Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome.

BACKGROUND: Myoclonus-dystonia (MD) is a syndrome characterized by subcortical myoclonus and milder dystonia. The main causative gene is the epsilon sarcoglycan gene (SGCE), but other genes may be involved. Response to medications is variable, with poor tolerability limiting their use. CASE PRESENTATION: We present the case of a patient with severe myoclonic jerks and mild dystonia since childhood. At first neurological visit at the age of 46 years old, she presented brief myoclonic jerks predominating in the upper limbs and neck, mild at rest and elicited by action, posture and tactile stimulus. Myoclonus was accompanied by mild neck and right arm dystonia. Neurophysiological tests suggested subcortical origin of myoclonus, brain MRI was unremarkable. Myoclonus-dystonia was diagnosed, and genetic testing identified a novel mutation in SGCE gene (c.907delC) in heterozygosis. Over time she assumed a large variety of anti-epileptics without beneficial effect on myoclonus and low tolerability. Add-on treatment with Perampanel was started, with a beneficial effect. No adverse events were reported. Perampanel is the first selective non-competitive AMPA receptor antagonist approved in add-on for focal and generalized tonic-clonic seizures. To our knowledge, this is the first trial of Perampanel in MD. CONCLUSIONS: We presented the case of a patient with MD due to SGCE mutation who was treated with Perampanel with beneficial effects. We propose Perampanel as a novel treatment for myoclonus in MD.

Bilateral Pallidal Stimulation in a Family With Myoclonus Dystonia Syndrome Due to a Mutation in the Sarcoglycan Gene.

OBJECTIVES: The study aimed to present a family with myoclonus dystonia (M-D) syndrome due to a mutation in the epsilon sarcoglycan gene (SGCE). Three members of the family suffered from treatment-refractory severe myoclonic jerks of the neck, trunk, and upper extremities. The mild dystonic symptoms recognized as cervical dystonia or truncal dystonia affected all individuals. The efficacy of pharmacotherapy, including anticholinergic, dopaminergic, and serotoninergic drugs, has failed. One individual developed an alcohol dependency and suffered from alcoholic epilepsy. MATERIALS AND METHODS: The patients were referred for stereotactic surgery. All individuals underwent bilateral implantation of deep brain stimulation (DBS) leads into the posteroventrolateral segment of the globus pallidus internus (GPi). Surgeries were uneventful. The formal preoperative objective assessment included the Unified Myoclonus Rating Scale (UMRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The postoperative UMRS and BFMDRS assessments were done only under continuous stimulation at 3, 6, and 12 months after the surgery and at the last available follow-up ranging from 6 to 15 months (mean, 10 months follow-up). RESULTS: At the last follow-up visit, the rest and action parts of UMRS were improved by 93.3% and 88.2%, respectively, when compared to the baseline scores. The motor and disability scales of BFMDRS were improved by 77% and 43% at the last follow-up visit compared to the baseline BFMDRS scores. There were no hardware or stimulation-induced complications over the follow-up period. Positive social adjustment allowed two patients to regain jobs and one patient continued his education and hobbies. CONCLUSION: Our experience gathered in three individuals in the family with a mutation in SGCE indicates that bilateral GPi DBS can be an effective and safe treatment for disabling pharmacological resistant, intractable M-D syndrome.

Successful Unilateral Surgical Approach to Internal Globus Pallidus and Ventral Intermediate Nucleus of the Thalamus in 3 Cases of Myoclonus-Dystonia Syndrome.

