Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency

Hove, Johan L.K. Van

doi:10.1136/jnnp.2004.051664

Cited by 101 publications

(92 citation statements)

References 35 publications

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“…Fluctuations in response, increased dose requirements, or long-term adverse effects such as the "on-off" phenomenon have not been described 4,12,[19][20][21] . The detection of the specifi c mutation is important to confi rm the diagnosis, and to provide accurate treatment and genetic counseling to the patients and their family.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Scola

Carducci

Amaral

et al. 2007

Arq. Neuro-Psiquiatr.

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-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.KEY WORDS: dystonia, levodopa, dopa-responsive dystonia, guanosine triphosphate cyclohydrolase 1, GCH1 gene. Novo padrão de mutação missense no gene GCH1 na distonia dopa-responsivaRESUMO -Distonia dopa-responsiva (DRD), classificada como DYT5, é um erro inato do metabolismo que pode ser causado por dois diferentes tipos de defeito bioquímico: deficiência de GTP ciclo-hidrolase 1 (GCH1) (autossômica dominante) ou de tirosina hidroxilase (autossômica recessiva). Descrevemos o caso de menina de 10 anos com distonia generalizada progressiva e alteração da marcha com importante melhora após uso de levodopa. A relação fenilalanina/tirosina estava aumentada após teste de sobrecarga com fenilalanina. O estudo molecular mostrou que o paciente apresenta uma combinação hererozigótica de mutação no gene GCH1: a já conhecida mutação P23L e uma nova mutação Q182E. Discutem-se as características da DRD e as alterações genéticas possíveis.

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Section: Discussionmentioning

confidence: 99%

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Scola

Carducci

Amaral

et al. 2007

Arq. Neuro-Psiquiatr.

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“…Also, our patients did not complain of significant sleep difficulties, as reported in prior studies. 31 We identified a novel mutation in this DRD kindred, a 54.1 kb deletion in GCH1, spanning exons 3 to 6. The deletion may be explained by the presence of repetitive sequence elements, non-long terminal repeats retro-transposons, which we found to flank the deleted region.…”

Section: Discussionmentioning

confidence: 99%

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Wider¹,

Melquist²,

Hauf³

et al. 2008

Neurology

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Objective-To repor the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD).Methods-Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis.Results-We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset doparesponsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.Conclusions-This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis. Dopa-responsive dystonia (DRD) is a rare disorder characterized by childhood-onset fluctuating foot dystonia, which later generalizes and becomes associated with tremor and parkinsonism. 1-3 Response to small doses of levodopa is dramatic. In its classic form, also Although close to 100 mutations have been described in GCH1, 6 comprehensive screening fails to identify the responsible mutation in 40 to 50% of the families. 7 Recently, families have been described with heterozygous exonic deletions in GCH1, which were not detected by conventional screening techniques. 8-11In this study, we report more comprehensive clinical and genetic investigations of a multigenerational DRD family, in which a previous study had found linkage to a novel locus nominated DYT14 on chromosome 14q13, adjacent to the DYT5 locus. 12 Expanded data allowed us to exclude DYT14, and to identify a novel deletion in GCH1 as the disease-causing mutation in this family. METHODS Genealogy and clinical evaluationsInformation on the pedigree was collected by means of historical material, family records, and medical charts review, along with interviews with elderly family members.The project was approved by the local ethics committee. After signing an informed consent, subjects underwent a detailed videotaped neurologic evaluation. A clinical diagnosis of definite DRD was established in pa...

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“…Motor complications of L-dopa treatment, seen in Parkinson’s disease, rarely develop. Association with anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [3]. …”

Section: Dopa-responsive Dystonia (Drd)mentioning

confidence: 99%

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

Casper

Kalliolia²,

Warner³

2013

Current Neuropharmacology

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The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.

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Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency

Cited by 101 publications

References 35 publications

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

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