Dystonia

INDEX

Monogenic dystonias are commonly divided into two major groups:

Isolated dystonia (with or without dystonic tremor)

Combined dystonias (dystonia plus parkinsonism or myoclonus).

A further category would be paroxysmal dystonia, since the phenomenon of paroxysmal dystonia is likely to indicate a specific subset of genetic causes.

An important issue with respect to clinically diagnosing a specific form of dystonia is related to the fact that genetic heterogeneity exists in cases with virtually identical forms of dystonia. For instance, isolated dystonia (with or without dystonic tremor) can be caused by mutations in any of the following genes:

DYT-TOR1A

DYT-THAP1

DYT-PRKRA

DYT-ANO3

DYT-GNAL

Similarly, phenotypic heterogeneity may be present: for example, the same mutation in the TOR1A gene may give rise to presentations which range from unaffected (due to reduced penetrance), to mild writer’s cramp, or to severe generalized dystonia.

The widespread availability and increasing affordability of technologies for the genetic investigation of dystonia have changed the approach to investigation of disease and the diagnostic yield of genetic testing, as has the identification of new pathogenic variants also expanded knowledge of disease mechanisms. The more genes are known, the more patients will potentially be able to receive a genetic diagnosis and information about the cause of their disease. This may be of great clinical importance, since uncertainty is sometimes even more difficult to cope with than an established diagnosis, even if the disease might have an unfavourable outcome8. With the increasing number of genetic causes of dystonia, it is also becoming more and more efficient to use exome sequencing for diagnostic work-up rather than single gene analyses and multiple MRI scans and other often non-specific ancillary tests.