Surgical approaches of internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (Vim) have been used to treat different movement disorders. Three subjects with myoclonus-dystonia syndrome were surgically treated, one of them with GPi and Vim stimulation, while radiofrequency ablation of these structures was performed in the other 2 subjects. Surgical approach of both targets was performed simultaneously on each subject. Mean follow-up was of 33.3 months (22-48 months), the Unified Myoclonus Rating Scale action myoclonus (AM), functional tests (FT), patient questionnaire (PQ) sub-scores, and the Unified Dystonia Rating Scale (UDRS) were used during assessments. Improvement in all scales were seen 6 months after surgery (AM: 74%, FT: 60%, PQ: 63%, UDRS: 65%), and this benefit persisted throughout follow-up (AM: 61%, FT:62%, PQ: 65%, UDRS: 86%). No adverse events were noticed. Simultaneous unilateral procedures of GPi and Vim by either stimulation or ablation techniques improve both motor and functional scores in myoclonus-dystonia syndrome.

Deep brain stimulation for myoclonus dystonia syndrome: a meta-analysis with individual patient data.

Good outcomes have been reported in deep brain stimulation (DBS) for myoclonus-dystonia syndrome (M-D), a heritable disease characterized by childhood-onset myoclonic jerks and dystonia in the upper body. This meta-analysis was to evaluate the clinical outcomes consecutively, compare the stimulation targets, and identify potential prognostic factors. A systematic literature search was performed on PubMed, Web of Science, and Embase. The primary outcome was the percent improvement in Burke-Fahn-Marsden Dystonia Rating Scale movement (BFMDRS-M) scores for dystonia and Unified Myoclonus Rating Scale (UMRS) scores for myoclonus at the last follow-up visit. BFMDRS-disability scores of the patients were also summarized. Pearson correlation analyses were performed to identify the myoclonus and dystonia outcome predictors. Thirty-one studies reporting 71 patients were included. There were significant improvements in BFMDRS-M and BFMDRS-disability scores in each time category and at the last follow-up visit. Mean improvement (%) in UMRS was 79.5 ± 18.2, and 94.1% of the patients showed > 50% improvement in UMRS scores at the last follow-up visit. There was a significant trend toward improved myoclonus outcome with older age at onset and shorter disease duration. Most of the adverse events were mild and transient, and pallidal stimulation seemed to be better with respect to fewer stimulation-induced events. Based on the current data, DBS is effective for even the severe M-D. Surgery at an early stage may predict a better outcome. Although targets do not serve as the outcome predictors, pallidal stimulation may be preferred due to fewer stimulation-induced events.

Clinical phenotype heterogeneity in a family with ε-sarcoglycan gene mutation.

AIM OF THE STUDY: This paper describes six cases of patients with myoclonus-dystonia syndrome who are members of a family in which an SGCE gene mutation has been confirmed. CLINICAL RATIONALE FOR THE STUDY: Myoclonus-dystonia syndrome is a very rare disease, with an incidence in Europe of about 2 in every million. Due to the fact that only a few case reports of this illness are accessible in the literature, the material we collected seems to be valuable for clinical practice. MATERIALS AND METHODS: A history was taken, and physical and genetic examinations of the patients were performed. Furthermore, the clinical examination of three patients was video-recorded. RESULTS: The clinical picture of the disease varied significantly between the described individuals, from a healthy carrier of the SGCE mutation to patients presenting mild to moderate symptoms. The differences concerned the age at onset of the disease, the initial symptoms, the intensity of involuntary movements, and the predominant symptoms. In addition to the typical movement disorders which are myoclonus and dystonia, in the described family there was also the coexistence of epilepsy, obsessive-compulsive behaviour, dyslexia, dysgraphia, non-harmonious development of cognitive processes, as well as mild phenotypic features of muscular dystrophy. The mutation (NM_001099401.2:c.806-809delACTG) found in the presented family has not been described elsewhere. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our description of six cases of patients demonstrates the heterogeneity of the natural course of the disease, even in patients with the same mutation. It seems reasonable to regularly examine relatives of patients with myoclonus-dystonia syndrome, who should be observed for involuntary movements as well as non-motor symptoms.

[Parasomnia and paroxysmal dyskinesia]. / Parasomnien und paroxysmale Dyskinesien.

