Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review.

This comprehensive MDSGene review is devoted to 7 genes - TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCA - mutations 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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Role of ANO3 mutations in dystonia: A large-scale mutational screening study.

BACKGROUND: The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls. OBJECTIVE: To screen >1000 patients with movement disorders for rare ANO3 variants. METHODS: We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis. RESULTS: Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation. CONCLUSION: This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.