Objective: To systematically review genotypes and phenotypes of monogenic isolated dystonia.

Background: The Movement Disorder Society Genetic mutation database (MDSGene at www.mdsgene.org) provides an overview on published genetic and phenotypic data including demographic and clinical information on movement disorder patients carrying causative gene mutations.

Method: Our systematic literature screen using PubMed identified >200 articles reporting at least one mutation-carrying individual with a diagnosis of dystonia and providing genetic and clinical information. Digenic variants or those with a minor allele frequency >1% (based on gnomAD or respective publications) were excluded. We extracted data for a total of 1,115 dystonia patients carrying 214 genetic variants in the following genes: TOR1A, THAP1, GNAL, ANO3, KMT2B, PRKRA and HPCA.

Results: Comparing phenotypes across all genes, there were differences regarding AAO, site of onset and distribution of dystonia. While carriers of HPCA, KMT2B, PRKRA, TOR1A and THAP1 variants mostly show childhood or adolescence onset, patients with GNAL and ANO3 mutations often develop first symptoms in adulthood (21 and older). DYT-HPCA has the youngest median AAO (5 years) and DYT-GNAL the oldest (38 years). Regarding site of onset, KMT2B, ANO3 and GNAL mutation carriers seem to have one predominant site of onset, i.e. the lower limbs in KMT2B and cervical in GNAL and ANO3 mutation carriers, respectively. Site of onset in DYT-TOR1A, DYT-THAP1, DYT-HPCA and DYT(/PARK)-PRKRA is broader. However, DYT-THAP1 mostly first manifests in the upper body half (upper limb, neck and craniofacial/ laryngeal), whereas onset in DYT-TOR1A, DYT(/PARK)-PRKRA and DYT-HPCA is frequently in an extremity, including both upper and lower ones. For ANO3, a segmental/multifocal distribution is typical, whereas KMT2B, TOR1A, HPCA and PRKRA mutation carriers commonly show a generalized type of dystonia. Interestingly, DYT-THAP1 presents with focal, segmental/multifocal, or generalized distribution at almost equal proportions. For GNAL, a focal or segmental/multifocal type of dystonia is common; they rarely show generalization.

Conclusion: Our review provides a comprehensive overview of the current knowledge of hereditary isolated dystonia. The MDSGene database is a useful tool to review genotype-phenotype data and to assist clinical diagnosis and genetic counseling.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-relations-for-the-isolated-dystonia-genes-tor1a-thap1-gnal-ano3-kmt2b-prkra-and-hpca-mdsgene-systematic-review/