Isolated dystonia: clinical and genetic updates

Area of Science:

• Genetics and Neurology
• Molecular Biology
• Movement Disorders

Background:

• Isolated dystonia is a complex neurological movement disorder with a significant genetic component.
• Four genes, THAP1, GNAL, ANO3, and TOR1A, are currently validated as major contributors to isolated dystonia.
• Understanding the genetic architecture is crucial for diagnosing and potentially treating dystonia.

Purpose of the Study:

• To review and analyze the genetic architecture and associated phenotypes of four key dystonia-associated genes: DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A.
• To consolidate case reports and perform variant classification using established pathogenicity criteria.
• To highlight the role of both rare and common genetic variations in the etiology of isolated dystonia.

Main Methods:

• Systematic literature review to collect case reports related to DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A.
• Variant classification using standardized pathogenicity criteria.
• Analysis of genotype-phenotype correlations based on collected data.

Main Results:

• DYT-THAP1 is associated with young-onset generalized dystonia, primarily affecting the craniocervical region, linked to THAP1 gene variations.
• GNAL and ANO3 variations cause focal/segmental dystonia with upper body preference and later onset.
• TOR1A GAG deletion is linked to childhood-onset generalized dystonia affecting lower limbs; rare variations in all four genes cause monogenic dystonia, while common variations may indicate polygenic risk.

Conclusions:

• Rare genetic variations in THAP1, GNAL, ANO3, and TOR1A are established causes of monogenic isolated dystonia.
• Common genetic variations may contribute to dystonia risk, suggesting a polygenic component in some individuals.
• Comprehensive genetic evaluation, including whole-genome/exome sequencing and careful variant interpretation, is essential for diagnosing isolated dystonia.