Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

Background GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD. Objectives This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.


GNAO1-related
disorder (GNAO1-RD) is a rare neurodevelopmental and movement disorder caused by pathogenic variants in the GNAO1 gene (1), encoding a G protein subunit crucial for neuronal signaling.GNAO1-RD exhibits significant clinical heterogeneity, with core symptoms consisting of early-onset epilepsy, developmental delay/intellectual disability, and a hyperkinetic movement disorder, which typically includes chorea, dystonia, and myoclonus (2).A particularly challenging and poorly understood aspect involves recurrent episodes of acute exacerbations of hyperkinetic movement disorders, which have been termed dyskinetic crises.
Despite their clinical significance, dyskinetic crises have not been well defined, which has hindered effective communication among healthcare professionals and impeded research efforts.Recently, the term "dyskinetic crisis" was defined by Dominguez-Carral and colleagues (2) as "sudden and marked exacerbation of abnormal involuntary movements (dyskinesias), which are distinct in onset and duration from the baseline dyskinetic movements of the patient, such as dystonia, chorea, or athetosis.During a dyskinetic crisis, alterations in facial expression may manifest, which are different from epileptic seizures, as there is no loss of awareness or disconnection from the surrounding environment (2)." Dyskinetic crises may have significant effects on the quality of life of both patients and their caregivers.It is essential to be aware of the potential short-and long-term complications of these crises, such as rhabdomyolysis (3-5), long bone fractures (6,7) and renal failure (4,8,9), as well as complications like denutrition (3, 10), hyperthermia (3, 11), and respiratory distress (10,12,13).In order to address dyskinetic crises, prompt intervention and tailored management strategies are essential.In severe cases, patients may need extended ICU stays, possibly requiring a tracheostomy (10,11), or gastrostomy (10,12).There are documented cases of dyskinetic crises resulting in fatalities (6,7,12,14), highlighting the urgent need for effective interventions.Considering the significant morbidity and mortality, dyskinetic crises were added as a severity indicator to the GNAO1-RD severity score (2).
The pathophysiology of dyskinetic crises is complex and not fully understood.In the mammalian striatum, Gαo plays a pivotal role in controlling movement in D1 and D2 dopamine receptor-expressing medium spiny neurons.GNAO1 pathogenic variants, including G42R, G203R, and R209C, are associated with loss of function and dominant negative effects, which have an adverse effect on motor behaviors and contribute to the development of dyskinetic crisis (15).The pathogenic variants cause disturbances in cAMP signaling pathways (16), which impede the regulation of GABA-B and α2 receptors and subsequently impact the release of neurotransmitters (9).Furthermore, these pathogenic variants affect functional polarity in developing neurons, calcium signaling, and neurite outgrowth by interfering with cytoskeletal remodeling and neuronal firing (17).
To address dyskinetic crises in GNAO1-RD, we have convened a Delphi consensus review involving an international panel of experts.Consensus was reached on a number of aspects pertaining to dyskinetic crises, including their definition, triggers, diagnostic criteria, potential short-and long-term complications, and effective management strategies and interventions.The establishment of this standardized framework for understanding dyskinetic crises will improve clinical management and future research in the field of GNAO1-RD.

Materials and methods
In this study, a Delphi consensus process was conducted to gather expert opinions on various aspects related to GNAO1-RD dyskinetic  S1), along with 13 international experts, was involved in the process.The study involved multiple voting rounds, where experts anonymously voted on statements using a 6-point Likert scale.The predefined consensus threshold was set at ≥67%, and statements not reaching this threshold were revised based on feedback.Discussions during the process led to the emergence of new topics, including appropriate terminology and medical management strategies, which were also voted on in the third round.Further details on the methodology, literature review, and statements can be found in the Supplementary Data and Supplementary Figure S1.Figures 1, 2 provide an overview of the GNAO1-RD dyskinetic crisis consensus process.Patients included in the videos were selected from the clinical practice of the authors, and their participation was contingent upon obtaining informed consent for the publication of these videos.

