Dopa-responsive dystonia (DRD) was first discovered by Segawa et al. in 1972 [1]. It is a progressive primary dystonia characterized by onset during childhood, marked diurnal fluctuation and a dramatic and long-term response to low doses of levodopa [2]. Mostly, defects in the GTP cyclohydrolase 1 (GCH1) gene and the tyrosine hydroxylase (TH) gene have been attributed to the pathogenesis of DRD [3]. The characteristics of low CSF homovanillic acid (HVA) levels with low HVA/5-hydroxyindolacetic acid (5-HIAA) ratio were discovered in DRD patients [4]. In our previous study, we found that the clinical phenotypes of patients in one pedigree may be different with the same mutation in one family.

A reported heterozygous mutation of GCH1 (c.550C>T) was detected in a family [5]. The age of onset of affected patients ranged from 13 to 60 years. Treatment with levodopa results in clinical improvement. However, the dose of levodopa varied from 50 mg twice daily to 100 mg twice daily. The mother of the affected patients was still normal at age 80, who carried the same mutation. The same feature had been reported in previous paper [6-8].

In another family, the father/daughter pair carrying the IVS2- 2A>G GCH1 mutation showed different phenotypes [9]. The daughter was diagnosed at age 8 with the symptom of dystonia. She presented excellent response to dopaminergic medications. However, her father was normal before the age of 53, Clinical examination showed asymmetrical bradykinesia, hypomimia, slow gait and poor postural reflexes, actually, more like parkinsonism. He preferred taking L-dopa (100 mg, twice daily), amantadine (100 mg, twice daily) and selegiline (5 mg, daily) to completely control symptoms. The patient was the only one who carried parkinsonian symptoms in our study of DRD patients, which supported the point of view that some GCH1 coding variants or mutation, like Q110X, V204I, might be associated with Parkinson’s disease (PD) [10].

Here, we show that the clinical phenotypes of DRD patients might be nonspecific. Old age and the symptom of parkinsonism should not be excluded, even with a negative family history. There are a number of issues worth considering. First, why the symptom varied for patients with the same mutation? It might be that apart from the exons, noncoding regions, promotor system, microRNA and other factors may all contributed to this disease [11-13]. Second, is GCH1 related to PD? Previous studies from Taiwan revealed parkinsonian features were common to DRD in 1996. Later, Shang et al. reported 5 of 16 DRD patients developed parkinsonism symptoms. However, in 2014, it was shown that the frequency of GCH1 variants was significantly higher in PD cases than in controls by Mencacci et al. (1% and 0.75%, p=0.0001). The authors also presented 4 patients with different GCH1 mutations fully met the Criteria for definite PD [10]. In 2015, Wang et al. reported a family with a novel GCH1 variant displayed different phenotypes of PD and DRD. In addition, it was also demonstrated that GCH1 rs11158026 increased the risk of developing PD [14]. Whether parkinsonism is an atypical symptom of DRD or GCH1 is a gene responsible for PD?

In further studies, we should do more research on non-coding regions of GCH1 gene to explain some phenotype variation, thus provide some strategies for new treatment. More GCH1 screening should be done in subjects with parkinsonism. And apart from gene test, cerebrospinal fluid (CSF) detection and Dopamine transporter imaging are also recommended to help differentiate between PD and DRD [10,15].

The authors acknowledge the patients and their families for their important help in data acquisition and the Cancer Institute of Zhejiang University for technical assistance and advice. This work was supported by grants from the National Natural Science Foundation of China (No. 81570698) and (No.81200984), the Natural Science Foundation of Zhejiang Province (LY16H070003).