADINGS: Brain-physiopathology; Models,-Neurological; Models,-Psychological; Receptors,-Dopamine-D1-physiology MAJOR MeSH HEADINGS: *Consciousness-physiology; *Lesch-Nyhan-Syndrome-physiopathology; *Lesch-Nyhan-Syndrome-psychology; *Pain-; *Self-Mutilation CHECKTAGS: Human; Support,-Non-U.S.-Gov't PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 0
NAME OF SUBSTANCE: Receptors,-Dopamine-D1 MEDLINE ACCESSION NUMBER: 98147505
UPDATE CODE: 9806
Record 7 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Evaluation of risperidone in the neonatal 6-hydroxydopamine model of Lesch-Nyhan syndrome. AUTHOR(S): Allen-SM; Freeman-JN; Davis-WM ADDRESS OF AUTHOR: Department of Pharmacology and the Research Institute of Pharmacological Sciences, University of Mississippi, University 38677, USA. SOURCE (BIBLIOGRAPHIC CITATION): Pharmacol-Biochem-Behav. 1998 Feb; 59(2): 327-30 INTERNATIONAL STANDARD SERIAL NUMBER: 0091-3057 PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Rats were treated as neonates with 6-hydroxydopamine (6-OHDA) 100 mg free base in 10 microl intracisternally. Upon maturation, animals were injected with L-dopa and placed in photocell cages for monitoring of locomotion, stereotypies, and self-mutilation. Pretreatment with either risperidone or SCH-23390 significantly reduced locomotion and stereotypies. SCH-23390 eliminated L-dopa induced self-mutilation in all subjects, while risperidone eliminated self-mutilation in all but one subject. MINOR MESH HEADINGS: Animals,-Newborn; Behavior,-Animal-drug-effects; Disease-Models,-Animal; Dopamine-Agents-pharmacology; Dose-Response-Relationship,-Drug; Lesch-Nyhan-Syndrome-chemically-induced; Lesch-Nyhan-Syndrome-psychology; Levodopa-pharmacology; Motor-Activity-drug-effects; Rats-; Rats,-Sprague-Dawley; Sch-23390-pharmacology; Self-Mutilation-drug-therapy; Self-Mutilation-psychology MAJOR MeSH HEADINGS: *Dopamine-Antagonists-therapeutic-use; *Lesch-Nyhan-Syndrome-drug-therapy; *Oxidopamine-toxicity; *Risperidone-therapeutic-use; *Sympatholytics-toxicity CHECKTAGS: Animal; Female; Male
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 0; 106266-06-2; 1199-18-4; 87075-17-0 NAME OF SUBSTANCE: Dopamine-Agents; Dopamine-Antagonists; Levodopa; Sympatholytics; Risperidone; Oxidopamine; Sch-23390 MEDLINE ACCESSION NUMBER: 98135844
UPDATE CODE: 9806
Record 8 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: Oral self-mutilation by a 17-month-old child with Lesch-Nyhan syndrome. AUTHOR(S): Rashid-N; Yusuf-H
ADDRESS OF AUTHOR: Department of Oral and Maxillofacial Surgery, North East Lincolnshire NHS Trust, Grimsby, UK. SOURCE (BIBLIOGRAPHIC CITATION): Int-J-Paediatr-Dent. 1997 Jun; 7(2): 115-7 INTERNATIONAL STANDARD SERIAL NUMBER: 0960-7439 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: ENGLAND
ABSTRACT: We report a 17-month-old boy who was a known case of Lesch-Nyhan syndrome and presented with self-inflicted oral ulcerations of his lips and cheeks. He had a normal complement of caries-free deciduous teeth. Initially a conservative approach was planned and a bite plate made, but as a result of poor compliance and persistent ulceration and after consultation with his parents it was decided to extract all deciduous teeth.MINOR MESH HEADINGS: Cheek-injuries; Infant-; Lip-injuries; Occlusal-Splints; Self-Mutilation-complications; Self-Mutilation-therapy; Tooth-Extraction MAJOR MeSH HEADINGS: *Lesch-Nyhan-Syndrome-physiopathology; *Oral-Ulcer-etiology; *Self-Mutilation CHECKTAGS: Case-Report; Human; Male
PUBLICATION TYPE: JOURNAL-ARTICLE
MEDLINE ACCESSION NUMBER: 98185150
UPDATE CODE: 9806
SUBSET: DENTAL
Record 9 of 17 in MEDLINE EXPRESS (R) 1998/01-1998/10