Overview
Thirty-five articles were identified in a targeted literature review (Supplementary Data; Supplementary Figure S1).Based on this evidence, 69 draft statements were developed.Following the participants' responses in the initial round, 18 statements were revised for the subsequent round, and an additional 3 statements were formulated for the second round.Following the investigator meeting at this stage, a statement was formulated regarding the nomenclature of movement disorder phenomena, along with a prioritized list of drugs for acute pharmacological management of dyskinetic crises and chronic management of background movement disorders.Overview of the GNAO1-RD dyskinetic crisis consensus process.
In the Supplementary Data, the genotype of patients, triggers, acute pharmacological management, chronic management, and deep brain stimulation, as well as complications, are described in detail.Supplementary Figure S2 shows the genotype of the 102 GNAO1-RD reported cases with dyskinetic crises.

Voting participation and consensus
All 13 voting members of the Delphi panel participated in at least one round of the process and thus qualified for membership in the final Delphi panel.In round 1, the participation rate was 100%.After this voting round, 23 of the 69 statements reached consensus.28 statements failed to reach consensus; these statements were revised based on feedback.In round 2, eight panel members voted on the revised statements.During this voting round, seven additional statements reached consensus.The third voting round focused on refining the terminology used to describe the phenomena and delving into more detailed aspects of medical management.The participation rate for the third round was 77% (10/13).Not all experts were able to participate in all three rounds.

Consensus statements
In total, the Delphi panel agreed on 31 consensus statements.The statements and the detailed voting responses are summarized, by theme, in Supplementary Tables S2-S13.

Dyskinetic crisis: definition Statements 1-7
A dyskinetic crisis in GNAO1-RD is characterized by abrupt, paroxysmal episodes of abnormal involuntary movements (Figure 3).These episodes typically involve multiple body regions, including the upper and lower limbs, trunk, and face.Dyskinetic crises in GNAO1-RD are commonly associated with dystonia, choreoathetosis, ballismus, or a combination of these movement disorders.They can last for minutes to hours (less commonly days to weeks) and may occur spontaneously or be triggered by various factors.Individuals experiencing a dyskinetic crisis often face significant functional impairment and a loss of voluntary control over their movements.These crises can recur multiple times per day.Additionally, it is important to note that in GNAO1-RD patients, the term "dyskinetic status" should be used instead of "dystonic status."However, it is crucial to recognize that both terms, dystonic status and dyskinetic status, are often interchangeable, particularly in the context of GNAO1-RD.The choice between "dystonic" or "dyskinetic" may depend more on the predominant phenomenology observed in each individual case, whether it manifests as dystonia or choreoathetosis.In the third round, the term "dyskinetic crisis" was endorsed to characterize this movement disorder phenomenon (Supplementary Videos S1-S4).

Comments
A dyskinetic crisis encompasses any sudden alteration in the baseline movement disorder, regardless of its duration or severity.This implies that previously used terms such as "spells" or "episodes" should be discouraged and replaced.The involuntary movements observed during a dyskinetic crisis may or may not deviate from the baseline motor patterns of the patient.These movements could resemble their usual movement disorders (most often chorea and dystonia), but with increased intensity or severity.Alternatively, they Moreover, a focal movement should raise suspicion of a focally aware or impaired-aware epileptic seizure.The assessment of consciousness in GNAO1-RD dyskinetic crises presents a clinical challenge, as there is a belief that consciousness remains unimpaired during these events, although distinguishing this from seizures can be challenging and may require confirmation via EEG.However, it is crucial to note that reaching definitive conclusions about impaired consciousness or awareness in individuals with GNAO1-RD during dyskinetic crises necessitates additional research and evidence.Further studies are required to provide a more comprehensive understanding and clarification of this particular aspect of the condition.The diagnosis of status dystonicus or dyskinetic status will be made following the recommendations of Allen et al., which include patients presenting with intolerance to lying down and disturbed sleep, along with metabolic disturbances such as fever (not related to infection), dehydration, abnormal electrolytes, CK >1,000 IU/L, and myoglobinuria (36) (Figure 3).It is therefore important to differentiate dyskinetic crises from dystonic or dyskinetic status, which must meet the previously described criteria.

