GCH1 mutation and clinical study of Chinese patients with dopa‐responsive dystonia

Abstract

Dopa-responsive dystonia (DRD) is typically caused by heterozygous mutations in GTP cyclohydrolase 1 gene (GCH1). Our aim was to investigate the clinical and genetic features of Chinese DRD patients. We analyzed a cohort of Chinese DRD patients' clinical data. Mutation of the GCH1 gene was screened by direct sequencing. Additionally, multiplex ligation-dependent probe amplification (MLPA) assay targeting the GCH1 and the TH gene to evaluate large exon deletion or duplicate mutation of the genes were performed in point mutation-negative patients. Ten sporadic DRD patients and two pedigrees including six patients were included in the study. The onset age ranged from 3 to 15 years old. All patients initially presented with walking problems due to lower limb dystonia. The delay between onset and diagnosis ranged from 1 to 42 years old. The symptoms were completely or near-completely abolished with low dose levodopa treatment (dosages ranged from 25 mg to 400 mg/day). Direct sequencing in 14 patients found two known mutations (Gly203Arg in exon 5 in four unrelated patients and Met102Lys in exon 1 in one patient) and one new mutation (Thr186Ile mutation in exon 5 in two unrelated pedigrees). A heterozygous exon 2 deletion in the GCH1 gene was found in one of three point mutation-negative patients by MLPA analysis. Our clinical findings in DRD patients were consistent with other studies. GCH1 gene mutations were quite common in Chinese patients. MPLA should be performed in routine deletion analysis of GCH1 in point mutation-negative DRD patients.

Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

“…This may suggest that the exonic deletion has a higher penetrance. In contrast to the familial cases found in the Taiwanese study, only one heterozygous exonic deletion was reported in one of ten sporadic Han Chinese patients (Liu et al, 2010). This case accounted for 6.25% (1/16) of the total patients in the study, which is similar to our finding.…”

“…In addition, most of the deletions of GCH1 identified in previous studies comprised the entire gene (Furukawa et al, 2000;Hagenah et al, 2005;Steinberger et al, 2007;Zirn et al, 2008) or were multi-exonic (Klein et al, 2002;Hagenah et al, 2005;Steinberger et al, 2007;Wu-Chou et al, 2010), but few were single-exon deletions [exon 1 (Klein et al, 2002); exon 2 (Liu et al, 2010)]. In our study, we found the third reported single-exon deletion of the GCH1 gene in patients with DRD.…”

Two novel mutations of the GTP cyclohydrolase 1 gene and genotype–phenotype correlation in Chinese Dopa-responsive dystonia patients

“…[9][10][11][12][13] All patients in this analysis met the diagnosis criteria for DRD. 14 Each mutation was classified as a (1) missense mutation; (2) exon-intron boundary variant, that is, a variant located in an exon-intron boundary region; (3) large deletion,which can be deleted only by multiple ligation-dependent probe amplification analysis; or (4) small deletion, which can be detected only by direct sequencing.…”

“…[9][10][11][12][13] To extent these studies to China and increase the clinical value of phenotype-genotype analysis of DRD patients, in the present study, we screened GCH1 mutations in two families containing members newly diagnosed with DRD. We also conducted phenotype-genotype correlation analysis on the largest cohort of Chinese DRD patients to date, comprising all patients previously reported.…”

Adult‐Onset Alcohol Suppressible Cervical Dystonia: A Case Report

“…4 This genotype has been reported previously in association with dystonia and parkinsonism. 5 Interestingly, this mutation 1 Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom; 2 Department of Neurology, Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom has also previously been reported by Leuzzi et al, 6 who describe a childhood-onset myoclonus dystonia-like syndrome resulting from GCH1 mutations, with other family members having adult-onset upper-limb tremor. They do not, however, describe alcohol sensitivity.…”