TITLE: [A Japanese family with Lesch-Nyhan syndrome resulting from a new point mutation in hypoxanthine-guanine phosphoribosyltransferase gene] AUTHOR(S): Maruta-K; Ohi-T; Yamada-Y; Goto-H; Ogasawara-N; Matsukura-S ADDRESS OF AUTHOR: National Nichinan Hospital, Miyazaki, Japan. SOURCE (BIBLIOGRAPHIC CITATION): No-To-Shinkei. 1997 Nov; 49(11): 1009-13 INTERNATIONAL STANDARD SERIAL NUMBER: 0006-8969 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: JAPANESE; NON-ENGLISH COUNTRY OF PUBLICATION: JAPAN
ABSTRACT: 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. MINOR MESH HEADINGS: Adolescence-; English-Abstract; Polymerase-Chain-Reaction MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics; *Point-Mutation CHECKTAGS: Case-Report; English-Abstract; Female; Human; Male PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8 NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase MEDLINE ACCESSION NUMBER: 98057814
UPDATE CODE: 9804
Record 10 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: [Renal insufficiency caused by Lesch-Nyhan syndrome] AUTHOR(S): Hikita-M; Hosoya-T; Sakai-O
ADDRESS OF AUTHOR: Department of Internal Medicine (II), Jikei University School of Medicine. SOURCE (BIBLIOGRAPHIC CITATION): Ryoikibetsu-Shokogun-Shirizu. 1997(17 Pt 2): 248-50 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: JAPANESE; NON-ENGLISH COUNTRY OF PUBLICATION: JAPAN
MINOR MESH HEADINGS: Adult-
MAJOR MeSH HEADINGS: *Kidney-Diseases-etiology; *Lesch-Nyhan-Syndrome-complications CHECKTAGS: Female; Human; Male
PUBLICATION TYPE: JOURNAL-ARTICLE; REVIEW; REVIEW,-TUTORIAL MEDLINE ACCESSION NUMBER: 97423966
UPDATE CODE: 9801
Record 11 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: [Xanthine urinary calculus in a patient with Lesch-Nyhan syndrome. Apropos of a case] ORIGINAL TITLE: Calcul urinaire de xanthine chez un patient porteur d'un syndrome de Lesh Nyhan. A propos d'un cas. AUTHOR(S): Volpe-P; Peyrottes-A; Lammle-M; Saquet-D; Choquenet-C ADDRESS OF AUTHOR: Service d'Urologie, Centre Hospitalier Princesse Grace, Monaco. SOURCE (BIBLIOGRAPHIC CITATION): Prog-Urol. 1997 Feb; 7(1): 74-7 INTERNATIONAL STANDARD SERIAL NUMBER: 1166-7087 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: FRENCH; NON-ENGLISH COUNTRY OF PUBLICATION: FRANCE
ABSTRACT: The authors report a case of xanthine stones in a 12-year-old child with Lesh Nyhan syndrome treated by allopurinol at the dose of 10 mg/kg/24 hours. This type of urinary stone is unusual and its structure was confirmed by spectrophotometric analysis. This type of stone, in the context of Lesh Nyhan syndrome, suggests the presence of allopurinol treatment. Discontinuation of this treatment prevents recurrence of xanthine stones. MINOR MESH HEADINGS: Bladder-Calculi-chemistry; Child-; English-Abstract; Enzyme-Inhibitors-analysis; Follow-Up-Studies; Kidney-Calculi-chemistry; Lesch-Nyhan-Syndrome-complications; Oxypurinol-analysis; Spectrophotometry- MAJOR MeSH HEADINGS: *Allopurinol-adverse-effects; *Antimetabolites-adverse-effects; *Bladder-Calculi-etiology; *Kidney-Calculi-etiology; *Lesch-Nyhan-Syndrome-drug-therapy; *Xanthines-analysis CHECKTAGS: Case-Report; English-Abstract; Human; Male PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 2465-59-0; 315-30-0; 69-89-6 NAME OF SUBSTANCE: Antimetabolites; Enzyme-Inhibitors; Xanthines; Oxypurinol; Allopurinol; Xanthine MEDLINE ACCESSION NUMBER: 97231483
UPDATE CODE: 9706
Record 12 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome. AUTHOR(S): Kim-KJ; Yamada-Y; Suzumori-K; Choi-Y; Yang-SW; Cheong-HI; Hwang-YS; Goto-H; Ogasawara-N ADDRESS OF AUTHOR: Department of Pediatrics, Seoul National University, College of Medicine, Korea. SOURCE (BIBLIOGRAPHIC CITATION): J-Korean-Med-Sci. 1997 Aug; 12(4): 332-9 INTERNATIONAL STANDARD SERIAL NUMBER: 1011-8934 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: KOREA