Dyskinetic crisis: clinical features aside from MD Statements 13-15, 87
In GNAO1-RD, dyskinetic crises may coexist with autonomic symptoms such as diaphoresis, tachycardia, and blood pressure changes.Autonomic symptoms, in isolation, along with increased movements, do not by themselves define a dyskinetic crisis.Autonomic symptoms should be recognized as potential features of various movement disorder presentations, not exclusive to dyskinetic crises, warranting a comprehensive evaluation.Speech and swallowing can also be affected by dyskinetic crises.Patients frequently experience fatigue or weakness following a dyskinetic crisis.

Dyskinetic crisis: triggers or precipitant factors
Statements [16][17][18]83 Dyskinetic crises in individuals with GNAO1-RD are commonly precipitated by stressors such as emotional stress, anxiety, excitement, and pain, as well as infections including respiratory or urinary tract infections, underscoring the importance of recognizing and avoiding these triggers when devising treatment strategies.

Comments
Certain triggers described anecdotally in the literature lack substantial empirical experience.Consequently, a consensus could not be reached on specific triggers previously mentioned, including bowel movements (6), high ambient temperature (12,28), purposeful movements (12,13,26), sound (14), and menstruation (23).Dyskinetic crises can occasionally arise in the absence of identifiable precipitating factors; therefore, it is indispensable that patients and families be appropriately informed.

Dyskinetic crisis: differences compared to background movement disorders
A consensus could not be achieved in this area.

Comments
Dyskinetic crises can resemble the patient's baseline movement disorder.Autonomic symptoms may be observed in other movement disorders without being specific to dyskinetic crises.

Dyskinetic crisis: distinctive patterns or variations
A consensus could not be achieved in this area.

Comments
Further evidence is essential to determine whether more severe phenotypes of GNAO1-RD correlate with a higher incidence of dyskinetic crises.Notably, some patients with milder phenotypes, characterized by a more dystonic presentation, occasionally limited to isolated cervical dystonia, have never experienced dyskinetic crises (20,37).It is crucial to highlight that individuals with GNAO1-RD might encounter dyskinetic crises several years after the onset of dystonia.Additionally, comprehensive research is required to investigate potential variations in the duration, frequency, and severity of dyskinetic crises across different age groups.Similarly, there is a need to explore whether the incidence of dyskinetic crises diminishes with age, necessitating further investigation.Natural history studies are imperative to assess whether the characteristics of crises change within the same patient over time.This includes examining potential genotype correlations with dyskinetic crises as well as exploring whether accompanying neurological features, such as cognitive impairment, epilepsy, or developmental delay, influence the nature of the dyskinetic crisis.

Dyskinetic crisis: diagnosis criteria and guidelines Statements 39-44
In the context of GNAO1-RD, diagnosing dyskinetic crises is challenging due to the absence of specific criteria.Individuals with acute, paroxysmal, and involuntary dyskinetic movements should be considered for dyskinetic crisis evaluation.Video documentation of these episodes is valuable, offering visual insights into the frequency and characteristics of abnormal movements.Longitudinal observation and comprehensive clinical assessments aid in identifying diagnostic patterns.Unlike epileptic seizures, dyskinetic crises most probably preserve awareness and exhibit inconsistent bilateral movements.Therefore, differential diagnosis involves excluding other potential causes of paroxysmal movement disturbances, emphasizing the need for meticulous evaluation and monitoring in individuals presenting with such symptoms in the GNAO1-RD context.

Comments
In the context of differentiating dyskinetic crises from other neurological events such as epileptic seizures, clarification is needed regarding the categorization of these events.Obtaining EEG recordings from patients experiencing dyskinetic crises poses significant challenges.While EEG recordings can be valuable, they are not obligatory; the distinctive patterns and accompanying signs observed during dyskinetic crises are likely adequate for distinguishing them from epileptic seizures on clinical grounds.Dyskinetic crisis can interfere with activities of daily living and functional independence, resulting in a lack of autonomy and decreased quality of life for individuals with GNAO1-RD.Dyskinetic crisis may disrupt the ability to maintain oral feeding and should be considered as a factor affecting nutritional management.Dyskinetic crisis may be associated with an increased risk of falls and/or injuries (pain, tongue biting, joint dislocations, bone fractures, etc.).

