The Significant Efficacy of Botulinum Toxin for Deafness Dystonia Syndrome Caused by ACTB Gene Mutation

1. Abstract Deafness-Dystonia Syndrome (DDS) is a rare and complicated disorder which can be caused by a pathogenic heterozygous mutation c.547C>T, p.(Arg183Trp) in the ACTB gene, typically leading to a combination of hearing impairment and dystonia. We presented a case of a patient with DDS associated with this mutation. Our report could further expand the phenotype of DDS, containing short stature, flattened zygomatic region and small pointed chin. In addition, compared to other patients who either experienced limited or only partial improvement by botulinum toxin injections, our patient achieved significant efficacy in the treatment of cervical dystonia, making it a valuable reference for DDS patients with focal dystonia.

2. Keywords: Deafness-Dystonia Syndrome; ACTB; Botulinum toxin; Globus Pallidus Deep Brain Stimulation; Cervical Dystonia

3. Introduction Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions leading to involuntary movements or abnormal postures [1]. One of the most distinguishing features of dystonia from other hyperactive disorders is its close connection to movement and posture. Dystonia is often induced or exacerbated by voluntary movement. Posture abnormalities can range from spasmodic to tonic, rhythmic to fixed, or any combination. Additionally, stereotyped or patterned features of movement often accompany this disorder [2]. Deafness-Dystonia Syndrome is a rare and complex disease manifested by hearing loss and dystonia, usually accompanied by other physical or intellectual developmental impairments. Its etiology is multi-faceted, encompassing genetic, acquired and unknown causes. In particular, the genetic etiology of DDS includes Mohr-Tranebjaerg Syndrome, Woodhouse-Sakati Syndrome, organic aciduria and mitochondrial diseases [3]. So far, one patient with DDS caused by ACTB p.(Arg183Trp) heterozygosity has been reported only partial relief following the injection of botulinum toxin in his neck without undergoing deep brain stimulation [4]. We present a female with this mutation to expand the phenotypic spectrum and demonstrate a significant efficacy of botulinum toxin in the treatment of cervical dystonia in this condition.

4. Case report A 24-year-old women presented with congenital sensorineural deafness at age 1 and a cochlear implant was subsequently fitted in her left ear at age 8. At age 16, she experienced dystonia which began from the right hand with mild tremor and rapidly deteriorated to generalized dystonia within a year, manifesting as cervical dystonia, laryngeal dystonia and dystonic tremor in the extremities and trunk. Physical exam revealed slight developmental abnormalities, characterized by a short stature of only 145cm in height. She had mild facial dysmorphism associated with wide nasal base, flattened zygomatic region, wide mouth and small pointed chin. Moderate dysarthria was presented. Generalized dystonia was observed with cervical dystonia, laryngeal dystonia and dystonic tremor in the extremities and trunk, accompanied by weakness in the lower limbs. Her intellectual development was normal and her Mini-Mental State Examination (MMSE) score was 28, while Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) score were 3 and 8 respectively. Based on a comprehensive clinical evaluation, no significant psychiatric symptom was observed . Patient with Deafness-Dystonia Syndrome caused by ACTB gene mutation presented with generalized dystonia(cervical dystonia, la-ryngeal dystoniaand dystonic tremor in the extremities and trunk). Cer-vical dystonia was specifically characterized by episodes of sudden and repetitive twisting movements of her neck to the left and backwards, as well as paroxysmaltilting of the neck to the right, accompanied by head tremor, neck pain and a slight shrug of the left shoulder After administration of 200 U of botulinum toxin, consisting of 100 U for bilateral semispinalis capitis, 60 U for the right sternocleidomastoid and 40 U for the left sternocleidomastoid in July 2023, she experienced a comparable positive response within one week, evident through her nor-mal head position and a significant decrease in neck tilt and twist. This improvement has persisted for over six months (Video 2). After the injec-tion of botulinum toxin, her Toronto Western Spasmodic Torticollis Rat-ing Scale score (TWSTRS) significantly reduced from 59 to 29, reflecting a remarkable improvement of 66.1% in her cervical dystonia.