ABSTRACT: Lesch-Nyhan syndrome is caused by the complete deficiency of hypoxanthine guanine phosphoribosyl-transferase (HPRT). By the analysis of genomic DNA and mRNA using the polymerase chain reaction (PCR) technique coupled with direct sequencing, five independent mutations in HPRT genes have been identified in Korean Lesch-Nyhan families. Two novel mutations and three previously reported mutations have been found in five independent families. Heterozygous carriers were detected in all the families, and prenatal diagnosis was carried out in two families. MINOR MESH HEADINGS: Korea-; Pedigree-; Polymerase-Chain-Reaction-methods; Prenatal-Diagnosis-methods; Transcription,-Genetic MAJOR MeSH HEADINGS: *Exons-; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics; *Point-Mutation CHECKTAGS: Case-Report; Human; Male; Support,-Non-U.S.-Gov't PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8 NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase MEDLINE ACCESSION NUMBER: 97434766
UPDATE CODE: 9712
Record 13 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. AUTHOR(S): Nyhan-WL
ADDRESS OF AUTHOR: Department of Pediatrics, University of California, San Diego, La Jolla 92093-0830, USA. SOURCE (BIBLIOGRAPHIC CITATION): J-Inherit-Metab-Dis. 1997 Jun; 20(2): 171-8 INTERNATIONAL STANDARD SERIAL NUMBER: 0141-8955 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: Lesch-Nyhan syndrome was first described over thirty years ago. The original patient was a 4-year-old boy with neurological abnormalities as well as haematuria. Crystals in his urine were identified and confirmed to be uric acid. The massive excretion of this purine led to metabolic studies using isotopically labelled uric acid to study turnover rates. Clues to the site of the enzyme defect resulted from studies with the immunosuppressive agent azathioprine, which normally causes uric acid concentrations to fall in blood and urine but was without effect in a Lesch-Nyhan patient. A deficiency of hypoxanthine phosphoribosyltransferase (HPRT) activity explained this observation in Lesch-Nyhan patients. Subsequent studies have indicated that the degree of HPRT deficiency appears to determine the severity of the disease. Molecular studies have shown that most families carry a unique mutation. Attempts are being made to correlate the type and site of a specific mutation with a particular phenotype.
MINOR MESH HEADINGS: Hypoxanthine-Phosphoribosyltransferase-genetics; Hypoxanthine-Phosphoribosyltransferase-metabolism; Lesch-Nyhan-Syndrome-metabolism; Lesch-Nyhan-Syndrome-physiopathology; Purine-Pyrimidine-Metabolism,-Inborn-Errors-metabolism; Purine-Pyrimidine-Metabolism,-Inborn-Errors-physiopathology MAJOR MeSH HEADINGS: *Lesch-Nyhan-Syndrome-genetics; *Purine-Pyrimidine-Metabolism,-Inborn-Errors-genetics CHECKTAGS: Human; Male
PUBLICATION TYPE: JOURNAL-ARTICLE; REVIEW; REVIEW,-TUTORIAL CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8 NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase MEDLINE ACCESSION NUMBER: 97354994
UPDATE CODE: 9711
Record 14 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: Differential effects of bilateral dopamine depletion in neonatal and adult rats. AUTHOR(S): Moy-SS; Criswell-HE; Breese-GR ADDRESS OF AUTHOR: Department of Anesthesiology, University of North Carolina at Chapel Hill 27599, USA. SOURCE (BIBLIOGRAPHIC CITATION): Neurosci-Biobehav-Rev. 1997 Jul; 21(4): 425-35 INTERNATIONAL STANDARD SERIAL NUMBER: 0149-7634 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Both Lesch-Nyhan syndrome and Parkinson's disease are associated with decreased brain dopamine, yet each disorder is characterized by a different set of motor symptoms. Lesch-Nyhan syndrome is manifested in early childhood, while parkinsonism usually does not appear until adulthood, suggesting that age at the time of dopamine loss is one determinant of the effects of neurotransmitter deficiency. Support for this view is found in studies of animals given dopamine-depleting lesions at different ages and then tested in adulthood. Animals lesioned as neonates show a supersensitivity to