GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness

Robinson, Richard O.; McCarthy, Gillian; Bandmann, Oliver; Dobbie, Michael S.; Surtees, Robert; Wood, Nicholas W.

doi:10.1136/jnnp.66.1.86

Cited by 46 publications

(23 citation statements)

References 12 publications

(9 reference statements)

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“…This variability indicates that other factors, be they environmental or other modifying genes, influence the expression of symptoms. 31 In this study, the frequency of major depressive disorder, particularly recurrent major depressive disorder, and of obsessive-compulsive disorders was clearly increased above the population frequency. However, this study may underestimate the frequency of psychiatric morbidity since several asymptomatic patients were less than 20 years of age, and psychiatric symptoms tended to have onset after 20 years of age (fig 3).…”

Section: Discussionmentioning

confidence: 42%

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

Hove¹

2006

Journal of Neurology, Neurosurgery & Psychiatry

101

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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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Section: Discussionmentioning

confidence: 42%

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

Hove¹

2006

Journal of Neurology, Neurosurgery & Psychiatry

101

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“…Two siblings (18.1 and 18.2) with initial hypotonia followed by the most severe phenotype of DRD with marked delay in motor development have been reported previously showing the Lys224Arg mutation 17 24. We now report that both patients are compound heterozygotes for GCH1 mutations.…”

Section: Resultsmentioning

confidence: 55%

Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients

Trender-Gerhard

Sweeney²,

Schwingenschuh

et al. 2009

Journal of Neurology, Neurosurgery & Psychiatry

163

138

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267Manuscript (excluding references, tables and figure legends): 3671References: 36Number of tables: 3 3 ABSTRACT An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower limb dystonia, diurnal fluctuations, and excellent response to levodopa has been well recognized in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow up of genetically proven cases. We present a detailed clinical evaluation of 34 patients (19 women, 15 men) with confirmed mutations in the GCH1 gene. We found that the classic phenotype was most frequent (n=23), with female predominance (F:M=16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a youngonset (mean 6.8 years) mild DRD variant not requiring treatment (n=4), or with an adult-onset (mean 37 years) Parkinson's disease-like phenotype (n=4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. We also describe a number of supplementary features including restless legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder, and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). We report that levodopa was used effectively and safely in 20 pregnancies, and did not cause any foetal abnormalities.

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“…Partial or lack of response to levodopa, however, and side effects like drug-induced dyskinesias have also been reported [3,5,9,18]. In our series, two patients belonging to Family 1 (III4 and III7) developed dyskinesias at the beginning of the treatment with low doses of levodopa.…”

Section: Discussionmentioning

confidence: 59%

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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GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness

Cited by 46 publications

References 12 publications

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

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

Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients

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

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