The phenotypic spectrum of DYT24 due to ANO3 mutations

Abstract

Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations.

Keywords: ANO3; DYT24; cervical dystonia; cranial dystonia; dystonic tremor; laryngeal dystonia.

FIG. 1

The family pedigrees are shown for (A) Family 1, (B) Family 2, and (C) Family 3.

FIG. 2

The dystonic activity of patient IV-1 (Family 2) is illustrated. There is intermittent activity in the orbicularis occuli muscles clinically presenting with blepharospasm. There is tremoulous torticollis to the right with continuous activity in the left sternocleidomastoid (LSCM) and the right levator scapulae (RLevSc) muscle. There is dystonic tremor at 6 Hz, superimposed myoclonic jerks at 3 to 4 Hz, and duration no shorter than 250 msec. There was underlying, continuous muscle over-activity in the extensor carpi radialis (ECR) and the flexor carpi radialis (FCR) [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.].