Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lesch-Nyhan syndrome (LN) is a severe X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HRT). Clinical features displayed by affected boys are particularly severe and disturbing and include hyperuricaemia, Characteristic neurological features including self-mutilation, choreothetosis, spasticity and mental retardation. A couple with a boy diagnosed with LN and a history of pregnancy termination was referred to the Hammersmith Hospital. Their affected son was born in 1982 after an uncomplicated pregnancy and vaginal delivery. Eight subsequent pregnancies had been unsuccessful. There were five therapeutic terminations and three spontaneous abortions, one at least directly caused by the sampling procedure during amniocentesis. From 1989 to 1991 two unsuccessful preimplantation genetic diagnosis (PGD) cycles by sexing were performed by DNA amplification. The mutation was characterized and a nested PCR protocol was designed which allowed the efficient amplification of the affected loci followed by the detection of the mutant allele by restriction digestion. Three PGD cycles were performed using this specific diagnostic test before a successful pregnancy was achieved resulting in the birth of a healthy unaffected baby girl.
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PMID:Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specific diagnosis. 1069 59

Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.
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PMID:An unexpected affected female patient in a classical Lesch-Nyhan family. 1076 82

Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter.
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PMID:Dopamine function in Lesch-Nyhan disease. 1085 37

The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) catalyzes the reutilization of hypoxanthine and guanine to the purine nucleotides IMP and GMP, respectively. HPRT deficiency is an X-linked disorder characterized by uric acid overproduction and variable neurologic impairment. The complete deficiency of HPRT is diagnostic of Lesch-Nyhan syndrome manifested by choreoathetosis, spasticity, mental retardation, and self-injurious behavior. In some HPRT-deficient patients the enzyme defect appeared to be "partial" and the neurologic symptoms mild to severe (Kelley-Seegmiller syndrome). This has prompted the classification of HPRT deficiency in 2 distinct groups: Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome, which has created much confusion. A spectrum of clinical consequences of HPRT deficiency has been recognized in small series of patients, but the complete spectrum of the neurologic disorder has not been described in a single series of patients examined by the same observers. We analyzed our experience with 22 patients belonging to 18 different families with HPRT deficiency diagnosed at "La Paz" University Hospital in Madrid over the past 16 years. The clinical spectrum of these HPRT-deficient Spanish patients was similar to the different phenotypes occasionally reported in the literature, in some cases diagnosed as Lesch-Nyhan "variants." The clinical, biochemical, enzymatic, and molecular genetic studies on these 22 patients allowed us to delineate a new classification of HPRT deficiency. Based on the neurologic symptoms, dependency for personal care, HPRT activity in hemolysate and in intact erythrocytes, and predicted protein size, patients were classified into 4 groups: Group 1 (2 patients), normal development with no neurologic symptoms, HPRT activity was detectable in hemolysates and in intact erythrocytes, and the mutation did not affect the predicted protein size. Group 2 (3 patients) mild neurologic symptoms that did not prevent independent lives, HPRT activity was detectable in intact erythrocytes, and the protein size was normal. Group 3 (2 patients), severe neurologic impairment that precluded an independent life, no residual HPRT activity, and normal protein size. Group 4 (15 patients), clinical characteristics of Lesch-Nyhan syndrome (some may not show self-injurious behavior), no residual HPRT activity, and in most (7 of 8 patients in whom the mutation could be detected) the mutation affected the predicted protein size. This classification of HPRT deficiency into 4 groups may be more useful in terms of accuracy, reproducibility, assessment for treatment trials and prognosis. The study of this Spanish series allows us to conclude that HPRT deficiency may be manifested by a wide spectrum of neurologic symptoms; the overall severity of the disease is associated with mutations permitting some degree of residual enzyme activity; and mutation analysis provides a valuable tool for prognosis, carrier identification, and prenatal diagnosis.
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PMID:The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. 1130 86

Lesch-Nyhan syndrome (LNS) is an X-linked hereditary disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. Patients with this syndrome are characterized by hyperuricemia, self-mutilation, developmental retardation, and movement disorders such as spasticity and dystonia. The authors performed bilateral chronic stimulation of the globus pallidus internus for control of dystonic movements in a 19-year-old man with LNS. His self-mutilating behavior unexpectedly disappeared after chronic stimulation. This is the first case of LNS that has been successfully treated with deep brain stimulation. The findings indicate that neurobehavioral features of this syndrome are either mediated in the basal ganglia pathways or secondary to the dystonia.
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PMID:Disappearance of self-mutilating behavior in a patient with lesch-nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. 1259 32