5. Discussion ACTB gene encodes a crucial component of cytoskeleton called β-actin, which involved in diverse functions. Actin can rapidly polymerize from globular subunits into polarized filaments, thereby performing a critical role in diverse functions ranging from whole-cell migration to the move-ments of subcellular components, such as muscle contract movements of neuronal processes, fast motility of immune cells, trans port of nutrients, conversion of energy and transmission of signals [5]. In addition, it’s involved in cell division and differentiation. ACTB gene mutation could lead to dysfunction of the system which regulate turnover of actin filaments, resulting in an accumulation of actin and its regulatory proteins actin depolymerizing factor/cofilin in the striatum, globus pal-lidus and substantia nigra, which frequently causes severe infant-onset deafness and juvenile or young-adulthood-onset dystonia [6]. The clinical manifestations of DDS with ACTB gene mutation are heterogeneous, typ-ically including varying degrees of facial dysmorphism, developmental delay, and neurodevelopmental deficits. Some patients also suffered from skeletal abnormalities, visual impairment, focal epilepsy, depression or psychotic episodes, etc [7]. One patient exhibited abnormalities in the bilateral caudate nuclei and basal ganglia on the brain MRI [8]. Brain imaging data indicated that striatal or putaminal neurons and structures containing D2-receptors may be dysfunctional or degenerated [9]. Studies have shown that globus pallidus deep brain stimulation (GPi-DBS) can ameliorate dystonia symptoms to a certain degree, potentially related to structural abnormalities in brain regions such as basal ganglia and stria-tum as observed through neuroimaging [4,7,9,10].

To date, only 11 cases of DDS with mutation in the ACTB gene c.547C>T, p. (Arg183Trp) have been reported. Due to the rarity of this disease, our report could further expand the phenotype, containing short stature, flat-tened zygomatic region, and small pointed chin. In addition, compared to other patients who either experienced limited or only partial improvement with botulinum toxin injections, as shown in Table 2 [6,10-13], our patient achieved significant efficacy in the treatment of cervical dystonia, making it a valuable reference for this condition. It is widely acknowledged that botulinum toxin type A is recommended as the first-line treatment for cer-vical dystonia [14]. Botulinum toxin can effectively block exocytosis at peripheral cholinergic sites including neuromuscular junctions, leading to temporary muscle relaxation through paralysis, ultimately alleviating in-voluntary movements and correcting postural abnormalities [15]. Besides, cervical dystonia-related pain could be alleviated continuously following repeated injections of IncobotulinumtoxinA [14]. Our patient who pre-sented with paroxysmal twisting of the neck and accompanying pain ex-perienced an improvement in neck posture and relief from associated pain after receiving injections of botulinum toxin into the targeted muscles. The previous patients’ inadequate response to treatment with botulinum toxin injections might be attributed to the following reasons. The range of their involuntary movements was extensive, exhibiting either generalized or multifocal dystonia. The local symptoms were severe and complicated, thus neither the standard dose nor even the recommended maximum dose was sufficient in their management [16]. Additionally, inappropriate mus-cle targeting could result in sub-optimal treatment responses or outright failure [17]. Moreover, as the dystonia was not limited to focal areas but instead generalized, focal botulinum toxin injections yielded limited ef-fectiveness or caused a subjective sense of ineffectuality.

Thus far, three patients have died, two of whom died of aspiration pneu- monia secondary to dystonia in their twenties and one of whom died of complications of the worsening and uncontrolled dystonia in his late teens [8,18]. Hence, discovering an efficient treatment is of utmost importance. It was reported that 5 patients with GPi-DBS received clinical improve-ment [4,7,9,10]. However, a patient developed parkinsonism 4 years after GPi-DBS, with imaging evidence displaying signs of degenerating striatal neurons [9]. Another patient underwent the surgery at age 35, and 3 years later she experienced progressive lower-body parkinsonism, associated with unresponsive to levodopa or prolonged GPi-DBS switching-off [7]. Therefore, we recommend considering individual injections of botulinum toxin as a conservative treatment option for managing focal dystonia in patients with DDS. Table 2: The efficacy of botulinum toxin treatment on patients diagnosed with Deafness-Dystonia Syndrome

6. Conclusion In conclusion, we expand the phenotypic spectrum of DDS with ACTB gene mutation and demonstrate the effectiveness of botulinum toxin injec-tions for the disease. The treatment of botulinum toxin injections should be considered as a conservative treatment for DDS patients with focal dystonia, such as cervical dystonia

7. Funding This study was supported by grants from Natural Science Foundation of Guangdong Province (2021A1515010313) and the Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Dis-eases (2020B1212060017).

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Weixi Zhang. The Significant Efficacy of Botulinum Toxin for Deafness Dystonia Syndrome Caused by ACTB Gene Mutation. Annals of Clinical and Medical Case Reports 2024