Comments
Differentiating between the motor deterioration resulting from frequent dyskinetic crises and the putative neurodegeneration associated with GNAO1-RD proves to be a challenging task.The distinction between these two factors is intricate and often unclear, making it difficult to ascertain the precise cause of the motor decline in individuals affected by GNAO1-RD.The assessment of motor decline in such cases is further complicated by the immediate harm and injuries patients experience during these events.In the literature, complications such as pressure ulcers (6), superficial injuries (7,9), skin breakdown (7), femur (6) or bone fractures (7), obstinate constipation (13), acute colitis (4), pneumatosis hepatis (4), and anxiety (25) have been described.

Dyskinetic crisis: management strategies and interventions Statements 49-55
In managing dyskinetic crises in GNAO1-RD, patients should receive comprehensive care following the guidelines outlined in the Dystonia Severity Action Plan (DSAP) (36), which includes criteria for escalation of care level, as needed medications, and appropriate laboratory tests.During prolonged dyskinetic crises, healthcare providers must rule out complications such as rhabdomyolysis, electrolyte imbalances, and renal abnormalities.Optimal management involves continuous monitoring and adjustment of medication regimens based on clinical response and side effect profiles.Deep brain stimulation (DBS) has emerged as a promising therapeutic approach, particularly for severe and refractory dyskinetic crises, significantly ameliorating motor symptoms.For patients experiencing frequent or severe crises requiring hospitalization, early consideration of DBS in the treatment plan is crucial.Additionally, educating and supporting parents and caregivers is essential, as is fostering a coordinated approach and ensuring adherence to treatment plans.A personalized strategy that integrates various therapeutic modalities, including medications, surgical options (DBS), and assistive devices, has proven effective in addressing dyskinetic crises in GNAO1-RD, highlighting the significance of tailored, multidisciplinary interventions.Figure 4 summarizes the recommended management of background movement disorders, dyskinetic crisis, and dystonic/ dyskinetic status.

Comments
Additionally, employing clonidine rescue therapy in combination with chloral hydrate (where available) has proven to be beneficial in preemptively addressing GNAO1-RD dyskinetic crises, both in a home and hospital setting, effectively averting respiratory compromise (9).It is important to note that chloral hydrate is not available in the US, Italy, or France.Furthermore, considering the use of dexmedetomidine as an alternative in intermediate care and ICU settings, where IV clonidine may not be feasible.In certain cases, plasma exchange (3) or dialysis (13) have been employed in the treatment of complications, including rhabdomyolysis.

Dyskinetic crisis: acute pharmacological and surgical approach
Individualized pharmacological recommendations for the acute treatment of dyskinetic crises cannot be provided.Experts commonly preferred clonazepam, diazepam, and clonidine as the primary medications for managing dyskinetic crises, as indicated in Table 1, which presents the list of drugs ranked by first, second, or third preference.It is crucial to reiterate that chloral hydrate is not readily obtainable in many countries, including the United States, France, and Italy.

Basal movement disorder: chronic pharmacological approach
Individualized pharmacological recommendations for the chronic management of movement disorders in GNAO1-RD patients cannot be provided.Tetrabenazine, clonazepam, gabapentin, and clonidine emerged as the most preferred medications for managing movement disorders in GNAO1-RD patients.Table 1 presents the ranking of these drugs based on first, second, or third preference.It is worth noting that tetrabenazine has been prescribed to children younger than 12 months of age, with doses up to 10 mg/kg/day administered to GNAO1-RD patients under the care of experts in this

Dyskinetic crisis: additional factors and considerations
Statements 63-64 Upon GNAO1-RD diagnosis, initiating parental or caregiver education is imperative, encompassing detailed information about dyskinetic crises, their nature, and appropriate actions to take when a child experiences such episodes.Additionally, the variability in duration and frequency of dyskinetic crisis episodes among individuals with GNAO1-RD must be taken into account when characterizing the condition.

Comments
As time progresses, parents or primary caregivers often develop a keen ability to distinguish between these dyskinetic crises and epileptic seizures.Despite the initial difficulty, the caregivers' increasing familiarity with the patient's condition enables them to discern the distinct characteristics of dyskinetic crises, contributing to a more accurate identification and understanding of these events over time.

