Dopa-Responsive Dystonia and Tourette Syndrome in a Large Danish Family

Romstad, Anne; Dupont, E.; Krag-Olsen, B; Østergaard, Karen; Guldberg, Per; Güttler, Flemming

doi:10.1001/archneur.60.4.618

Cited by 31 publications

(17 citation statements)

References 34 publications

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“…A wide range of neurological features in individuals with identical mutations in the GCH1 gene is a well documented characteristic of this disease [19,22,24]. Our study further confirms this clinical variability.…”

Section: Discussionsupporting

confidence: 85%

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Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

et al. 2009

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Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations/deletions in the GCH1 gene. The finding of the mutation Q89X in the GCH1 gene in 23 patients from two pedigrees in an area inhabited by a population of 800,000 prompted us to consider that our cohort may have descended from a single founder. Twelve Q89X mutation-positive cases belonging to two families and 100 unrelated control subjects from the same geographical region were studied. Six microsatellite markers located near GCH1 were analyzed to validate a possible mutation-related founder haplotype. Haplotype analysis revealed two different haplotypes for six microsatellite markers that segregated with the Q89X mutation. A common haplotype in 10 out of 12 mutation carriers studied was identified. Two subjects carried a second haplotype, most probably because of a recombination event. However, at least 186 different haplotypes were established in the control subjects. In contrast with the frequencies of 83.3% and 16.7%, respectively, found for both mutation-segregating haplotypes, the frequency of none of the control haplotypes exceeded 1.5%. Dystonia was the most frequent symptom in our series, and parkinsonism was present in five patients. The large number of Q89X mutation carriers in our community is because of a founder effect. The same mutation in GCH1 causes a wide phenotypic spectrum of clinical variability occurring in this population of affected patients.

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Section: Discussionsupporting

confidence: 85%

“…We have not however, found this effect in our series, as other authors have also previously described [19,24].…”

Section: Discussioncontrasting

confidence: 65%

Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

et al. 2009

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“…Mutation analysis of the gene for GTP cyclohydrolase (GCH1) was completed using denaturing gradient gel electrophoresis (DGGE) followed by sequencing. 16 In families A and B, deletion analysis of the GCH1 gene was performed using a quantitative duplex PCR assay on the LightCycler (Roche Diagnostics, Mannheim, Germany) with an internal standard for each exon. 17 For linkage analysis at the locus of the GCH1 gene at position 53,290,900 to 53,360,000, CA repeats D14S984 at position 48,087,470, D14S978 at 49,903,270, and D14S276 at 53,673,110 on chromosome 14 were amplified by PCR, using the primer sequences available in the Human Genome Database.…”

Section: Methodsmentioning

confidence: 99%

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

Hove¹

2006

Journal of Neurology, Neurosurgery & Psychiatry

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Background: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by L-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. Objective: To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. Methods: GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. Results: Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to L-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. Conclusion: Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.

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“…Given the pleiotropic effects Abbreviations: BH4, tetrahydrobiopterin; NO, nitric oxide; NOS, nitric oxide synthase; GTP-CH1, guanosine triphosphate cyclohydrolase 1; DRD, DOPA-responsive dystonia; hph-1, hyperphenylalaninemia 1; WT, wild-type; hph, homozygous hph-1; DOPAC, deuterium-labelled 3,4-dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hydroxytryptophan; HVA, homovanillic acid; VMA, Vanillylmandelic acid; DHBA, dihydroxybenzylamine; DA, dopamine; 5-HT, serotonin; NA, noradrenaline; MHPG, 3-methoxy-4-hydroxyphenylglycol; EZM, elevated zero maze; SAP, stretched-attend posture; MB, marble burying; TST, tailsuspension test; FST, forced swim test; ANOVA, analysis of variance; SEM, standard error of the mean; EPM, elevated plus maze. disorder characterised by dystonia-related gait problems (Romstad et al, 2003). Besides this classical clinical manifestation, studies report increased prevalence of anxiety and major depression in DRD patients (Hahn et al, 2001;Van Hove et al, 2006;TrenderGerhard et al, 2009;Tadic et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin

Nasser

Møller

Olesen

et al. 2014

Neuroscience Research

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Dopa-Responsive Dystonia and Tourette Syndrome in a Large Danish Family

Abstract: This study confirms the large variability in DRD symptoms and emphasizes the usefulness of molecular analysis for diagnosis and treatment of DRD. The presence of TS is suggested to be coincidental, though the development of TS-like symptoms due to mutations in GCH1 cannot be excluded.

Cited by 31 publications

References 34 publications

Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

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

Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin

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