Isolated dystonia: clinical and genetic updates
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NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Isolated dystonia: clinical and genetic updates Aloysius Domingo1,2,3 · Rachita Yadav1,2,3 · Laurie J. Ozelius2,4 Received: 4 September 2020 / Accepted: 9 October 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract Four genes associated with isolated dystonia are currently well replicated and validated. DYT-THAP1 manifests as youngonset generalized dystonia with predominant craniocervical symptoms; and is associated with mostly deleterious missense variation in the THAP1 gene. De novo and inherited missense and protein truncating variation in GNAL as well as primarily missense variation in ANO3 cause isolated focal and/or segmental dystonia with preference for the upper half of the body and older ages at onset. The GAG deletion in TOR1A is associated with generalized dystonia with onset in childhood in the lower limbs. Rare variation in these genes causes monogenic sporadic and inherited forms of isolated dystonia; common variation may confer risk and imply that dystonia is a polygenic trait in a subset of cases. Although candidate gene screens have been successful in the past in detecting gene-disease associations, recent application of whole-genome and wholeexome sequencing methods enable unbiased capture of all genetic variation that may explain the phenotype. However, careful variant-level evaluation is necessary in every case, even in genes that have previously been associated with disease. We review the genetic architecture and phenotype of DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A by collecting case reports from the literature and performing variant classification using pathogenicity criteria. Keywords Dystonia · THAP1 · GNAL · ANO3 · TOR1A · Exome sequencing Isolated dystonia refers to familial or sporadic cases of dystonia in the absence of other movement phenotypes, or syndromic neurologic or non-neurologic features, with the exception of dystonic tremor. This is in contrast to combined dystonia (i.e., dystonia–parkinsonism or Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00702-020-02268-x) contains supplementary material, which is available to authorized users. * Laurie J. Ozelius [email protected] Aloysius Domingo [email protected] 1
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
4
Collaborative Center for X‑linked Dystonia‑Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA
myoclonus–dystonia), and to complex dystonia syndromes that may include ataxia, pyramidal signs, or other systemic signs and symptoms in the phenotype. While dystonia may be acquired secondary to anatomic or environmental affronts, this review focuses on the
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