Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of glutaric aciduria, a recently discovered inborn error of tryptophan-lysine metabolism, is reported. Development was normal during the first year of life. Signs of dyskinesia and dystonia associated with developmental regression occurred twice during gastrointestinal disease. By two years of age, a dystonic syndrome with a severe motor and language disability had resulted.
 ...
PMID:Intermittently progressive dyskinetic syndrome in glutaric aciduria. 57 37

Glutaric aciduria is a disorcer of lysine, tryptophan, and hydroxylysine metabolism characterized by intermittent metabolic acidemia, dystonia, athetosis and mental retardation. It is due to a recessively inherited deficiency of glutaryl-CoA dehydrogeanse, the enzyme(s) which catalyze the dehydrogenation of glutaryl-CoA to glutaconyl-CoA and decarboxylation of the latter to crotonyl-CoA. Abnormal quantities of glutaric, beta-hydroxyglutaric, and glutaconic acids are found in the urine of these patients. The nature of the movement disorder prompted study of the effects of the abnormally excreted metabolites on brain glutamate decarboxylase, an enzyme implicated in the pathogenesis of Huntington's chorea. Glutamate decarboxylase activity was examined in rat and rabbit brain acetone powders, stabilized with pyridoxal phosphate and glutathione. Glutarate, beta-hydroxyglutarate, and glutaconate were competitive inhibitors of this emzyme, Ki values being 1.3 X 10(-3) mol/l, 2.5 X 10(-4) mol/l, respectively. This inhibition may explain the neurological accompaniments of this syndrome.
 ...
PMID:Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and beta-hydroxyglutarate: explanation of the symptoms in glutaric aciduria? 124 44

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson's disease, tardive dyskinesia, akathisia, dystonia, Huntington's disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette's syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.
 ...
PMID:L-tryptophan in neuropsychiatric disorders: a review. 130 30

In a male infant with macrocephaly and dystonic cerebral palsy glutaric aciduria type I was detected by analysis of urine for organic acids. Glutaric aciduria type I is an inherited metabolic disorder of organic acids due to a defect of glutaryl-CoA-dehydrogenase in the intermediate metabolic step of lysine and tryptophan degradation. In the urine glutaric acid is usually accompanied by 3-hydroxy-glutaric acid in abnormal quantities. The enzyme defect in our patient was proved in cultured fibroblasts. In the cerebral computer tomography marked atrophy of bilateral frontotemporal regions could be demonstrated. The amount of urinary glutarat excretion decreased after protein but especially after lysine and tryptophan restriction in the diet. The administration of carnitine improved carnitine levels in blood and urine. Although the progression of neurological impairment could be stopped, dystonia and dyskinesis remained nearly unaltered. In spite of severe motor retardation, recognition and vocalisation were established. In the two year old patient mental retardation is relatively mild comparing with motor retardation. The administration of 100 or 200 mg Riboflavin/day was stopped, as it did not alter clinical symptoms or excretion of glutarat. Baclofen, an analogue of gamma-amino-butyric acid, was orally given (2 mg/kg/day) and improved dystonia, but did not influence organic aciduria. The neurological manifestations may be due in part to inhibition of neuronal glutamat decarboxylase by glutaric acid with decreased gamma-amino-butyric acid biosynthesis. The characteristic clinical symptoms with macrocephaly and dystonia and the very typical pattern of organic acids in urine are a challenge for rapid diagnosis and therapy.
 ...
PMID:[Macrocephaly and dystonic cerebral palsy in a child with type I glutaric aciduria]. 194 71

A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-indoleacetic acid concentration was less than or equal to 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two-fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; however, trihexyphenidyl (1-2 mg/kg/day) dramatically improved it. Hartnup disease should be considered in children with unexplained dystonia.
 ...
PMID:Intermittent dystonia in Hartnup disease. 271 44

The pteridine cofactor of tyrosine and tryptophan hydroxylases, tetrahydrobiopterin (BH4), is concentrated in the striatum and other sites of brain monoamine synthesis and is a regulatory factor in the rate-limiting step of catecholamine synthesis. CSF content was decreased in eight patients with dystonic disorders (mean, 13.0 +/- 0.8 pmol/ml CSF compared with 20.6 +/- 1.4 in age-matched normals). We gave several trials of synthetic BH4 intravenously to 10 dystonic patients with benefit for 2 subjects with diurnally fluctuating dystonia, 1 with hemidystonia and parkinsonism, and 1 with generalized torsion dystonia. The findings of biopterin abnormality and the observed clinical improvements may point to a role for the cofactor in the pathogenesis and, possibly, the treatment of some forms of primary dystonia.
 ...
PMID:Tetrahydrobiopterin in dystonia: identification of abnormal metabolism and therapeutic trials. 370 82

