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)

The Lesch-Nyhan syndrome results from a complete or virtually complete deficiency of the purine salvage enzyme, hypoxanthine guanine phosphoribosyl transferase (HPRT). The disease is characterized by hyperuricemia, choreoathetosis, spasticity, compulsive self-mutilation, and mental retardation. Patients with a partial deficiency of HPRT are spared most of the neurological disorder of Lesch-Nyhan syndrome. The specific relationship between HPRT deficiency and the neurological dysfunction in the Lesch-Nyhan syndrome is not known, at present. The genetic lesion which result in HPRT deficiency are heterogeneous. About 90 different mutations were found in over 110 families. The DNA-based mutation detection technique can be used for the diagnosis of affected males and for the determination of carrier status of asymptomatic females. This technique is also applicable for the prenatal diagnosis for Lesch-Nyhan syndrome. Transgenic mice, deficient in HPRT activity, have been obtained but they do not show any neurological dysfunction. After administration of 9-ethyladenine, however, they showed the self-injury behavior.
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PMID:[Complete and partial deficiency of HPRT]. 897 12

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.
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PMID:Use of propofol anesthesia during outpatient radiographic imaging studies in patients with Lesch-Nyhan syndrome. 905 48

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

Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs between 6 and 18 months of age and is probably linked to changes in metabolic demand caused by normal maturational changes and superimposed catabolic stress. Recognition of this biochemical disorder before the brain has been injured is essential to outcome. Diagnosis depends upon the recognition of relatively non-specific physical findings such as hypotonia, irritability and macrocephaly, and on performance of urine organic acid quantification by gas chromatography--mass spectrometry or selective searches of urine or blood specimens by tandem mass spectrometry for glutarylcarnitine. The diagnosis may also be suggested by characteristic findings on neuroimaging. In selected patients diagnosis can only be reached by enzyme assay. Specific current management by the authors of this paper includes pharmacological doses of L-carnitine, as well as dietary protein restriction. Metabolic decompensation must be treated aggressively to avoid permanent brain damage. Multicentre studies are needed to establish best methods of diagnosis and optimal therapy of this disorder.
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PMID:Diagnosis and management of glutaric aciduria type I. 970 May 90

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.
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PMID:Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. 1040 75

A variety of cerebral insults can result in static encephalopathy with developmental delays and relatively fixed motor and cognitive deficits. We describe two boys with static encephalopathy who experienced recurrent episodes of generalized, violent ballism seemingly provoked by relatively minor infectious illnesses or surgical procedures. These episodes first began at ages 14 and 9 years, respectively. The baseline clinical states included relatively mild choreoathetosis plus cognitive impairment, as well as spasticity and/or ataxia. These episodes of ballism developed over hours, remained for weeks, and ultimately returned to baseline. Neuroleptics, anticonvulsants, and benzodiazepines were only partially beneficial; responses corresponded to the degree of sedation. Potential for self-injury or rhabdomyolysis/myoglobinuria led to the use of general anesthetics or neuromuscular blocking agents during selected episodes. Blood, urine, and cerebrospinal fluid studies, magnetic resonance imaging head scans, and electroencephalography revealed no diagnostic clues as to the precise causative factor precipitating these episodes.
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PMID:Violent recurrent ballism associated with infections in two children with static encephalopathy. 1083 Apr 25

Paroxysmal dyskinesias are genetically and clinically heterogeneous. Paroxysmal kinesigenic choreoathetosis is frequently familial, with autosomal-dominant transmission. Benign infantile convulsions can be observed in these families and both diseases as linked to the pericentromeric region of chromosome 16. Two different forms of paroxysmal dystonic choreoathetosis are distinguished on clinical grounds, by the presence or absence of spasticity, and genetically, as they are linked with loci on different chromosomes. Among the paroxysmal disorders, these diseases may belong to the group of channelopathies.
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PMID:Paroxysmal dyskinesias as a paradigm of paroxysmal movement disorders. 1097 65

We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy. Magnetic resonance imaging showed decreased intensity in the globus pallidus, substantia nigra, and dentate nuclei in T2-weighted images, supporting the clinical diagnosis of neurodegeneration with brain iron accumulation type 1 (NBIA-1; formerly known as Hallervorden-Spatz syndrome). At autopsy the brain showed mild frontotemporal atrophy and discoloration of the globus pallidus and the substantia nigra pars reticularis. Histologically, features typical of NBIA-1 were found including widespread axonal spheroids and large deposits of iron pigment in the discolored regions. Additionally, excessive numbers of Lewy bodies (LBs) were found throughout all examined brain stem and cortical regions. LBs of both types, as well as Lewy neurites in this case of NBIA-1, were strongly labeled by antibodies against alpha-synuclein. These findings give further evidence that accumulation of alpha-synuclein is generally associated with LB formation, i.e., in Parkinson's disease, dementia with Lewy bodies and NBIA-1. The case presented here is particularly notable for its high number of LBs in all areas of the cerebral cortex.
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PMID:Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. 1104 80

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

We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.
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PMID:Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. 1131 Jun 26


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