Objective: To assess clinical spectrum of genetic forms of dystonia (GD) in a cohort of Russian patients with non-focal dystonia.

Background: Dystonia is the third most common movement disorder¹. GD constitutes a large part of all dystonia patients ². Because of its vast clinical and genetic heterogeneity, molecular diagnosis often remains unknown³. With the development and increasing availability of MPS methods, spectrum of genes associated with GD has grown considerably.

Method: A total of 22 patients with primary non-focal dystonia were included in this study (6 males, 16 females). Of all patients six had a family history of dystonia, in all of these pedigrees autosomal-dominant mode of inheritance could be traced. All patients underwent an extensive neurological examination. 15 patients were tested using the original targeted MPS panel (genes associated with isolated, combined and complex dystonia). In 7 cases other methods of molecular diagnostics were applied (WES/WGS/single gene sequencing). Pathogenicity of found variants was evaluated in accordance with the ACMG guidelines.

Results: The mean age of onset was 20 years. Genetic cause was established in 11 out of 22 patients (50%). Our study found pathogenic and likely pathogenic variants in the well-known dystonia genes (GCH1, THAP1, ATP1A3, KMT2B, SGCE), as well as in the candidate gene COL6A3 (n=1). 7 patients with isolated dystonia had classic GD forms: DYT-GCH1 (n=1), DYT-THAP1 (n=2), DYT-ATP1A3 (n=3), DYT-KMT2B (n=1). Patient with DYT-GCH1 had characteristic phenotype of dopa-responsive dystonia. 5 patients had combined myoclonus-dystonia phenotype, causative variants in SGCE were identified in 2 of these patients. In a patient with a complex phenotype (generalized dystonia, cerebellar ataxia, epilepsy, speech difficulties, cognitive impairment) two pathogenic variants in CLN6 gene were found in a compound-heterozygous state. The body distribution of dystonia among patients with confirmed diagnosis was as follows: 55% of patients (n=6) had generalized form, 36% (n=4) had multifocal form, and 9% (n=1) had segmental form.

Conclusion: In a relatively small cohort of patients with non-focal dystonia we found 7 different GD forms, showing high clinical and genetic diversity of GD in Russian population. Abundance of phenotypically overlapping forms dictates the need of using MPS techniques in the diagnostic process.

References: 1. Grütz K, Klein C. Dystonia updates: definition, nomenclature, clinical classification, and etiology. J Neural Transm (Vienna). 2021 Apr;128(4):395-404. doi: 10.1007/s00702-021-02314-2. Epub 2021 Feb 19. PMID: 33604773; PMCID: PMC8099848.
2. Balint B, Mencacci NE, Valente EM, Pisani A, Rothwell J, Jankovic J, Vidailhet M, Bhatia KP. Dystonia. Nat Rev Dis Primers. 2018 Sep 20;4(1):25. doi: 10.1038/s41572-018-0023-6. Erratum in: Nat Rev Dis Primers. 2018 Oct 19;4(1):37. doi: 10.1038/s41572-018-0039-y. PMID: 30237473.
3. Thomsen M, Lange LM, Zech M, Lohmann K. Genetics and Pathogenesis of Dystonia. Annu Rev Pathol. 2024 Jan 24;19:99-131. doi: 10.1146/annurev-pathmechdis-051122-110756. Epub 2023 Sep 22. PMID: 37738511.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/screening-for-genetic-forms-in-non-focal-dystonia-patients-in-russian-population/