A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics

BMC Medical Genetics, Dec 2016

Background Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison. Case presentation In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. Conclusions ANO3 encodes anoctamin-3, a Ca +2 -dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.biomedcentral.com/content/pdf/s12881-016-0354-7.pdf

A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics

Blackburn et al. BMC Medical Genetics A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics Patrick R. Blackburn 0 3 Michael T. Zimmermann 2 Jennifer M. Gass 0 6 Kimberly G. Harris 1 Margot A. Cousin 2 5 Nicole J. Boczek 2 5 Owen A. Ross 1 6 Eric W. Klee 2 4 5 Paul W. Brazis 7 8 Jay A. Van Gerpen 7 Paldeep S. Atwal 0 1 0 Center for Individualized Medicine, Mayo Clinic , Jacksonville, FL , USA 1 Department of Clinical Genomics, Mayo Clinic , 4500 San Pablo Road South, Jacksonville, FL 32224 , USA 2 Department of Health Sciences Research, Mayo Clinic , Rochester, MN , USA 3 Department of Health Sciences Research, Mayo Clinic , Jacksonville, FL , USA 4 Department of Clinical Genomics, Mayo Clinic , Rochester, MN , USA 5 Center for Individualized Medicine, Mayo Clinic , Rochester, MN , USA 6 Department of Neuroscience, Mayo Clinic , Jacksonville, FL , USA 7 Department of Neurology, Mayo Clinic , Jacksonville, FL , USA 8 Department of Ophthalmology, Mayo Clinic , Jacksonville, FL , USA Background: Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotypegenotype comparison. Case presentation: In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. Conclusions: ANO3 encodes anoctamin-3, a Ca+2-dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease. ANO3; Anoctamin-3; Dystonia-24; DYT24; Craniocervical dystonia - Background Dystonias are a heterogeneous group of movement disorders with both primary genetic and secondary environmental etiologies [1]. Over the last few decades, several novel disease associated genes (DYT1-27) have been identified in dystonic syndromes, but the underlying genetic diagnosis remains elusive in most patients [1]. Inherited isolated craniocervical dystonias are rare, and most commonly caused by pathogenic variants in THAP1 (Dystonia-6, DYT6, MIM# 602629) and GNAL (Dystonia-25, DYT25, MIM# 615073) and have adolescent to late adult onset with variable penetrance [2]. To date, targeted clinical gene testing has been performed with limited success, however with the advent of next generation sequencing technologies in the clinic, we are beginning to unravel the complex genetic landscape of primary dystonias. Using exome sequencing, Charlesworth et al. [3] identified pathogenic variants in the anoctamin-3 gene (ANO3) in three families in the UK with craniocervical dystonia, including the index family described in Münchau et al. [3, 4]. The age at onset ranges from early childhood to the 5th decade with patients typically presenting in the late 4th decade of life with cervical and laryngeal dystonia (Table 1) [5]. Most affected individuals also have dystonic tremor that © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Table 1 Previously described ANO3 variants that are likely associated with disease The novel variant described in this report is highlighted in red affects the upper limbs, which can be misdiagnosed as familial essential tremor [5]. Patients can also develop ataxia, head tremor, dystonic posturing of the upper limbs, oromandibular dystonia, dysarthria, blepharospasm, and mild cognitive (...truncated)


This is a preview of a remote PDF: http://www.biomedcentral.com/content/pdf/s12881-016-0354-7.pdf

Patrick Blackburn, Michael Zimmermann, Jennifer Gass, Kimberly Harris, Margot Cousin, Nicole Boczek, Owen Ross, Eric Klee, Paul Brazis, Jay Van Gerpen, Paldeep Atwal. A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics, BMC Medical Genetics, 2016, pp. 93, 17, DOI: 10.1186/s12881-016-0354-7