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

Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon I of the GTP-CH I gene and a new mutation at the splice acceptor site of intron I were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.
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PMID:GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia. 861 46

We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.
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PMID:Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. 956 61

Dopa-responsive dystonia, an autosomal-dominant disorder caused by mutations in the guanosine triphosphate (GTP)-cyclohydrolase I gene, is characterized by severe striatal dopamine depletion. Tardive dyskinesia, on the other hand, has often been associated with striatal dopamine overactivity. This article reports on a 44-year-old man with dopa-responsive dystonia who developed tardive dyskinesia on long-term haloperidol therapy. Nigrostriatal dopamine deficiency may be necessary for the development of tardive dyskinesia.
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PMID:Tardive dyskinesia in dopa-responsive dystonia: a reappraisal of the dopamine hypothesis of tardive dyskinesia. 956 61

A 26 year old woman with dopa responsive dystonia and cytogenetically confirmed Turner's syndrome had bilateral globus pallidus hypointensity on brain MRI. Among the living members of a five generation pedigree the patient's mother and the mother's sister also had dopa responsive dystonia; a maternal grandfather had senile parkinsonism, his niece isolated postural tremor. No other family member had Turner's syndrome. A new missense mutation in exon I of the gene of GTP-cyclohydrolase I was found in the three family members with dopa responsive dystonia. With levodopa substitution the patients with dopa responsive dystonia improved clinically as well as in quantitative tests on hand tapping, verbal and performance IQ, concept formation, and set shifting abilities.
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PMID:Dopa responsive dystonia with Turner's syndrome: clinical, genetic, and neuropsychological studies in a family with a new mutation in the GTP-cyclohydrolase I gene. 964 18

Mutations in the GTP-cyclohydrolase I (GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.
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PMID:Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. 966 88

The development of autosomal dominant DOPA-responsive dystonia (AD-DRD) is stipulated by mutation in GTP-cyclohydrolase I gene. GTP-cyclohydrolase I is the first and key enzyme of tetrahydrobiopterin biosynthesis. Its deficiency in nigrostriatal dopaminergic neurons cause a decrease in tyrosine hydroxylase activity and therefore dopamine deficiency. However, administration of low doses of dopamine can control the development of AD-DRD. Determination of GTP-cyclohydrolase I activity in mononuclear blood cells is convenient diagnostic method.
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PMID:[Autosomal-dominant DOPA-responsive dystonia, caused by mutations in the GTP-cyclohydrolase I gene]. 970 21

Reduction of biopterin (BP) due to a mutation in the GTP-cyclohydrolase I gene causes hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). To determine whether an age-related BP decline may contribute to HPD/DRD onset (from 1 to 13 years of age), we measured brain BP levels in 57 normal subjects ranging in age from 1 day to 92 years. Putaminal BP showed a significant increase in postnatal period, reaching a plateau at 1 to 13 years of age, and a decrease in adulthood. The HPD/DRD onset in childhood is unlikely to be caused by a brain BP decline during the first decade of life, but that in adulthood could be related to the age-dependent decrease.
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PMID:Influence of development and aging on brain biopterin: implications for dopa-responsive dystonia onset. 971 58

We have studied the GTP-cyclohydrolase 1 (GCH-1) gene in 30 patients with the diagnosis of clinically definite (n = 20) or possible (n = 10) dopa-responsive dystonia (DRD) as well as in a child with atypical phenylketonuria due to complete GCH-1 deficiency. A large number of new heterozygote mutations (seven point mutations, two splice site mutations, and one deletion) as well as a new homozygote mutation in the child with atypical phenylketonuria were detected. In addition, two previously described mutations were found in two other cases. We further extended our investigation of GCH-1 to the 5' and 3' regulatory regions and report the first detection of point mutations in the 5' untranslated region. Demethylation of CpG islands does not appear to be an important causative factor for the GCH-1 mutations in DRD. In addition, we have extended the clinical phenotype of genetically proven DRD to focal dystonia, dystonia with relapsing and remitting course, and DRD with onset in the first week of life. None of our DRD patients without a mutation in GCH-1 had the 3-bp deletion recently detected in DYT1, the causative gene for idiopathic torsion dystonia with linkage to 9q34.
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PMID:Dopa-responsive dystonia: a clinical and molecular genetic study. 977 64

Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.
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PMID:Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? 1082 51

Mutations of the guanosine triphosphate (GTP)-cyclohydrolase I (GCH-I) gene, which catalyzes the first step in the tetrahydrobiopterin (the natural cofactor for tyrosine hydroxylase) biosynthesis, are demonstrated to cause HPD, i.e. strictly defined dopa-responsive dystonia. We analyzed the GCH-I gene of patients who fulfilled clinical criteria for typical hereditary progressive dystonia (HPD) to finalize the diagnosis. Two novel point mutations in two independent families and one novel de novo point mutation in one sporadic patient were identified. In a Japanese family, a T-to-C transition was found at exon 2, which resulted in a substitution of Cys 141 to Arg. In another Japanese family, a C-to-T mutation in exon 4 caused a nonsense codon Gln180Stop. In a clinically sporadic Japanese patient, T-to-G transition in exon 1 brought Met 102 Arg missense mutation, which was not observed in its biological parents. These three mutations were not observed in previously reported 57 pedigrees/patients and no polymorphisms in the coding region of the GCH-I gene were identified. None of the mutations of GCH-I gene in HPD reported to date or in this study have been detected more than once in any ethnicity suggesting a relatively high spontaneous mutation rate in this gene.
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PMID:Gene mutation in hereditary progressive dystonia with marked diurnal fluctuation (HPD), strictly defined dopa-responsive dystonia. 1098 68


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