Genotype–Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review

Abstract

A BS TRACT: This comprehensive MDSGene review is devoted to 7 genes -TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCAmutations in which may cause isolated dystonia. It followed MDSGene's standardized data extraction protocol and screened a total of~1200 citations. Phenotypic and genotypic data on~1200 patients with 254 different mutations were curated and analyzed. There were differences regarding age at onset, site of onset, and distribution of symptoms across mutation carriers in all 7 genes. Although carriers of TOR1A, THAP1, PRKRA, KMT2B, or HPCA mutations mostly showed childhood and adolescent onset, patients with GNAL and ANO3 mutations often developed first symptoms in adulthood. GNAL and KMT2B mutation carriers frequently have 1 predominant site of onset, that is, the neck (GNAL) or the lower limbs (KMT2B), whereas site of onset in DYT-TOR1A, DYT-THAP1, DYT-ANO3, DYT-PRKRA, and DYT-HPCA was broader. However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones. For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia. THAP1 mutation carriers presented with focal, segmental/multifocal, or generalized dystonia in almost equal proportions. GNAL mutation carriers rarely showed generalization. This review provides a comprehensive overview of the current knowledge of hereditary isolated dystonia. The data are also available in an online database (http://www.mdsgene.org), which additionally offers descriptive summary statistics.

Dystonia updates: definition, nomenclature, clinical classification, and etiology

“…Different shades of blue indicate the different clinical presentations with darker tones relating to more severe presentations. The fractions are in accordance with the numbers reported byLange et al (2021)…”

GPi‐DBS for KMT2B‐Associated Dystonia: Systematic Review and Meta‐Analysis

“…The KMT2B (Histone‐lysine N ‐methyltransferase 2B) gene is associated with early‐onset generalized dystonia with a complex phenotype including facial dysmorphism, intellectual disability and prominent gait and laryngeal dystonia with anarthria in many affected individuals 11–13 . This gene is being increasingly identified in dystonia cohorts worldwide and is now understood to be one of the commonest monogenic dystonia syndromes 14 . The dystonia is often medically refractory and early evidence from multiple groups suggests good response to pallidal stimulation in KMT2B dystonia, though only few patients have been systematically reported worldwide.…”

The importance of genetic testing for dystonia patients and translational research

“…All MDSGene data are obtained and curated, utilizing a standardized data extraction protocol with predefined inclusion and exclusion criteria, from relevant scientific articles identified through PubMed literature searches. Application of this resource has already resulted in important genotype-phenotype relations for dystonia genes (Pauly et al 2020;Lange et al 2021).…”