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International Parkinson and Movement Disorder Society
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        VOLUME 27, ISSUE 2 • JUNE 2023  Full issue »

2023 Junior Research award

Genetic profile in primary dystonia: An experience from a quaternary centre 

I am truly humbled to have received the 2023 Junior Award at the 8th Asian and Oceanian Parkinson’s Disease and Movement Disorders Congress (AOPMC) for my study on the clinical and genetic profile of patients with primary dystonia of presumed genetic etiology using whole exome sequencing (WES).

The research was considered in the backdrop of an ardent need to understand the phenotype and genotype correlations of a large number of patients of primary dystonia who present to our centre. Particularly in this era of deep brain stimulation (DBS), identifying the genotype has even greater importance.1,2 The study, conducted from May 2021 to September 2022, focused on patients with primary dystonia from the Indian population, where the genetic basis of the disease has remained underexplored.

Our study recruited 65 patients who presented with primary dystonia of presumed genetic etiology, of which 69.2% were males. To rule out acquired and secondary causes, we conducted relevant investigations before proceeding for genetic testing. We applied the standard motor and disability scores that included the global dystonia rating scale (GDS), unified dystonia rating scales (UDRS), Burke Fahn Marsden rating scale (BFMDRS), and Toronto Western Spasmodic Torticollis Rating Scale TWSTRS (when applicable).

Subsequently, WES was performed on 62 patients. The results of WES were positive in 50% of the patients. Barring the variants of uncertain significance (VUS), the genetic yield was 32.3%. The mean age of onset and assessment was 25.0 ± 16.6 and 31.7 ± 15.2 years, respectively. We found that the genetically determined group had significantly younger age at onset, longer duration of illness, higher prevalence of generalized dystonia, were more commonly associated with combined forms, and had higher motor scores on UDRS and BFMDRS.

Furthermore, we identified disease-causing variants in both classical and non-classical DYT genes, as well as in genes not previously associated with dystonia. Specifically, 14 patients had disease-causing variants in the classical DYT genes: TOR1A and KMT2B in three patients each, SGCE in two patients, and GNAL, ADCY5, TUBB4A, VPS16, EIF2AK2 and KCTD17 in one patient each. Eight patients with combined dystonia had disease-causing variants in non-classical DYT genes: PINK1 in two patients and MME, KIF1A, VPS13C, ATP13A2, MAN2B1 and MICU1 in one patient each. Two patients with isolated dystonia had disease-causing variants in TSPOAP1 and PNPLA4. In the remaining six patients, there was partial phenotypic discordance with the identified genotype PANK2, AFG3L2, CTSF, KIDINS220, NSD1 and CTSA in one patient each.

Our study highlighted the yield of WES in dystonia when appropriate phenotypic characterization is made. These findings provide insights into the genetic basis of dystonia that could lead to better understanding of the underlying mechanisms, development of targeted therapies, and selecting appropriate patient for DBS. 

We acknowledge that our study has some limitations. First, the genetic yield at our institution may not be an accurate representation of the actual estimate, as our facility is one of the referral centres in the country and may have a selection bias. Second, the study had a relatively small sample size, which may limit the power to detect the true prevalence of various mutations in this part of the world. Third, parental testing, functional studies and segregation analysis were not available in the majority of the cases. Finally, there was non-consecutive recruitment of patients in this study, hence, the actual yield may be lower than estimated. Interestingly, in a significant number of genetically determined cases, family history was not a factor, emphasizing the necessity of not exclusively relying on family history for genetic testing, especially when there are compelling clinical indications. Despite these limitations, our study provides valuable insights into the genetic basis of dystonia and underscores the importance of deep clinical phenotyping to improve the yield of genetic testing.

 

References

  1. Tisch S, Kumar KR. Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome. Front Neurol 2021;11. 

  2. Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, et al. Clinical exome sequencing in early onset generalized dystonia and large scale resequencing follow up. Movement Disorders. 2017;32:549-559 

 

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