GTP Cyclohydrolase I and Tyrosine Hydroxylase Gene Mutations in Familial and Sporadic Dopa-Responsive Dystonia Patients

Chunyou Cai,Wei-Dong Li,Zheng Zeng,Chao Ling,Chunquan Cai,Lei Chen,Benshu Zhang,Wentao Shi,Meiyun Zhang

doi:10.1371/journal.pone.0065215

Abstract

Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases. We used PCR to sequence all exons and splicing sites of the GCH1 and TH genes. Three novel heterozygous GCH1 mutations (Tyr75Cys, Ala98Val, and Ile135Thr) were identified in three DRD pedigrees. We failed to identify any GCH1 or TH mutation in two affected sisters. Three symptom-free male GCH1 mutation carriers were found in two DRD pedigrees. For those DRD siblings that shared the same GCH1 mutation, symptoms and age of onset varied. In 10 sporadic cases, only two heterozygous TH mutations (Ser19Cys and Gly397Arg) were found in two subjects with unknown pathogenicity. No GCH1 and TH mutation was found in 40 unrelated normal Han Chinese controls. GCH1 mutation is the main etiology of familial DRD. Three novel GCH1 mutations were identified in this study. Genetic heterogeneity and incomplete penetrance were quite common in DRD patients, especially in sporadic cases. Genetic screening may help establish the diagnosis of DRD; however, a negative GCH1 and TH mutation test would not exclude the diagnosis.

Highlights

Dopa-responsive dystonia (DRD), known as Segawa’s syndrome, was first reported in 1976 [1]
In family 10 (Figure 1B), we found a mutation in exon 2 (37449T.C) that resulted in an isoleucine/threonine transition at codon 135
Since GCH1mutations were first found in DRD pedigrees [5], more than 100 GCH1 mutations have been identified in DRD patients [13]

Summary

Introduction

Dopa-responsive dystonia (DRD), known as Segawa’s syndrome, was first reported in 1976 [1]. The clinical manifestations of DRD include postural or motor disturbances, generalized or focal dystonia, abnormal gait, and sometimes tremor or writing disturbance[2,3,4]. A significant therapeutic response to levodopa is a diagnostic hallmark of DRD. Treatment with levodopa results in significantly clinical improvement in almost all the patients with GCH1 mutations, response of levodopa treatment in some patients with TH mutations was limited [7,8]. Given the rare incidence of DRD (1 in 106), it is difficult to explore genotype-phenotype correlations in patients. The disease is rare, genetic heterogeneity is quite common in DRD, as well as in other dopamine pathway disorders

Methods

Results

Conclusion