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

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.

• 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)

Chemical References

• Dopamine Agents
• Hormones
• Levodopa
• GTP Cyclohydrolase

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