Discussion
GNAO1-RD represents a range of neurodevelopmental and movement disorders arising from pathogenic variants in the GNAO1 gene.Dyskinetic crises stand out as a highly distinctive feature, with significant morbidity and mortality.Using a modified Delphi consensus procedure and a literature review, we generated 90 statements regarding the dyskinetic crisis.These statements, which reflect the consensus of field experts, offer insights into the diagnostic and therapeutic landscapes of dyskinetic crises in patients with GNAO1-RD.Through this rigorous methodology, we reached a consensus on crucial aspects, including the definition of dyskinetic crises.This consensus framework addresses a substantial body of knowledge and management of various aspects of dyskinetic crises, yet it also reveals certain gaps in the clinical setting.By establishing a standardized foundation for research and clinical management of GNAO1-RD, it sheds light on areas that require further attention and development.
In the context of defining the movement disorder phenomenon, we assert that the terminology employed to accurately depict this manifestation should encompass essential attributes, including deviations from baseline movement disorders, duration, and intensity.Following the voting process during the third round of discussions, the decision was reached to retain the term "dyskinetic crisis," among other options considered.The term "crisis" signifies a sudden and intense manifestation or deterioration of a disorder, making it a fitting descriptor for the discussed phenomenon.Moreover, from the perspective of families with GNAO1-RD patients, referring to these events as "dyskinetic crisis" rather than using terms like "exacerbation" or "episode" might simplify communication and enhance clarity and understanding.
We also considered whether focal symptoms, such as orolingual dyskinesias (5,9,11,26), which are highly prevalent and sometimes Management of background movement disorders, dyskinetic crisis, and dystonic/dyskinetic status.The clinical approach for each state and recommended treatment strategies are shown.Importantly, consider the early initiation of treatment with DBS.incapacitating in patients with GNAO1-RD, should be included in the term "dyskinetic crisis."Although they may satisfy the paroxysmal onset and termination criterion, we have chosen to describe them separately from dyskinetic crises.Notably, orolingual dyskinesias have preceded the dyskinetic crisis in some cases.
An integral part of this consensus is the understanding of the triggers of these crises.The fact that GNAO1-RD has less-defined triggers, some of which may be anecdotal.Others, such as temperature changes (12,28), the use of antiemetics (e.g., metoclopramide), and anticholinergics (e.g., scopolamine, trihexyphenidyl) (26), are shared with other diseases characterized by paroxysmal phenomena.It is recommended that these medications be avoided or used with caution by these patients, beginning with very small doses and gradually increasing them as necessary.
Regarding diagnosis, we believe that clinical evaluation alone is adequate for diagnosing a dyskinetic crisis and that additional complementary assessments, such as video EEG, are not routinely required.
In our study, a genotype-phenotype correlation regarding the risk of dyskinetic crises could not be established.According to previously published articles, the most frequent pathogenic variants, including c.736G > A (11 patients), c.607G > A (7 patients), c.626G > A (6 patients), c.625C > T (5 patients), and c.709G > A (3 patients), are also associated with more frequent dyskinetic crises (13).Therefore, it cannot be ruled out that the occurrence of dyskinetic crises is related to the frequency of a variant rather than the specific susceptibility of a pathogenic variant to develop dyskinetic crises.
Dyskinetic crises pose significant risks to patients, both in the short and long term, as evidenced by the literature.Hence, mitigating these crises is paramount.While individualized recommendations may vary, we advocate for a multi-faceted approach to acute pharmacological intervention, emphasizing the use of clonidine, benzodiazepines, and chloral hydrate (where accessible).These agents have shown efficacy in mitigating acute dyskinetic crises.Moreover, to forestall exacerbations and recurrent crises, we advocate for sustained pharmacological management of the underlying In parallel, we acknowledge the potential of surgical interventions, particularly DBS, in refractory cases.While further research is needed to clearly establish precise indications and optimize its utilization as an advanced therapeutic modality, the literature provides ample examples of cases where DBS treatment has proven effective in managing treatment-resistant dystonic status and preventing recurrent crises.Therefore, we underscore the importance of continued research to elucidate the precise indications and optimize the utilization of DBS as an early and advanced therapeutic modality.
