Clinical And Genetic Analysis Of Twelve Cases Of Dopa-Responsive Dystonia

ObjectiveDopa-responsive dystonia (DRD) is a set of dystonic disorder characterized by clinical and genetic heterogeneity, childhood or adolescence-onset dystonia with marked diurnal fluctuation, aggravation of symptoms toward evening and their alleviation in the morning after sleep, and a dramatic and sustained response to relatively low doses of levodopa. Dopa-responsive dystonia is mostly caused by mutations in the GCH-1gene and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARKIN gene which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. Since clinical manifestations and genetic mutations of Dopa-responsive dystonia are complex and various, its diagnosis is relatively difficult. Raising the level of understanding, diagnosis and treatment of the disease has vital significance to patients.In our research,we summarized the clinical features and gene mutations of12cases of Dopa-responsive dystonia, in order to investigate the genotype-phenotype correlations in our series of patients and to evaluate the relative frequency of the mutations of the above genes.Methods1.According to the diagnosis criteria of Dopa-responsive dystonia proposed by Nygaard,8DRD patients from two DRD families and4sporadic DRD patients from August2007to March2013in the Department of Neurology, Qilu Hospital of Shandong University were enrolled in the study.2.A total of12DRD patients and6asymptomatic immediate family members was screened for mutation in GCH-1gene using PCR and DNA direct sequencing. Those who didn’t harbor GCH-1gene mutation were screened for mutation in TH gene, SPR gene and PARKIN gene in turn.Results1. Three kinds of mutations in GCH-1gene were checked out, including c.631632delAT, c.316A>C and c.239G>A. c.631632delAT and c.239G>A were mutations which could cause DRD previously reported, c.316A>C was a novel mutation. We also found one known Polymorphisms of TH gene(c.321G>A) and one known Polymorphisms of PARKIN gene(c.450G>A) which has been proved to represent a genetic risk factor for development of early-onset sporadic PD.2. After the gene tests,11patients were still diagnosed as DRD, but1patient was considered to be suffering from Parkinson’s disease.3. There were more women than men in our series, and the ratio was about2:1. The onset age of the11DRD patients range from less than1year old to40years old, and the average onset age was14.4+11.7years old. There were8childhood-onset and3adult-onset DRD patients in our series.4. Clinical heterogeneity were found in11DRD patients. The clinical symptoms varied inter-and intra-families. Family1and sporadic patient1and2belong to action dystonia type, while Family2and sporadic patient4belong to postural dystonia type.5. Symptoms of9DRD patients and1Parkinson’s disease patient were markedly remitted by low doses of Madopar without dyskinesia. Conclusions1. Clinical heterogeneity is an important characteristic of DRD and clinical symptoms varied inter-and intra-families. While the hall mark of DRD is a dramatic and sustained response to relatively low doses of levodopa.2. Dopa-responsive dystonia is mostly caused by mutations in the GCH-1gene and more rarely by mutations in the TH or SPR genes.3. No significant correlations were found between the genotype and phenotype of DRD patients.4. It is relatively difficult to distinguish DRD and Juvenile Parkinsonism caused by mutations in PARKIN gene.