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

Autor: Asbjørg Stray-Pedersen, Greg Eigner Jablonski, James P. Connelly, Joel C. Glover, Ane Konglund, Nadja Kvernmo, Bård Nedregaard, Inger Marie Skogseid, Oddveig Røsby
Rok vydání: 2018
Předmět:
0301 basic medicine
Pathology
Neurology
Deep Brain Stimulation
Dopamine
Case Report
Gene mutation
Loss of heterozygosity
0302 clinical medicine
Deaf-Blind Disorders
Pallidal deep brain stimulation
Exome sequencing
Dystonia
Putamen
Dopaminergic
Brain
Magnetic Resonance Imaging
Treatment Outcome
Female
Striatal neuronal dysfunction
medicine.drug
Adult
medicine.medical_specialty
Heterozygote
Cognitive Neuroscience
Globus Pallidus
Pathology and Forensic Medicine
lcsh:RC321-571
03 medical and health sciences
Young Adult
Intellectual Disability
medicine
otorhinolaryngologic diseases
Humans
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
business.industry
medicine.disease
Actins
Dopaminergic dysfunction
Optic Atrophy
030104 developmental biology
Positron-Emission Tomography
ACTB p.Arg183Trp
Pediatrics
Perinatology and Child Health
Neurology (clinical)
business
Dystonia-deafness syndrome
030217 neurology & neurosurgery
Zdroj: Journal of Neurodevelopmental Disorders
Journal of Neurodevelopmental Disorders, Vol 10, Iss 1, Pp 1-8 (2018)
ISSN: 1866-1955
Popis: 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.
Databáze: OpenAIRE
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