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)

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.
 ...
PMID:Diagnosis and treatment of neurotransmitter disorders. 1703 64

Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes, i.e. the aromatic amino acid hydroxylases (AAHs). The reactions catalyzed by these enzymes are important for biomedicine and their mutant forms in humans are associated with phenylketonuria (phenylalanine hydroxylase), Parkinson's disease and DOPA-responsive dystonia (tyrosine hydroxylase), and possibly neuropsychiatric and gastrointestinal disorders (tryptophan hydroxylase 1 and 2). We attempt to rationalize current knowledge about substrate and inhibitor specificity based on the three-dimensional structures of the enzymes and their complexes with substrates, cofactors and inhibitors. In addition, further insights on the selectivity and affinity determinants for ligand binding in the AAHs were obtained from molecular interaction field (MIF) analysis. We applied this computational structural approach to a rational analysis of structural differences at the active sites of the enzymes, a strategy that can help in the design of novel selective ligands for each AAH.
 ...
PMID:Selectivity and affinity determinants for ligand binding to the aromatic amino acid hydroxylases. 1730 46

AMPT (alpha-methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. In clinical settings, AMPT is approved to treat pheochromocytoma. Dystonias and dyskinesias seem to have their origin in inconsistent regulation of dopamine function in dopamine pathways. This paper presents case histories of the clinical efficacy of AMPT for treating certain individuals with neuroleptic-induced dystonia or dyskinesia. The authors propose that a special utility of AMPT in tardive disorders may be related to a downregulation of tyrosine hydroxylase activity that may be increased by neuroleptic-induced effects on tyrosine hydroxylase phosphorylation.
 ...
PMID:Low dose alpha-methyl-para-tyrosine (AMPT) in the treatment of dystonia and dyskinesia. 1730 29

Dopa-responsive dystonia (DRD) is a rare, autosomal dominant (GTP-cyclohydroxylase gen mutation on chromosome 14q) or rarely recessive (tyrosine hydroxylase gene mutation on chromosome 11p) inherited disorder. Both enzymes take part in dopamine synthesis. Their deficiencies cause the dopamine level reduction. The first clinical symptoms occur in the childhood. The authors present the case of a 24-year-old woman in whom the lower limb dystonia occurred when she was five. Then the trunk and upper limbs dystonia appeared with skeleton deformities leading to deep disability. DRD was recognized when she was 19 and L-Dopa was administered. The clinical status improved, dystonic movements disappeared completely. The authors indicate that DRD must be taken into account in differential diagnosis of movement disorders in children, mostly in progressive cases. Good effect of L-Dopa treatment is one of the basic phenomena helpful in DRD recognition.
 ...
PMID:[Dopa-responsive dystonia (Segawa syndrome) with secondary skeleton deformity]. 1733 36

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to relatively low doses of levodopa. There are at least three causative genes for DRD: 1) the GCH1 gene on chromosome 14q22.1-q22.2, coding for the enzyme GTP cyclohydrolase I (GTPCH) that catalyzes the rate-limiting step in the tetrahydrobiopterin (BH4; the cofactor for tyrosine hydroxylase [TH]) biosynthesis, 2) the TH gene on 11p15.5, and 3) an as yet undefined gene on 14q13 (DYT14). In our series, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD (the major form of DRD) is caused not only by decreased TH activity resulting from a low cofactor level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum (especially in the putamen) may be due to a diminished regulatory effect of BH4 on stability of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum.
 ...
PMID:[Dopa-responsive dystonia]. 1743 76

Tyrosine hydroxylase deficiency, a cause of the autosomal recessive form of L-DOPA responsive dystonia, has been associated with a broad spectrum of movement disorders and clinical courses. We describe a new patient presenting with an early onset spastic paraplegia who later developed a progressive generalized dystonic-dyskinetic syndrome. He markedly improved with a very low dosage of L-DOPA/carbidopa, while higher dosages were not tolerated. Two novel mutations (p.G414R/p.L510Q) were detected in the TH gene.
 ...
PMID:Tyrosine hydroxylase deficiency presenting with a biphasic clinical course. 1805 33

