Objective: To describe the clinical and genetic profile of DYT-THAP1 in Asian Indian patients.

Background: Variants in the thanatos-associated protein 1 (THAP1) gene are recognized as the second most prevalent cause of isolated monogenic dystonia, following TOR1A. DYT-THAP1 is characterized by early-onset generalized or multifocal dystonia, often with significant brachial and craniocervical involvement. A recent study by Saini A et al. on a cohort of Asian Indian patients with dystonia identified the THAP1 gene as the site of the most frequently observed variants. Understanding the clinical and genetic characteristics of DYT-THAP1 in the Indian cohort is essential

Method: We collected and analysed the clinical (demographics, manifestations, imaging, treatment) and genetic data of patients with DYT-THAP1 from various movement disorder clinics across India.

Results: Nineteen patients from 15 families with dystonia were enrolled (14 males and five females). The mean (SD) age at onset was 17.6 (12.54) years, with an average disease duration of 10.93 (8.76) years. Most patients (57.9%) had isolated dystonia; 47.4% experienced tremors. One individual presented with late-onset brachial tremors, without associated dystonia. Approximately 58% of the cohort had brachial dystonia, 32% presented with cervical dystonia, and one-fourth had laryngeal dystonia at onset. At the time of recruitment, dystonia was generalised in 11 patients (57.9%), multifocal in 4 (21%), and segmental in 3 (15.8%). Cranio-cervical and brachial involvement was noted in 89.5% of the cohort, with 57.8% showing laryngeal involvement during examination. All neuroimaging results were normal except for one case [Figure-1]. The genetic variants identified are summarized in Table [Figure 1], with pathogenic or likely pathogenic missense variants (in 11 patients, including six novel variants) in exon 2 (n=9) being the most common in this cohort. Patients received oral medications and botulinum neurotoxin for symptomatic relief, achieving mild-to-moderate benefits. Most patients reported no response to levodopa.

Conclusion: DYT-THAP1 usually manifests as early-onset generalized or multifocal dystonia, frequently starting in the brachial or cervical areas. More than half of the individuals in our cohort exhibited laryngeal involvement, while tremors were noted in nearly half as well. Within our group, most pathogenic variants identified were missense variants in exon 2 of the THAP1 gene.

Table: Clinical & Genetic profile of DYT-THAP1

References: 1. Blanchard A, Ea V, Roubertie A, Martin M, Coquart C, Claustres M, et al. DYT6 dystonia: review of the literature and creation of the UMD Locus‐Specific Database (LSDB) for mutations in the THAP1 gene. Human mutation. 2011 Nov;32(11):1213-24.
2. Lange LM, Junker J, Loens S, Baumann H, Olschewski L, Schaake S, et al. Genotype–phenotype relations for isolated dystonia genes: MDSGene systematic review. Movement Disorders. 2021 May;36(5):1086-103.
3. Saini A, Singh I, Kumar M, Radhakrishnan DM, Agarwal A, Garg D, et al. Genetic Landscape of Dystonia in Asian Indians. Movement Disorders Clinical Practice. 2025 Jan 3.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-profile-of-dyt-thap1-in-asian-indian-patients/