dopamine agonists, especially D1-dopamine receptor agonists, and to MK-801, an NMDA receptor antagonist. In addition, neonatally treated animals show a 'priming' effect following repeated exposure to D1-dopamine agonists. Animals depleted of dopamine as adults are more supersensitive to agonists acting on the D2-dopamine receptor, and do not evidence priming to dopamine agonists or an enhanced response to MK-801. These differential pharmacological profiles suggest that the changes in neurotransmitter systems following dopamine depletion are, at least in part, determined by age at the time of the lesion. MINOR MESH HEADINGS: Adult-; Brain-pathology; Brain-Chemistry-drug-effects; Dopamine-Antagonists-pharmacology; Rats- MAJOR MeSH HEADINGS: *Aging-physiology; *Animals,-Newborn-physiology; *Brain-Chemistry-physiology; *Dopamine-physiology CHECKTAGS: Animal; Human
PUBLICATION TYPE: JOURNAL-ARTICLE; REVIEW; REVIEW,-ACADEMIC CAS REGISTRY NUMBER OR EC NUMBER: 0; 51-61-6 NAME OF SUBSTANCE: Dopamine-Antagonists; Dopamine MEDLINE ACCESSION NUMBER: 97339040
UPDATE CODE: 9710
Record 15 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: Use of propofol anesthesia during outpatient radiographic imaging studies in patients with Lesch-Nyhan syndrome. AUTHOR(S): Williams-KS; Hankerson-JG; Ernst-M; Zametkin-A ADDRESS OF AUTHOR: Department of Anesthesiology, Georgetown University at National Institutes of Health, Bethesda, MD 20892-1512, USA. SOURCE (BIBLIOGRAPHIC CITATION): J-Clin-Anesth. 1997 Feb; 9(1): 61-5 INTERNATIONAL STANDARD SERIAL NUMBER: 0952-8180 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan syndrome is a rare, x-linked, recessive disorder of purine metabolism resulting in hyperuricemia, spasticity, choreoathetosis, dystonia, self-injurious behavior, and aggression, without significant cognitive impairment. Anesthetic management of inpatients who demonstrate classic manifestations of Lesch-Nyhan syndrome and require surgical interventions have been described. There are no guidelines in the literature addressing the anesthetic management of the outpatient with Lesch-Nyhan syndrome. Specifically, sudden, unexplained death, abnormalities in respiration, apnea, severe bradycardia, and an increased incidence of vomiting and chronic pulmonary aspiration may preclude this patient population from receiving anesthesia for outpatient procedures. General anesthesia with spontaneous ventilation was performed for diagnostic, radiographic imaging in 11 outpatients with Lesch-Nyhan syndrome using intravenous propofol. A bolus dose of 1.5 to 2.0 mg/kg propofol was followed by maintenance doses of 60 to 160 mcg/kg/min. Results during and following sedation indicated end-tidal carbon dioxide ranges between 34 mmHg and 59 mmHg. Respiratory rates were never below 10 breaths/min and no partial/complete airway obstruction or labored breathing was clinically evident. Hemodynamics were within 30% of presedation values. No patient demonstrated nausea, vomiting, or pulmonary aspiration. Baseline neuropsychologic status was achieved following sedation, and patients were discharged from the hospital 35 to 90 minutes after sedation was completed. Potential risks and benefits of using propofol in this patient population are discussed. MINOR MESH HEADINGS: Adolescence-; Adult-; Ambulatory-Care; Anesthesia-Recovery-Period; Child-; Hemodynamics-; Lesch-Nyhan-Syndrome-radiography; Respiratory-Mechanics-drug-effects; Respiratory-Mechanics-physiology MAJOR MeSH HEADINGS: *Anesthesia,-General; *Anesthetics,-General; *Lesch-Nyhan-Syndrome-physiopathology; *Propofol- CHECKTAGS: Human; Male
PUBLICATION TYPE: CLINICAL-TRIAL; JOURNAL-ARTICLE CAS REGISTRY NUMBER OR EC NUMBER: 0; 2078-54-8 NAME OF SUBSTANCE: Anesthetics,-General; Propofol MEDLINE ACCESSION NUMBER: 97203976
UPDATE CODE: 9707