In terms of treatment, we have not discussed potential pharmacological interventions currently under investigation, such as the use of caffeine (40) and zinc acetate (41).Regarding caffeine, Di Rocco et al. demonstrated its ability to attenuate hyperkinetic behavior in mutated R209H and E246K Caenorhabditis elegans.Additionally, the use of istradefylline, a selective adenosine A2A receptor antagonist, indicated that caffeine operates via both adenosine receptordependent and receptor-independent mechanisms.Furthermore, caffeine has been shown to effectively reduce the frequency and duration of paroxysmal movement disorders in ADCY5 (42).Moreover, it has exhibited improvements in baseline movement disorders and various other motor and non-motor symptoms, consistently resulting in an enhanced quality of life.Regarding zinc acetate, a single-patient treatment involving a 3-year-old with a common GNAO1 mutation c607G > A/p.Gly203Arg, administered oral 50 mg Zn2+ daily for 11 months, resulted in the cessation of daily dyskinetic crises.These authors have categorized pathogenic Gαo mutations into three classes based on their sensitivity to Zn 2+ , with mutations in groups II and III potentially benefiting from zinc acetate treatment (41).
In the realm of movement disorders, it is also important to consider the differential diagnosis of dyskinetic crises with paroxysmal dyskinesias.In this regard, it is relevant to mention patients with GNB1 encephalopathy, in whom paroxysmal dyskinesias lasting for hours may be observed, usually triggered by fever and related to awakening (16).Additionally, episodes of dyskinesias in patients with ADCY5 mutations are noteworthy, consisting of severe, sleepdisrupting movements occurring during stages N2 and N3 of sleep (42,43).An important distinction in the case of GNB1 is the later age of onset compared to GNAO1-RD patients.Regarding ADCY5, a significant difference lies in its very close association with sleep.
Fundamentally, our research highlights the critical need for targeted parental and caregiver education following the diagnosis of GNAO1-RD.Parents and caregivers can become frontline advocates for managing their child's condition if they are well-informed about dyskinetic crises, their nature, and the appropriate actions to take during such episodes.By fostering an in-depth understanding of the distinctive characteristics of dyskinetic crises, caregivers will be able to recognize and respond swiftly to dyskinetic events.This proactive approach is invaluable, as it not only mitigates the immediate impact of dyskinetic crises but also potentially reduces the short-and longterm impacts.Early recognition leads to timely interventions, allowing for the administration of appropriate treatments, which may reduce the duration and severity of these episodes.
It is essential to acknowledge the limitations of our study.The difficulties in distinguishing dyskinetic crises from other neurological events, specifically epileptic seizures, require additional study.In addition, the lack of data on certain triggers, such as acute or chronic lack of sleep (which clonidine can ameliorate), necessitates further research to improve our understanding of the varied triggers that precipitate dyskinetic crises.Poor sleep hygiene and quality may precede a dyskinetic crisis by days or weeks, a phenomenon that can be monitored with easy-to-collate 24-h sleep-wake charts.Fragmented sleep patterns could represent early-warning 'weather patterns' of an impending dyskinetic crisis for which prophylactic nocturnal clonidine as a sleep regulator in GNAO1-RD requires further investigation.
Our findings challenge previously held beliefs regarding the correlation between GNAO1-RD severity and the incidence of dyskinetic crises.Milder phenotypes, which are frequently characterized by dystonic symptoms, do not always correlate with the presence of dyskinetic crises, emphasizing the need for additional research.Comprehensive long-term follow-up and natural history studies are required to identify specific risk factors, such as genotypes, age, and comorbid neurological characteristics, that may influence the occurrence and nature of dyskinetic crises.
In conclusion, our study represents an important step toward elucidating the complex nature of dyskinetic crises in GNAO1-RD.We have developed a comprehensive framework that not only defines dyskinetic crises but also outlines their clinical characteristics, triggers, and management.This foundational work lays the groundwork for improved clinical management, enhanced stakeholder communication, and future research endeavors.
field.It is important to note the potential role of DBS, although its application in emergency situations is inconsistent, despite its proven efficacy.

TABLE 1
Order of drug selection for the acute management of dyskinetic crisis and basal movement disorder in GNAO1-RD.