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
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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
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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)