Record 16 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: Lesch-Nyhan syndrome: clinical diagnosis and confirmation by biochemical and genetic methods [letter] AUTHOR(S): Erhard-U; Herkenrath-P; Benz-Bohm-G; Querfeld-U SOURCE (BIBLIOGRAPHIC CITATION): Pediatr-Nephrol. 1997 Feb; 11(1): 124-5 INTERNATIONAL STANDARD SERIAL NUMBER: 0931-041X PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: GERMANY
MINOR MESH HEADINGS: Fibroblasts-enzymology; Infant-; Kidney-ultrasonography; Lesch-Nyhan-Syndrome-metabolism MAJOR MeSH HEADINGS: *Lesch-Nyhan-Syndrome-diagnosis; *Lesch-Nyhan-Syndrome-genetics CHECKTAGS: Case-Report; Human; Male
PUBLICATION TYPE: LETTER
MEDLINE ACCESSION NUMBER: 97187733
UPDATE CODE: 9707
Record 17 of 17 in MEDLINE EXPRESS (R) 1997
TITLE: Kinetic mechanism of human hypoxanthine-guanine phosphoribosyltransferase: rapid phosphoribosyl transfer chemistry. AUTHOR(S): Xu-Y; Eads-J; Sacchettini-JC; Grubmeyer-C ADDRESS OF AUTHOR: Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. SOURCE (BIBLIOGRAPHIC CITATION): Biochemistry. 1997 Mar 25; 36(12): 3700-12 INTERNATIONAL STANDARD SERIAL NUMBER: 0006-2960 PUBLICATION YEAR: 1997
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) is the locus of Lesch-Nyhan syndrome, the activator of the prodrugs 6-mercaptopurine and allopurinol, and a target for antiparasitic chemotherapy. The three-dimensional structure of the recombinant human enzyme in complex with GMP has recently been solved [Eads, J., Scapin, G., Xu, Y., Grubmeyer, C., & Sacchettini, J. C. (1994) Cell 78, 325-334]. Here, ligand binding, pre-steady state kinetics, isotope trapping, and isotope exchange experiments are presented which detail the sequential kinetic mechanism of the enzyme. In the forward reaction, in which a base (hypoxanthine or guanine) reacts with PRPP to form nucleoside monophosphate and PPi, binding of PRPP precedes that of the base, and in the reverse direction, IMP binds first. Compared to k(cat), phosphoribosyl group transfer is rapid in both the forward (131 vs 6.0 s(-1)) and reverse (9 vs 0.17 s(-1)) directions. In the forward direction, product pyrophosphate dissociates rapidly (> 12 s(-1)) followed by release of IMP (6.0 s(-1)). In the reverse direction, Hx dissociates rapidly (9.5 s(-1)) and PRPP dissociates slowly (0.24 s(-1)). The more rapid rate of utilization of guanine than hypoxanthine in the forward reaction is the result of the faster release of product GMP rather than the result of differences in the rate of the chemical step. The kinetic mechanism, with rapid chemistry and slow product dissociation, accounts for the previously observed ability of the alternative product guanine to stimulate, rather than inhibit, the pyrophosphorolysis of IMP. The overall equilibrium for the hypoxanthine phosphoribosyl transfer reaction lies far toward nucleotide product (Keq approximately 1.6 x 10(5)), at the high end for PRPP-linked nucleotide formation. The three-dimensional structure of the HGPRTase x IMP complex has been solved to 2.4 A resolution and is isomorphous with the GMP complex. The results of the ligand binding and kinetic studies are discussed in light of the structural data. MINOR MESH HEADINGS: Guanine-metabolism; Hypoxanthine-metabolism; Inosine-Monophosphate-metabolism; Kinetics-; Models,-Chemical; Models,-Molecular; Protein-Conformation; Recombinant-Proteins-metabolism; 5'-Guanylic-Acid-metabolism MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-metabolism; *Phosphoribosyl-Pyrophosphate-metabolism CHECKTAGS: Human; Support,-U.S.-Gov't,-P.H.S. PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: GM52125GMNIGMS CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 0; 131-99-7; 68-94-0; 73-40-5; 7540-64-9; 85-32-5 NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; Recombinant-Proteins; Inosine-Monophosphate; Hypoxanthine; Guanine; Phosphoribosyl-Pyrophosphate; 5'-Guanylic-Acid MEDLINE ACCESSION NUMBER: 97238573
UPDATE CODE: 9707