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Dopa-responsive dystonia in Bulgarian patients: report of three cases

European Journal of Human Genetics (2023)Cite this article

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Dopa-responsive dystonia (DRD) comprises a group of rare autosomal inherited neurotransmitter disorders characterized with childhood or adulthood onset. We report three cases of DRD. Two boys (1.5-year-old and 1.3-year-old) were diagnosed with TH deficiency and found to have compound heterozygous missense variants in the TH gene. For the first patient p.Arg202His and the p.Leu205Pro in the TH gene, were reported. In the second patient were revealed p.Thr373Met and p.Arg202His variants in the same gene. The third patient, a 10-years old boy was diagnosed with GCH1 deficiency due to heterozygous pathogenic variant (p.Lys224Arg) in the GCH1 gene. The diagnosis of DRD was determined by whole exome sequencing (Patient 1) and whole genome sequencing (Patients 2 and 3). Here, we describe the first two patients with TH deficiency in Bulgaria and one with GCH1 deficiency. We also review the molecular mechanism of the disorder and summarized the reported pathogenic or likely pathogenic variants in the TH and GCH1 genes. The disorder has broad clinical and genetic heterogeneity which is often misdiagnosed. Our aim is to improve awareness for the DRD, especially in Bulgaria because early diagnosis is essential for the better prognosis and therapy outcome.

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Fig. 1: The precursors of dopamine and serotonin are synthesized from tyrosine and tryptophan by the enzyme tyrosine and tryptophan hydroxylase.

Data availability

The dataset analyzed during the current study are publicly available in ClinVar database. Also, may be available from the corresponding author following an application to and with approval from the local ethics committee.

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Author notes

  1. These authors contributed equally: Maya Atanasoska, Radoslava Vazharova.

Authors and Affiliations

  1. GMDL “CellGenetics”, Sofia, Bulgaria

    Maya Atanasoska, Radoslava Vazharova, Irena Bradinova, Slavyana Yaneva Staykova, Lubomir Balabanski, Daniela Mircheva & Draga Toncheva

  2. Department of Genetics, Faculty of Biology, Sofia University St Kliment Ohridski, Sofia, Bulgaria

    Maya Atanasoska

  3. Department of Biology, Medical genetics and Microbiology, Faculty of Medicine, Sofia University St Kliment Ohridski, Sofia, Bulgaria

    Radoslava Vazharova

  4. Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia

    Galina Stevanović

  5. National Genetic Laboratory, UHOG “Maichin dom” Sofia, Sofia, Bulgaria

    Irena Bradinova

  6. Department of Clinical Genetics, University Pediatric Hospital, Medical University, Sofia, Bulgaria

    Daniela Avdjieva-Tzavella

  7. Bulgarian Academy of Science, Sofia, Bulgaria

    Draga Toncheva

Authors
  1. Maya Atanasoska
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Contributions

MA, RV, GS and DT have made a substantial contribution to the concept or design of the article; analysis, or interpretation of data for the article. GS, IB, SYS, LB, DM, DATz and DT revised the manuscript and approved the final version.

Corresponding authors

Correspondence to Maya Atanasoska or Radoslava Vazharova.

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The authors declare no competing interests.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. All patients participated voluntarily. The participants provided written informed consent to participate in this study.

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Atanasoska, M., Vazharova, R., Stevanović, G. et al. Dopa-responsive dystonia in Bulgarian patients: report of three cases. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01370-4

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