Abstract | BACKGROUND: 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 recognised 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. METHODS: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. RESULTS AND CONCLUSIONS: 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 young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson 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. The study also describes 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). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.
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Authors | I Trender-Gerhard, M G Sweeney, P Schwingenschuh, P Mir, M J Edwards, A Gerhard, J M Polke, M G Hanna, M B Davis, N W Wood, K P Bhatia |
Journal | Journal of neurology, neurosurgery, and psychiatry
(J Neurol Neurosurg Psychiatry)
Vol. 80
Issue 8
Pg. 839-45
(Aug 2009)
ISSN: 1468-330X [Electronic] England |
PMID | 19332422
(Publication Type: Journal Article)
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Chemical References |
- Dopamine Agents
- Hormones
- Levodopa
- GTP Cyclohydrolase
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Topics |
- Adolescent
- Adult
- Age of Onset
- Aged
- Aged, 80 and over
- Cohort Studies
- Comorbidity
- Disease Progression
- Dopamine Agents
(therapeutic use)
- Dystonia
(drug therapy, genetics, psychology)
- Female
- GTP Cyclohydrolase
(genetics)
- Hormones
(blood)
- Humans
- Levodopa
(therapeutic use)
- Long-Term Care
- Male
- Mental Disorders
(etiology, psychology)
- Middle Aged
- Mutation
(genetics)
- Treatment Outcome
- Young Adult
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