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

• Published in: Journal of neurodevelopmental disorders Vol. 10; no. 1; p. 17
• Main Authors: Skogseid, Inger Marie, Røsby, Oddveig, Konglund, Ane, Connelly, James P, Nedregaard, Bård, Jablonski, Greg Eigner, Kvernmo, Nadja, Stray-Pedersen, Asbjørg, Glover, Joel C
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.05.2018; BioMed Central; BMC
• Subjects: ACTB p.Arg183Trp; Actin; Activity patterns; Adolescents; Age; Brain stimulation; Case Report; Child development; Cochlea; Cochlear implants; Cognition & reasoning; Cognitive ability; Computed tomography; Constipation; CT imaging; Deafness; Diagnosis; Dopamine; Dopamine receptors; Dopamine transporter; Dopaminergic dysfunction; Dystonia; Dystonia-deafness syndrome; Eye contact; Gene mutations; Genetic aspects; Heterozygosity; Learning disabilities; Magnetic resonance imaging; Medical imaging; Mutation; Neostriatum; Neural crest; Neuroimaging; Pallidal deep brain stimulation; Pallidum (ventral); Patients; Point mutation; Positron emission tomography; Putamen; Single photon emission computed tomography; Striatal neuronal dysfunction; Ultrasonic imaging; Urogenital system; ACTB p.Arg183Trp; Dopaminergic dysfunction; Dystonia-deafness syndrome; Striatal neuronal dysfunction; Pallidal deep brain stimulation
• ISSN: 1866-1947; 1866-1955
• DOI: 10.1186/s11689-018-9235-z

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. 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 I-ioflupane single photon emission computed tomography (Dopamine Transporter-SPECT), SPECT with I-epidepride (binds to dopamine type 2-receptors) and 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. 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.