Segawa disease was first reported in 1971 as 'Hereditary progressive basal ganglia disease with marked diurnal fluctuation'. In 1976, after experience of a 51 year old patient with 43 years non-treatment periods, I confirmed this disease as dystonia. Polysomnographies revealed selective involvement of the dopamine (DA) neuron without involvement of the D2 receptors. These were confirmed by PET studies performed early 90's. The clinical course of this adult patient was correlated to the age variation of the activities of tyrosine hydroxylase (TH) in the striatum and suggested non-progressive decrease of TH at the terminal of the nigrostriatal DA neuron. Histochemical studies confirmed selective involvement of the D1-direct pathways without any pathological changes. In 1990, Fujita and Shintaku suggested the deficiency of the GTP cyclohydrolase I (GCH-I) as the cause of this disease. In 1993, Ichinose and his colleagues clarified the gene of GCH-I as the causative gene. After the discovery of the gene, it is realized that Segawa disease has two clinical types, postural dystonia and action dystonia. The latter with involvement of the DA neuron innervating to the subthalamic nucleus with D1 receptor has focal or segmental dystonia or adult onset cases and provides phenotypical variation.
 ...
PMID:[Japanese originality, clinical symptoms to the causative gene 1 Segawa disease]. 1821 Jul 86

The first report of Segawa disease was a report of two girls, cousin each other, with dystonic posture, under the title of "Hereditary progressive basal ganglia disorder" in 1971. After accumulation of cases with an adult case, I confirmed this disease does not transform to Parkinson's disease in adulthood and published with a nomenclature of "Hereditary progressive dystonia with marked diurnal fluctuation" in 1976. Polysomnographical examination for evaluating the sleep effects and correlation of the natural course to the age variation of the tyrosine hydroxylase activities in the striatum, these speculated this is a particular disorder caused by non-progressive decrement of the tyrosine hydroxylase at the terminal of the nigrostriatal dopamine neuron. This was supported by PET studies in early 1990's. Evaluation of pteridine metabolites in cerebrospinal fluid revealed partial decrement of the GTP cyclohydrolase I as the cause of this disease and induced the discovery of the causative gene. After the discovery of the gene, an autopsied case with dopa-responsive dystonia was confirmed as Segawa disease and the neuropathological and histochemical findings confirmed the hypothesis. Furthermore, these showed rather selective involvement the D1-direct pathways in the disease. However, it was also clarified existence of two types, one, classic type, postural dystonia and the other action dystonia with vigorous dystonic movements besides dystonic posture, which, is postulated to be caused by the dopamine neuron innervating to the subthalamic nucleus with D1 neuron. Existence of these two phenotypes also provides phenotypical variation of Segawa disease.
 ...
PMID:[Segawa disease]. 1823 27

Dopa-responsive dystonia (DRD) is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 (GCH1) deficiency or autosomal recessive tyrosine hydroxylase deficiency. We report the case of a 10-years-old girl with progressive generalized dystonia and gait disorder who presented dramatic response to levodopa. The phenylalanine to tyrosine ratio was significantly higher after phenylalanine loading test. This condition had two different heterozygous mutations in the GCH1 gene: the previously reported P23L mutation and a new Q182E mutation. The characteristics of the DRD and the molecular genetic findings are discussed.
 ...
PMID:A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia. 1834 35

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of catecholamine neurotransmitters. Primary inherited defects in TH have been associated with l-DOPA responsive and non-responsive dystonia and infantile parkinsonism. In this study, we show that both the cofactor (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) and the feedback inhibitor and catecholamine product dopamine increase the kinetic stability of human TH isoform 1 in vitro. Activity measurements and synthesis of the enzyme by in vitro transcription-translation revealed a complex regulation by the cofactor including both enzyme inactivation and conformational stabilization. Oral BH(4) supplementation to mice increased TH activity and protein levels in brain extracts, while the Th-mRNA level was not affected. All together our results indicate that the molecular mechanisms for the stabilization are a primary folding-aid effect of BH(4) and a secondary effect by increased synthesis and binding of catecholamine ligands. Our results also establish that orally administered BH(4) crosses the blood-brain barrier and therapeutic regimes based on BH(4) supplementation should thus consider the effect on TH. Furthermore, BH(4) supplementation arises as a putative therapeutic agent in the treatment of brain disorders associated with TH misfolding, such as for the human TH isoform 1 mutation L205P.
 ...
PMID:Tetrahydrobiopterin shows chaperone activity for tyrosine hydroxylase. 1841 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>