Dystonia‐Deafness Syndrome: <scp><i>ACTB</i></scp> Pathogenic Variant in an Argentinean Family

Abstract

Dystonia is a movement disorder characterized by abnormal postures due to sustained or intermittent muscle contractions. Within the dystonia spectrum, Dystonia-Deafness syndrome (DDS) is a distinct clinical entity associating dystonia and sensorineural deafness.1 The p.Arg183Trp pathogenic variant in the ACTB gene has been associated with a form of DDS inherited in an autosomal dominant manner. Mutations in the gene encoding for the cytoplasmic β-actin frequently cause the Baraitser-Winter syndrome (BRWS), a developmental disorder characterized by facial dysmorphism and ocular coloboma, brain malformations, and often associated with sensorineural deafness.2 There are few reported cases in the literature of ACTB mutations causing DDS, some of them without the typical manifestations of BRWS.2, 3 The first report is a 2006 study in twins.4 We report a family with multiple members affected with craniofacial anomalies, congenital deafness and dystonia, where the p.Arg183Trp pathogenic variant in the ACTB gene was identified. A 34-year-old Argentinian woman, born from non-consanguineous parents, presented with dystonia at age 24. Dystonic symptoms started with writer's cramp, followed by blepharospasm 9 years later. She progressed rapidly to a severe multifocal dystonia, with prominent cervical dystonia (retrocollis and left head rotation). In addition, she had hearing loss since birth without cognitive impairment. Physical exam was remarkable for the presence of craniofacial abnormalities characterized by retrognathia, wide nasal base, marked hypertelorism, wide mouth, high-arched eyebrows and bilateral ptosis (Fig. 1A). Regarding dystonia, a multifocal pattern was observed with blepharospasm, cervical and right upper limb dystonia (Video 1). Numerous family members were also affected with sensorineural hearing loss (both parents, her two sisters and her niece). Furthermore, exhaustive interrogation and review of family photographs revealed dysmorphism in both her mother and sister, and facial dystonia in her mother (Fig. 1A). In addition, the patient's mother had been diagnosed with a parkinsonian syndrome. According to family reports she exhibited upper limb tremor and developed slowness of movement by the age of 41. Early-onset focal dystonia with rapid progression to a multifocal pattern, congenital deafness, dysmorphic facial features and a positive family history should raise clinical suspicion of an inherited dystonia. Routine laboratories were normal and brain MRI was unremarkable (Fig. 1B). Blepharospasm showed limited benefit to Clonazepam, Zolpidem and Botulinum Toxin injections. Given that positive family history pointed towards a genetic cause of DDS, whole exome sequencing on proband was performed using a Twist Human Core Exome Plus kit (Twist bioscience, San Francisco, CA, USA) in a commercial diagnostic lab and was later confirmed by Sanger sequencing. It revealed the presence of a heterozygous pathogenic variant in the ACTB gene, NM_001101.3: c.547C>T: p.(Arg183Trp). Actins are the monomeric subunit of cytoskeletal filaments, involved in fundamental processes such as conservation of cell shape, muscle contraction, cell signaling, motility and division.2 β-actin is encoded by ACTB, and pathogenic variants in this gene have been typically associated with BRWS, a congenital malformation disorder characterized by short stature, craniofacial anomalies and malformations of cortical development (heterotopia, pachygyria, lissencephaly).5 In 2014 a description of the genotypic-phenotypic spectrum in 42 cases with BRWS was published.5 While high phenotypic variability has been previously reported, dystonia is a feature, so far, only associated with the p.Arg183Trp pathogenic variant. Presence of parkinsonism in the patient's mother could further broaden the clinical spectrum related to this variant. Moreover, the p.Arg183Trp pathogenic variant in the ACTB gene, present in our patient, manifested as a DDS autosomal-dominant syndrome, with facial dysmorphism typical of BWRS. There are, to date, 10 reported cases in the literature, the first one described in a 2006 study in twins,4 and the last one in 2021.6 All of them displayed infant-onset deafness and dystonia starting in adolescence or young adulthood. In contrast with most of the reported cases, our patient has neither developmental delay nor cognitive impairment. A causal association between dystonia and striatal dopaminergic dysfunction has been proposed in ACTB mutations due to a bilateral reduction in tracer uptake in the striatum (particularly the putamen) in FDG-PET and Epidepride-SPECT. In line with this, pallidal deep brain stimulation (DBS) has been proposed as a potential treatment, with beneficial results.7 Our patient showed no improvement of dystonia with botulinum toxin and therefore DBS could be attempted in the future. The clinical phenotype of ACTB gene mutation related disorders remains to be fully elucidated. It has been previously hypothesized that the reported pathogenic variant affects the actin ATP-binding domain4, 8 and replacement of arginine with tryptophan could have an impact on actin polymerization, resulting in shorter and less stable filaments.9 Nonetheless, a molecular-phenotype relationship regarding dystonia is still lacking. Our case contributes to the knowledge of ACTB gene disorders, expands the phenotypic spectrum and highlights the importance of including ACTB gene sequencing in the workup of DDS.10 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. D.G.M.: 1A, 1B, 1C, 3B G.Z.: 1A, 1C, 3A L.Z.: 1A, 1C, 3A N.G.: 1A, 1B, 1C, 3B This article is a Genotype & Phenotype Letter to the Editor and therefore no IRB approval was necessary. Patient gave verbal and written consent for this work and a photograph of the written consent is provided. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

Topics & Concepts