Short involuntary paroxysmal movements or behavioral patterns are an important differential diagnosis to epileptic seizures, especially when occurring for the first time. Typically, these attacks are not witnessed by medically trained personnel and the patient anamnesis or observations by a third party are often not specific enough to differentiate between epileptic seizures and the differential diagnoses. This review presents the epidemiology, the clinical presentation, the necessary diagnostic steps and the differential diagnostic approach to parasomnias and dyskinesias. The focus is on the clinical aspects, and therapeutic principles are also briefly described.

Progression of neuropsychiatric and cognitive features due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene: a case report.

Physical symptoms of myoclonus dystonia due to epsilon-sarcoglycan mutations are well documented; however, the progression of neuropsychiatric and cognitive symptoms remains unclear. We present a case of a 34-year-old woman with early childhood onset of myoclonic jerks, dystonic posture and developmental delay due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene. Over time, she developed neuropsychiatric symptoms. She underwent bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus for her motor symptoms, which greatly improved but she exhibited slow deterioration of her neuropsychiatric and cognitive symptoms, particularly apathy, aggression and severe executive dysfunction.

Japanese familial case of myoclonus-dystonia syndrome with a splicing mutation in SGCE.

Myoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by brief, frequently alcohol-responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the ε-sarcoglycan gene (SGCE). The patient was a 6-year-old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements.

Myoclonus-Dystonia Plus Syndrome With Early-Onset Multiple Cerebral Cavernous Malformation Type 1 and Growth Hormone Deficiency Associated With Novel 7q21.13-q21.3 Deletion: A Pediatric Case Report.

Myoclonus-dystonia syndrome (MDS) presents with both rapid myoclonus and dystonia, which is caused by mutations in the sarcoglycan (SGCE) gene. However, its complications and management remain unclear. Here, we report a case involving a girl with MDS due to a 7q21.13-q21.3 microdeletion complicated by early-onset multiple cerebral cavernous malformations (CCMs). The patient presented with myoclonus and dystonia at two and eight years of age, respectively. In addition to MDS, the patient developed growth hormone (GH) deficiency and mild intellectual disability. Magnetic resonance imaging of the brain showed multiple CCMs. Array-based comparative genomic hybridization revealed 7q21.13-21.3 microdeletion. The deletion size was 4.11 Mb, which included SCGE and KRIT1. After the introduction of zonisamide, both myoclonus and dystonia showed improvement, and GH therapy led to an increase in patient height. In cases of MDS, multiple early-onset CCMs and GH deficiency may occur; moreover, careful follow-up management may be necessary.

Incomplete nonsense-mediated decay facilitates detection of a multi-exonic deletion mutation in SGCE.

Mutations in SGCE represent the major cause of the myoclonus-dystonia syndrome (DYT11), an autosomal dominant disorder of reduced penetrance. Virtually all affected individuals have myoclonus, which is concentrated in the upper extremities, neck and trunk. Over half of patients have dystonia, usually affecting the neck or arms. SGCE is maternally imprinted. Of the more than 70 SGCE mutations reported in the literature, 18 are large deletions disrupting at least one exon. Therefore, testing for exonic deletions should be considered in individuals with a classic phenotype in whom Sanger sequencing is unrevealing. However, standard methodologies for detection of exonic deletion mutations are expensive, labor intensive and can produce false negatives. Herein, we report the use of cDNA derived from leukocyte RNA to identify a deletion mutation (exons 4 and 5) of SGCE in a family with DYT11. Residual RNA from incomplete nonsense-mediated decay permitted reverse transcription to cDNA. Breakpoints of the 8939 bp heterozygous deletion were then defined with long-range polymerase chain reaction and Sanger sequencing. Use of cDNA generated by reverse transcription of leukocyte RNA can reduce the costs associated with diagnostic genetic testing and can facilitate detection of deletion mutations.

