Objective: The aim of this study was to retrospectively assess the efficacy of deep brain stimulation in patients with confirmed monogenic dystonia.

Background: Treatment of dystonia with deep brain stimulation can be considered as a disease modifying therapy and is known to be most effective for segmental and generalized dystonia. Advancements in the field of clinical genetics has influenced the rate at which genetic dystonia is diagnosed, with new variants and genes discovered regularly. There is evidence that not all genetic forms of dystonia respond the same to deep brain stimulation, and there is a need to characterize efficacy depending on gene and variant due to the rarity of cases.

Method: Our study cohort includes dystonia patients treated with deep brain stimulation from the Clinic of Neurology at the Clinical Hospital Centre Rijeka, referred to genetic testing during previous ten years. Genetic testing for some cases was Sanger sequencing while whole exome sequencing was performed in the last five years. Identified variants were classified according to the ACMG and AMP 2015 joint consensus recommendation. Globus pallidus internus was a target for all cases, and was done at the Department of Neurosurgery, Clinical Hospital Dubrava.

Results: We present eleven cases of confirmed monogenic dystonia patients treated with deep brain stimulation. Five patients (n=5, 45.5%) were diagnosed using Sanger sequencing, with the majority patients sequenced with whole exome sequencing (n=6, 54,5%). Genetic diagnosis in three of those patients was made after negative Sanger sequencing for most common dystonia genes. The found pathogenic mutations are: THAP1 (n=3), TOR1A (n=2), PANK2 (n=1), GNAL (n=1), GNAO (n=1), GNB1 (n=1), KMT2B (n=1), YY1 (n=1). All patients taken together had a beneficial effect of globus pallidus internus deep brain stimulation therapy as measured with the Burke-Fahn-Marsden Dystonia Rating Scale (p<0.05), even though there was a variable response present.

Conclusion: Deep brain stimulation can be considered as a disease modifying treatment for dystonia patients, as was present in our cohort as well. With growing evidence, we can now recommend it without reserve for some clinical types and genotypes. Importantly, changes in possibilities for genetic testing over the years have led to an improvement in establishing genetic diagnosis, even prior to initiating deep brain stimulation.

References: Tisch S, Kumar KR. Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome. Front Neurol. 2021 Jan 8;11:630391. doi: 10.3389/fneur.2020.630391. PMID: 33488508; PMCID: PMC7820073.

Powis Z, Towne MC, Hagman KDF, Blanco K, Palmaer E, Castro A, Sajan SA, Radtke K, Feyma TJ, Juliette K, Tang S, Sidiropoulos C. Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions. Clin Genet. 2020 Feb;97(2):305-311. doi: 10.1111/cge.13657. Epub 2019 Oct 30. PMID: 31628766.

Artusi CA, Dwivedi A, Romagnolo A, Bortolani S, Marsili L, Imbalzano G, Sturchio A, Keeling EG, Zibetti M, Contarino MF, Fasano A, Tagliati M, Okun MS, Espay AJ, Lopiano L, Merola A. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2020 Apr;91(4):426-433. doi: 10.1136/jnnp-2019-322169. Epub 2020 Feb 20. PMID: 32079672.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/monogenic-dystonia-and-deep-brain-stimulation-single-center-experience/