Glutaric aciduria type I (GA-I) is an inborn error in the degradation of lysine, hydroxylysine, and tryptophan due to a deficiency of glutaryl-CoA dehydrogenase. Glutaric, 3-OH-glutaric, and glutaconic acids are excreted in the urine, particularly during intercurrent illness. The enzyme may be assayed in leukocytes, cultured fibroblasts and chorionic villi. Twelve new cases, 9 months-16 years of age, are reported, comprising all known cases of GA-I in Sweden and Norway. Ten had a severe dystonic-dyskinetic disorder, one had a mild hyperkinetic disorder, and one was asymptomatic. Two children died in a state of hyperthermia. Carnitine deficiency and malnutrition developed in patients with severe dystonia and dysphagia, which necessitated substitution and gastrostomy. A slowly progressive dyskinetic disorder developed in spite of adequate early dietary treatment in one subject. Macrocephaly was found in three. Computed tomography and magnetic resonance investigations in 10 showed deep bitemporal spaces in 7. Neuropsychological testing of 8 of 12 subjects demonstrated receptive language function to be superior to expressive language and motor function. Cognitive functions were obviously less affected than motor functions. A review of 57 pooled cases showed that a severe dystonic syndrome developed in 77%, a mild extrapyramidal syndrome in 10%, and 12% were asymptomatic. This disorder may pass undetected in the cerebral palsy and mentally retarded child and adult populations. Repeated urine examinations of organic acids in the urine and enzyme assay may be necessary to confirm GA-I.
 ...
PMID:Dystonia and dyskinesia in glutaric aciduria type I: clinical heterogeneity and therapeutic considerations. 813 2

Serial trans-fontanellar sonographic examination in a patient with glutaric aciduria type I (GA I) demonstrated that the typical frontotemporal cerebral atrophy developed postnatally within three months paralleling the onset of dystonic symptoms. Pathogenesis of the accompanying macrocephaly remains unclear and can form a diagnostic pitfall. Diet low in lysine and tryptophan led to a dramatic fall in urinary glutaric acid (GA) excretion but as in other patients with GA I did not substantially influence clinical symptoms and course. We determined unchanged levels of GA in plasma and cerebrospinal fluid resulting from variable renal tubular secretion and reabsorption of GA. Monitoring urinary excretion of GA appears inappropriate to control dietary treatment in GA I. Substitutive correction of secondary carnitine depletion seems to protect from deleterious metabolic crises. Treatment with valproic acid resulted in a rise of GABA-concentration in cerebrospinal fluid but did not ameliorate clinical symptoms. This finding is in contrast with the hypothesis that inhibition of cerebral GABA-synthesis by GA is responsible for the development of dystonia in GA 1. Although we observed impressing fluctuation of dystonic symptoms, levodopa did not show therapeutic effects. The extreme variability in the severity of neurologic disease in metabolically identical individuals leads to a "two-hit"-hypothesis.
 ...
PMID:[Development of brain atrophy, therapy and therapy monitoring in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency)]. 844 49

We measured homovanillic acid (HVA), 5-hydroxy indole acetic acid (5-HIAA), and tryptophan (TP) in cerebrospinal fluid (CSF) of 20 neuroleptic-free patients with Huntington's disease (HD), and compared mean values with those from four control groups including 15 normal individuals, 38 patients with dystonia, 23 untreated patients with Parkinson's disease, and 61 patients with other neurological diseases (ONDs). The mean levels of HVA in the CSF of patients with HD were reduced compared with those from normal controls (p < 0.001), dystonic patients (p < 0.005), individuals with ONDs (p < 0.0001), and even from untreated parkinsonian patients (p < 0.05). 5-HIAA and TP levels in the CSF of patients with HD were not significantly different from those in the CSF of control patients. Our data suggest a reduced dopamine neurotransmission in HD and may account for the bradykinesia observed in our patients.
 ...
PMID:Cerebrospinal fluid homovanillic acid is reduced in untreated Huntington's disease. 866 35

Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
 ...
PMID:Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. 1032 73


1 2 3 4 Next >>