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. Apart from phenotypic heterogeneity, there is also overlap between the different genes, and identification of genes based on clinical features is difficult. However, ANO3 and GNAL mutations have a late median age of onset, and typically remain focal with craniocervical involvement. These two conditions may be distinguished by the presence of myoclonus, which is a common feature of DYT-ANO3 but is rare in DYT-GNAL.  All genetic conditions listed above frequently also affect the limbs, except DYT-GNAL1.

For most inherited dystonias, both genders are affected equally. Approximately half of patients with DYT-THAP1, DYT-ANO3,  DYT-GNAL, and DYT-PRKRA  have a family history1.

Mutations in TOR1A, THAP1, and GNAL are usually inherited, and de-novo mutations in these three genes are rare.
PRKRA is an autosomal recessive condition, and a history of consanguinuity may be obtained.

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 outcome. 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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

  1. Lange LM, Junker J, Loens S, Baumann H, Olschewski L, Schaake S, Madoev H, Petkovic S, Kuhnke N, Kasten M, Westenberger A, Domingo A, Marras C, König IR, Camargos S, Ozelius LJ, Klein C, Lohmann K. Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review. Mov Disord. 2021 May;36(5):1086-1103.