Abstract
Dopa-responsive dystonia (DRD), a movement disorder, is characterized by young onset dystonia and dramatic response to levodopa treatment. However, the wide range of phenotypic spectrum of the disease often leads to misdiagnosis. DRD is usually caused by mutation in GCH1 gene coding for GTP cyclohydrolase 1 (GTPCH1) enzyme, which is involved in biosynthesis of tetrahydrobiopterin (BH4) and dopamine. In this study, the entire GCH1 gene was screened in 14 Indian DRD patients and their family members. A family was identified where the proband was found to be a compound heterozygote for GCH1 (p.R184H and p.V204I) variants; the former variant being inherited from the father and the latter from the mother. All other family members harboring one of these GCH1 variants were asymptomatic except for one (heterozygous for p.R184H) who was diagnosed with DRD. In silico analyses predicted these two variants to be pathogenic and disruptive to GCH1enzymatic activity. This proband was misdiagnosed as cerebral palsy and remained untreated for 25 years. He developed retrograde movements and gait problems in lower limbs, deformity in upper limbs, and difficulty in swallowing, and became mute. However, most of his symptoms were alleviated upon levodopa administration. Our study confirms the variability of DRD phenotype and the reduced penetrance of GCH1 mutations. It also emphasizes the need of molecular diagnostic test and L-dopa trial especially for those with atypical DRD phenotype.
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Acknowledgments
Authors are thankful to the patients and the family members for participating in this study. Authors are also thankful to Dr. Arindam Biswas for his technical help with MLPA assay and Dr. Pabitradeb Mukherjee for initial clinical analysis of the index patient. SG was supported by INSPIRE fellowship provided by Department of Science & Technology, Govt. of India. TN and GD were supported by fellowships from Council of Scientific & Industrial Research (CSIR), Govt. of India.
Funding
The study was supported partially by grants from University Grant Commission [grant no. F.14-38/2007(Inno./ASIST)], Council of Scientific and Industrial Research (CSIR) (grant no. MLP-0016 and SIP-007), Department of Science and Technology [(DST-PURSE) and (DST-CSI) to JR], Govt. of India.
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Subhajit Giri and Tufan Naiya are joint first author.
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Giri, S., Naiya, T., Roy, S. et al. A Compound Heterozygote for GCH1 Mutation Represents a Case of Atypical Dopa-Responsive Dystonia. J Mol Neurosci 68, 214–220 (2019). https://doi.org/10.1007/s12031-019-01301-3
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DOI: https://doi.org/10.1007/s12031-019-01301-3