Genetics of Primary Torsion Dystonia

Abstract

Advances in the genetics of dystonia have further elucidated the pathophysiology of this clinically and etiologically heterogeneous group of movement disorders. Currently, 20 monogenic forms of dystonia, designated by the acronym DYT, are grouped as 1) pure dystonias, 2) dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes and loci, including the 1) detection of two primary dystonia genes (DYT6, DYT16), 2) identification of the DYT17 locus, 3) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 (glucose transporter of the blood-brain barrier) deficiency syndrome (DYT18), 4) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, and 5) redefinition of DYT14 as DYT5. Further, we review current knowledge regarding genetic modifiers and susceptibility factors. Because recognizing and diagnosing monogenic dystonias have important implications for patients and their families with regard to counseling, prognosis, and treatment, we highlight clinical "red flags" of individual subtypes and review guidelines for genetic testing.

The BiP Molecular Chaperone Plays Multiple Roles during the Biogenesis of TorsinA, an AAA+ ATPase Associated with the Neurological Disease Early-onset Torsion Dystonia

“…EOTD is associated with an autosomal mutation in DYT1 (43,44). Although dominant, the mutation in DYT1 has low penetrance, indicating the existence of other environmental and genetic factors that are critical for EOTD development (45). The average age of EOTD onset is ϳ13 years, usually beginning in the lower limbs and spreading to other parts of the body.…”

Alternative Approaches to Modeling Hereditary Dystonias

“…Indeed most dystonias are idiopathic and show no clear or consistent pathological aberrations of the brain [2,[43][44][45]. Many common dystonias have been linked to mutations in 1 of at least 18 genetic loci [2,[46][47][48]. These mutations are responsible for disorders encompassing pure dystonias in which the patients exhibit no other symptoms, and dystonia-plus syndromes in which dystonia is part of a constellation of neurological findings.…”

Invertebrate Models of Dystonia

“…The gene products associated with nine different forms of dystonia have been identified. These gene products are torsinA (DYT1), TAF1 (DYT3), GTP-cyclohydrolase 1 (DYT5a), tyrosine hydroxylase (DYT5b), THAP1 (DYT6), myofibrillogenesis regulator 1 (DYT8), ε-sarcoglycan (DYT11), Na+/K+ ATPase α3 subunit (DYT12), PRKRA (DYT16), and SLC2A1 (DYT18) [2]. These findings provide the opportunity to develop animal models for in vivo evaluation of the encoded proteins, as well as identification of genetic and/or physical interactions.…”