Lesch-Nyhan syndrome (LN) is a severe X-linked disorder of males characterized by hyperuricaemia, choreoathetosis, spasticity, mental retardation and self-mutilation. The disorder is caused by a wide spectrum of mutations distributed throughout the hypoxanthine phosphoribosyltransferase (HPRT) gene. Female carriers of LN display no clinical symptoms but are at 50% risk of passing on the affected gene to their male offspring. A couple who had a boy with LN were referred to Monash IVF for preimplantation genetic diagnosis (PGD) because the woman had undergone tubal ligation and the couple wanted to have another child. A test was developed for the causative mutation IVS8+6 T-->G mutation based on minisequencing primer extension that also incorporated the co-analysis of an informative tetranucleotide marker in intron 3 of the HPRT gene to identify allelic dropout. All four biopsied embryos from their first IVF cycle were diagnosed as unaffected, and transfer of two embryos in the cohort with the highest morphological quality resulted in a singleton pregnancy and the birth of a healthy girl. Direct mutation detection by mini-sequencing and parallel analysis of an informative linked marker provides an alternative strategy for molecular diagnosis of point mutations that will have useful application in PGD for other single gene disorders.
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PMID:Preimplantation diagnosis of Lesch-Nyhan using mini-sequencing primer extension. 1465 97

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.
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PMID:The biochemical basis of the neurobehavioral abnormalities in the Lesch-Nyhan syndrome: a hypothesis. 1519 65

Lesch-Nyhan syndrome (LSN, McKusick 300322) is an X-linked genetic disease due, in its typical form, to the complete absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) enzyme activity. It is characterized by hyperuricaemia, leading to gout and kidney stones, accompanied by severe neurological dysfunction with self-injurious behaviour, choreoathetosis and spasticity. Based on a worldwide birth incidence estimate of about 1:380000, one or two new cases are expected every year in Italy. We performed biochemical and molecular genetic studies on 28 Italian patients from 25 families who are likely to represent most living individuals with the syndrome in the country. They all had absent HPRT activity and a typical LNS phenotype. Genetic analysis identified 24 HPRT mutations, 9 of which had not been previously reported: 74C>G (P25R), IVS2+1G>C, 194-195delTC, 329-332delCAAC insTCTs, IVS9-1G>A, 506insC, IVS8-1G>C, 606G>T (L202F), 418G>C (G140R). No mutation hotspots were identified. Only two mutations were found in more than one family, indicating the lack of any major mutation causing LNS in Italy. Three mutations arose de novo , two in the proband's mother, one in the maternal grandmother. The virtual complete absence of HPRT activity was related to deletions, nonsense, or missense mutations leading to nonconservative amino acid changes.
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PMID:Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in Italian Lesch-Nyhan patients: identification of nine novel mutations. 1550 82

The first description of Lesch-Nyhan disease was in 1964; the first two patients were seen in 1963. The disease has caught the imagination of a variety of clinicians and scientists. The clinical picture is striking, combining spasticity, involuntary movements, and cognitive retardation with self-injurious behavior and the manifestations of gout. Biochemically, the overproduction of uric acid--the end product of purine metabolism--was, when measured, the largest ever seen. The disease is now well understood on a molecular basis. Enzyme analysis and mutational analysis have made available a full range of genetic testing, including diagnosis, carrier detection, and prenatal diagnosis. Therapy with allopurinol has been effective for those manifestations the disease shares with gout. Treatment for the neurological and behavioral features of the disease remains elusive.
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PMID:Lesch-Nyhan Disease. 1580 53

Lesch-Nyhan syndrome (LNS), first described in 1964 by Lesch and Nyhan, is a rare X-linked genetic disorder involving (near) absence of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT). It occurs in 1:100,000 to 380,000 live births (1, 2). The deficiency of HPRT activity leads to an excessive uric acid production resulting in neurological, renal and musculoskeletal manifestations. Death usually occurs in the second or third decade from infection or renal failure. Clinical presentation is characterized by mental retardation, choreoathetosis, spasticity, hyperuricemia and cerebral palsy. A characteristic feature of LNS is the appearance of intractable self-injurious behaviour (SIB), usually in the form of severe lip and finger biting, gouging of eyes, face scratching and head banging requiring extreme management techniques such as the application of restraints and or extraction of teeth at an early age. In this case report a unique approach of SIB in LNS is presented.
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PMID:Self-mutilation behaviour in Lesch-Nyhan syndrome. 1613 97


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