Two-Generation Epsilon-Sarcoglycan Gene (SGCE) Mutation-Associated Myoclonus-Dystonia (DYT-SGCE) Misdiagnosed as Tourette's Syndrome: A Case Series.

This case series provides a diagnosis of myoclonus-dystonia syndrome (MDS) in two patients whose original presentation was thought to be Tourette's syndrome. The first patient presented with dystonia and myoclonus, which progressively worsened with age, and was diagnosed with an epsilon-sarcoglycan gene (SGCE) mutation. The patient's father, who was diagnosed in his childhood with Tourette's syndrome, also received genetic testing, which proved that to be a misdiagnosis and confirmed that he was the carrier of the SGCE mutation. Both patients were subjected to a levodopa trial, which proved to be an effective treatment. To our knowledge, these are the first reported cases of heterozygous pathogenic mutation of SGCE in Puerto Rico.

Translating Genetic Discovery into a Mechanistic Understanding of Pediatric Movement Disorders: Lessons from Genetic Dystonias and Related Disorders.

The era of next-generation sequencing has increased the pace of gene discovery in the field of pediatric movement disorders. Following the identification of novel disease-causing genes, several studies have aimed to link the molecular and clinical aspects of these disorders. This perspective presents the developing stories of several childhood-onset movement disorders, including paroxysmal kinesigenic dyskinesia, myoclonus-dystonia syndrome, and other monogenic dystonias. These stories illustrate how gene discovery helps focus the research efforts of scientists trying to understand the mechanisms of disease. The genetic diagnosis of these clinical syndromes also helps clarify the associated phenotypic spectra and aids the search for additional disease-causing genes. Collectively, the findings of previous studies have led to increased recognition of the role of the cerebellum in the physiology and pathophysiology of motor control-a common theme in many pediatric movement disorders. To fully exploit the genetic information garnered in the clinical and research arenas, it is crucial that corresponding multi-omics analyses and functional studies also be performed at scale. Hopefully, these integrated efforts will provide us with a more comprehensive understanding of the genetic and neurobiological bases of movement disorders in childhood.

A Case Report of Siblings with Dystonia: A Potential Link Between DYT11 Mutation and Platelet Dysfunction.

Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon-sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.

Frameless robot-assisted pallidal deep brain stimulation surgery in pediatric patients with movement disorders: precision and short-term clinical results.

OBJECTIVE: The purpose of this study was to verify the safety and accuracy of the Neuromate stereotactic robot for use in deep brain stimulation (DBS) electrode implantation for the treatment of hyperkinetic movement disorders in childhood and describe the authors' initial clinical results. METHODS: A prospective evaluation of pediatric patients with dystonia and other hyperkinetic movement disorders was carried out during the 1st year after the start-up of a pediatric DBS unit in Barcelona. Electrodes were implanted bilaterally in the globus pallidus internus (GPi) using the Neuromate robot without the stereotactic frame. The authors calculated the distances between the electrodes and their respective planned trajectories, merging the postoperative CT with the preoperative plan using VoXim software. Clinical outcome was monitored using validated scales for dystonia and myoclonus preoperatively and at 1 month and 6 months postoperatively and by means of a quality-of-life questionnaire for children, administered before surgery and at 6 months' follow-up. We also recorded complications derived from the implantation technique, "hardware," and stimulation. RESULTS: Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months. The average accuracy in the placement of the electrodes was 1.24 mm at the target point. At the 6-month follow-up, patients showed an improvement in the motor (65%) and functional (48%) components of the Burke-Fahn-Marsden Dystonia Rating Scale. Patients with myoclonus and SGCE mutations also showed an improvement in action myoclonus (95%-100%) and in functional tests (50%-75%) according to the Unified Motor-Rating Scale. The Neuro-QOL score revealed inconsistent results, with improvement in motor function and social relationships but worsening in anxiety, cognitive function, and pain. The only surgical complication was medial displacement of the first electrode, which limited intensity of stimulation in the lower contacts, in one case. CONCLUSIONS: The Neuromate stereotactic robot is an accurate and safe tool for the placement of GPi electrodes in children with hyperkinetic movement disorders.

