Blepharospasm in <scp>GNAO1</scp> Syndrome May Benefit From Botulinum Toxins

Guanidine nucleotide-binding protein alpha-activating activity polypeptide O (GNAO1) syndrome is a neurodevelopmental disorder characterized by a broad spectrum of neurological phenotypes, including severe developmental delay and an early-onset movement disorder, with or without epileptic features.1 Dystonia is the most frequently observed motor manifestation, followed by dyskinesias and choreoathetosis.2 Moreover, hypokinetic presentations, such as hypokinesia, bradykinesia, and other neurological signs (eg, tremor, oculogyric crises, spasticity), have also been reported.1 Dystonia in GNAO1-related disorders can present with variable severity and topography, including generalized, segmental, or focal involvement. Episodes of status dystonicus, often life-threatening, are a known complication. Recent literature highlights cranial involvement, with oromandibular and laryngeal dystonia frequently affecting speech and swallowing.2 Blepharospasm (BS) is a focal cranial dystonia defined by involuntary eyelid closure and impaired voluntary eyelid opening, resulting in an increased frequency of blinking or an uncontrollable urge to close the eyes completely. In advanced stages, it can progress to persistent eyelid closure and even functional visual impairment.3 Although orofacial dyskinesias are commonly reported in patients with GNAO1-related disorders,1 BS remains an exceedingly rare manifestation. Herein, we present the case of a 16-year-old female patient with GNAO1 syndrome who developed BS during the disease course, which was effectively managed with botulinum toxin therapy. The patient had exhibited bradykinesia, postural instability, and dystonic features since the age of five. The pregnancy progressed uneventfully, except for a mild perinatal compromise due to respiratory distress. Clinical evaluation revealed a predominant generalized dystonic syndrome involving the upper and lower limbs, as well as the oromandibular and laryngeal regions, blepharospasm, gait disturbances, leading to reduced functional autonomy in daily activities, and speech impairment characterized by dystonic dysarthria and dysphonia. Due to the progressive nature of the symptomatology, further investigations were conducted to explore an alternative etiology beyond perinatal distress. Brain magnetic resonance imaging (MRI) findings were unremarkable, prompting genetic testing that identified a GNAO1 c.724-8G>A variant. Pharmacological treatments including L-dopa, trihexyphenidyl, tetrabenazine, and clonazepam yielded partial benefit; consequently, bilateral globus pallidus internus deep brain stimulation (GPi-DBS) was performed leading to moderate improvement, particularly under intermittent stimulation (iDBS). As she entered adolescence, the functional burden of BS became increasingly significant in her daily activities. BS was managed successfully with 5 U of onabotulinumtoxinA (Botox®; Allergan, USA) with a combined injection protocol in the orbicularis oculi and pretarsal muscles bilaterally, resulting in significant symptomatic relief (Video 1). See Video 2 and Supplementary Materials for overview of the patient's clinical evolution, pharmacological treatments, and DBS settings. DBS has become an increasingly recognized treatment strategy for GNAO1-related movement disorders, especially in drug-resistant dystonia and status dystonicus. Bilateral GPi-DBS is the most widely used approach, with data suggesting sustained improvements in dystonia severity and reduced hospitalization for dystonic crises.2 Nevertheless, DBS may show limited efficacy in cranial dystonia components such as BS, where botulinum toxin therapy remains the first-line symptomatic intervention. BS is commonly induced by STN stimulation4 but exacerbation of blepharospasm has been associated also after placement of the GPi in craniocervical dystonia.5 However, given the correct electrode positioning (assessed with postoperative lead localization and trajectory reconstruction using dedicated neuroimaging software) we believe that BS in our patient is more likely to reflect disease progression rather than a stimulation-induced side effect. The positive and sustained response to botulinum toxin further supports a dystonia-related etiology rather than a device-related adverse event. This case highlights the atypical presentation of BS in GNAO1 syndrome and underscores the therapeutic efficacy of botulinum toxin in its management. Given the limited literature on this manifestation, further studies are warranted to better characterize its prevalence and optimize treatment strategies in GNAO1-related movement disorders. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. E.M.: 3A G.D.: 1B, 3B G.Z.: 1A, 3B F.G.: 3B F.G.: 1A, 1B, 1C, 3A, 3B We acknowledge the Pierfranco and Luisa Mariani Foundation and the Paolo Zorzi Association for Neuroscience ONLUS. We are grateful to our patient and her family for consent of publication of the report. Ethical Compliance Statement: Ethical guidelines were followed in the absence of an institutional review board. Written informed patient consent was obtained for this work by the legal guardian. 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. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Overview of the patient's clinical evolution across four key time points (Pre-deep brain stimulation [DBS], Post-DBS, pre-Botulinum Toxin [iDBS], and Post-Botulinum Toxin). The table includes clinical features, pharmacological treatments, BFMDRS scores, and DBS settings. Data S2. Additional clinical characteristics and phenotypic details of the patient. Data S3. Detailed timeline of deep brain stimulation (DBS) programming and parameter adjustments over the course of follow-up. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.