<scp>MDSGene</scp>: Extending the List of Isolated Dystonia Genes by <scp><i>VPS16</i></scp>, <scp><i>EIF2AK2</i></scp>, and <scp><i>AOPEP</i></scp>

Abstract

Following MDSGene's protocol, seven genes linked to isolated dystonia were recently reviewed.1 Since then, pathogenic variants in three additional genes, VPS16,2 EIF2AK2,3, 4 and AOPEP,5, 6 have unequivocally been shown to cause isolated dystonia.7 In this letter, we summarize phenotypic and genetic data from 15 publications reporting on 56 dystonia patients carrying pathogenic variants in these genes (see supporting information methods).1 All data are available on the MDSGene website (https://www.mdsgene.org); key data are illustrated in Figure 1 and in the supporting information. Variants in VPS16 are the most frequent novel cause of isolated dystonia.2 To date, 33 mutation carriers from 25 families were reported (median age at onset [AAO]: 13.5 years). The most frequent site of onset was the neck (13/33). Over the course of the disease, limb involvement was prominent (29/33), but also axial (25/33), cervical (25/33), and laryngeal dystonia (24/33) were common. Dystonia generalized in 26 of 33 cases. The majority (22/33) of patients had isolated dystonia, whereas 4 of 33 had dystonia combined with myoclonus, and 7 of 33 featured a more complex phenotype (co-occurring with other (non)neurological presentations). DYT-VPS16 is usually inherited in an autosomal dominant fashion. Family history was positive in 12 of 25 index patients. Negative family history was linked to inheritance from an unaffected parent (seven patients) or de novo occurrence (one patient). Fifteen of the 18 reported pathogenic variants are truncating. In EIF2AK2, 14 heterozygous mutation carriers from seven families have been reported with a median AAO of 6 years. Symptoms most frequently started in the limbs (10/14), with subsequent generalization in 11 of 14 patients. Limb involvement was characteristic (13/14). Dystonia was reported to be isolated in 11 of 14 and complex in 3 of 14 patients. DYT-EIF2AK2 follows an autosomal dominant mode of transmission; family history was positive in three of seven index patients. Interestingly, 11 of 14 patients carried a recurrent missense mutation (NM_001135651.3:c.388G>A;p.Gly130Arg), which arose de novo at least twice.3, 4 Finally, 11 AOPEP biallelic mutation carriers from nine (including three consanguineous) families have been reported (median AAO: 20 years). Symptoms often started in the hands (5/11). With disease progression, the arms were most frequently affected (10/11). Dystonia was mostly generalized (8/11) and isolated (9/11). DYT-AOPEP follows a recessive inheritance pattern. Family history was positive in two of nine index patients; 15 of 18 variants are truncating. Regarding treatment, mixed responses to deep brain stimulation (DBS) have been described, warranting further evaluation: DBS significantly alleviated symptoms in 5 of 11 DYT-VPS16 and both DYT-AOPEP patients, whereas 3 of 6 DYT-EIF2AK2 patients only moderately benefited. To summarize, there is significant phenotypic overlap between these three novel dystonia forms; for example, most patients presented with isolated dystonia, but ~20% of patients had combined (AOPEP) or complex (VPS16, EIF2AK2) dystonia. Common generalization and limb involvement are also shared with other forms of isolated dystonia, particularly DYT-TOR1A and DYT-KMT2B. Similar to DYT-THAP1, laryngeal involvement appears to be frequent in the three novel forms. DYT-VPS16 and DYT-AOPEP stand out for relatively common cervical involvement, comparable with DYT-GNAL. Despite the described phenotypes and patterns, it is currently not possible to establish a diagnosis on clinical grounds alone. Hence these three genes should be included in genetic testing panels for hereditary dystonia. MDSGene is funded by the International Parkinson and Movement Disorder Society, the Parkinson's Foundation, and the University of Lübeck. We thank Natascha Bahr for creating Figure S2, and Harutyun Madoev for maintaining and expanding the MDSGene website. Open Access funding enabled and organized by Projekt DEAL. M.T.: execution of (genetic) data abstraction, analysis, writing the first draft and preparing the display items, and double-checking of correct upload of the data to the MDSGene database. L.M.L.: execution of (clinical) data abstraction, analysis, and editing of final version of the manuscript. C.K.: study design and reviewing the second draft of the manuscript. K.L.: study design, supervision, and reviewing the second draft of the manuscript. Mirja Thomsen: Stock Ownership in medically-related fields: None; Consultancies: None; Advisory Boards: None; Partnerships: None; Honoraria: None; Grants: None; Intellectual Property Rights: None; Expert Testimony: None; Employment: University Hospital of Schleswig-Holstein/University of Lübeck; Contracts: None; Royalties: None; Other: None. Lara Mariah Lange: Stock Ownership in medically-related fields: None; Consultancies: None; Advisory Boards: None; Partnerships: None; Honoraria: None; Grants: None; Intellectual Property Rights: None; Expert Testimony: None; Employment: University Hospital of Schleswig-Holstein/University of Lübeck; Contracts: None; Royalties: None; Other: None. Christine Klein: Stock Ownership in medically-related fields: None; Consultancies: Medical advisor to Centogene and Retromer Therapeutics; Advisory Boards: Else Kroener Fresenius Foundation; Partnerships: None; Honoraria: Speaking Honoraria from Desitin; Grants: Movement Disorder Society, German Research Foundation, the BMBF, the Michael J. Fox Foundation, intramural funds from the University of Lübeck; Intellectual Property Rights: None; Expert Testimony: None; Employment: University of Lübeck; Contracts: None; Royalties: Oxford University Press; Other: None. Katja Lohmann: Stock Ownership in medically-related fields: None; Consultancies: None; Advisory Boards: None; Partnerships: None; Honoraria: None; Grants: German Research Foundation, Movement Disorders Society, Parkinson's Foundation; Intellectual Property Rights: None; Expert Testimony: None; Employment: University of Lübeck; Contracts: None; Royalties, None; Other: None. Figure S1. Overview of literature search. The different steps and respective numbers of articles of the systematic literature review are indicated. Figure S2. Overview of mutations per gene and protein. Variants scored as benign are not included in the figure but listed in Table S4. Table S1. Search terms for the literature search in PubMed. Table S2. List of included publications. Table S3. List of extracted variables. Table S4. List of benign variants. Table S5. List of excluded patients and variants (other than benign variants). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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