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Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation.

ABSTRACT: BACKGROUND:Dystonia-deafness syndrome is a well-known clinical entity, with sensorineural deafness typically manifesting earlier than dystonia. ACTB p.Arg183Trp heterozygosity has been reported in six patients to cause combined infant-onset deafness and dystonia manifesting in adolescence or young adulthood. Three of these have received beneficial pallidal stimulation. Brain imaging to assess striatal function has not been reported previously, however. Nor has a comprehensive hypothesis been presented for how the pleiotropic manifestations of this specific beta-actin gene mutation originate developmentally. CASE PRESENTATION:A 19-year-old girl with congenital mild dysmorphic facial features, cochlear implants for infant-onset deafness, and mild cognitive and emotional disability, presented with an adolescent-onset, severe generalized dystonia. Brain MRI and multiple single gene sequencing were inconclusive. Due to life-threatening dystonia, we implanted a neurostimulation device, targeting the postero-ventral internal pallidum bilaterally. The Burke-Fahn-Marsden Dystonia Rating Scale motor/disability scores improved from 87/25 to 21/13 at 2.5 months postoperatively, 26/14 at 3 years, and 30/14 at 4 years. Subsequent whole exome sequencing identified heterozygosity for the ACTB p.Arg183Trp variant. Brain imaging included 123I-ioflupane single photon emission computed tomography (Dopamine Transporter-SPECT), SPECT with 123I-epidepride (binds to dopamine type 2-receptors) and 18 Fluoro-Deoxy-Glucose (FDG)-PET. Both Epidepride-SPECT and FDG-PET showed reduced tracer uptake in the striatum bilaterally, particularly in the putamen. DaT-SPECT was slightly abnormal. CONCLUSIONS:In this patient with dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity, unprecedented brain imaging findings strongly indicate striatal neuronal/dopaminergic dysfunction as the underlying cause of the dystonia. Pallidal stimulation provided a substantial improvement of the severe generalized dystonia, which is largely sustained at 4-year follow-up, and we advise this treatment to be considered in such patients. We hypothesize that the pleiotropic manifestations of the dystonia-deafness syndrome caused by this mutation derive from diverse developmental functions of beta-actin in neural crest migration and proliferation (facial dysmorphogenesis), hair cell stereocilia function (infant-onset deafness), and altered synaptic activity patterns associated with pubertal changes in striatal function (adolescent-onset dystonia). The temporal differences in developmental onset are likely due to varying degrees of susceptibility and of compensatory upregulation of other actin variants in the affected structures.

SUBMITTER: Skogseid IM

PROVIDER: S-EPMC5964724 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation.

Skogseid Inger Marie IM Røsby Oddveig O Konglund Ane A Connelly James P JP Nedregaard Bård B Jablonski Greg Eigner GE Kvernmo Nadja N Stray-Pedersen Asbjørg A Glover Joel C JC

Journal of neurodevelopmental disorders 20180522 1

<h4>Background</h4>Dystonia-deafness syndrome is a well-known clinical entity, with sensorineural deafness typically manifesting earlier than dystonia. ACTB p.Arg183Trp heterozygosity has been reported in six patients to cause combined infant-onset deafness and dystonia manifesting in adolescence or young adulthood. Three of these have received beneficial pallidal stimulation. Brain imaging to assess striatal function has not been reported previously, however. Nor has a comprehensive hypothesis ...[more]

PMID: 29788902

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Project description:Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Dataset Information

Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation.

Publications

Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation.

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