Psychiatric symptoms in myoclonus-dystonia syndrome are just concomitant features regardless of the SGCE gene mutation.

INTRODUCTION: Among myoclonus-dystonia syndrome (MD) patients, psychiatric disorders including depression, anxiety, alcohol dependence, obsessive-compulsive disorder (OCD) and panic disorder have been frequently reported to be related with the epsilon-sarcoglycan gene (SGCE) mutation. However, the rate of psychiatric disorders has not been compared between MD patients with the SGCE mutation (SGCE (+)) and without the SGCE mutation (SGCE (-)). We analyzed the psychiatric data in both SGCE (+) and SGCE (-) MD patients to determine the association of the SGCE mutation with psychiatric disorders in MD. METHODS: Twenty-six MD patients who fulfilled the Grunewald's criteria and underwent a SGCE gene study were enrolled. Patients were divided into two groups according to their SGCE status (SGCE (+) and SGCE (-) group). They were systematically assessed using a standardized protocol including motor severity scales and psychiatric questionnaires for depression, anxiety, alcohol dependence, OCD and panic disorder. RESULTS: Fifteen SGCE (+) and eleven SGCE (-) patients were enrolled. Mean age at onset, disease duration, family history, alcohol responsiveness and motor severity were not different between the SGCE (+) and SGCE (-) group. Although more than half (53.8%) of all the MD patients had psychiatric symptoms, there were no significant differences between the SGCE (+) and SGCE (-) group in terms of their psychiatric questionnaire scores and rate of psychiatric disorders. CONCLUSIONS: Psychiatric features are not likely to be related with the SGCE mutation itself but just bespeak disability in clinical MD syndrome regardless of the SGCE mutation.

Early deep brain stimulation in patients with myoclonus-dystonia syndrome.

Myoclonus-dystonia (MD) is a rare movement disorder which is disabling and frequently refractory to medical treatment. Deep brain stimulation (DBS) of the globus pallidus interna (GPi) has been used to treat some patients. Although there is significant motor improvement with DBS, the impact on disability and on quality of life has been infrequently reported. Also, the benefit of the procedure is not established in patients without ε-sarcoglycan gene (SGCE) mutations. We present two patients with severe MD treated with GPi-DBS, one of the patients without a SGCE mutation. Motor improvements (rest/action/total subscores of the Unified Myoclonus Rating Scale and movement subscore of the Burke-Fahn-Marsden Dystonia Rating Scale [BFMRS]) and disability (BFMRS disability subscore) were carefully evaluated preoperatively and at 6 and 12months after surgery. Quality of life (addressed using the Portuguese version of the Medical Outcomes Study 36-item Short-Form General Health Survey, version 2.0 [SF-36v2]) was tested preoperatively and 12months after DBS. At 12-month follow-up, myoclonus improved 78.6% in Patient 1 and 80.7% in Patient 2, while dystonia improved 37% and 86.7%, respectively. Improvements in disability ranged from 71.4% to 75%. With regard to quality of life, all parameters addressed by the SF-36v2 improved or stabilized in both patients. No major adverse effects were noticed. Improvements in motor symptoms are consistent with reports in the literature and were obtained regardless of the identification of a SGCE gene mutation. There were also significant benefits on disability and quality of life. DBS should be considered for MD.

Deep brain stimulation for the treatment of hyperkinetic movement disorders.

INTRODUCTION: Deep brain stimulation effectiveness is well recognized for different movement disorders including Parkinson's disease, dystonia and essential tremor, however several other diseases in this field may benefit from the technique although experience is sparse and evidences of benefit and risks are not established. AREAS COVERED: In this review, we explored available evidence for effectiveness and safety of DBS in selected hyperkinetic movement disorders, including tardive dyskinesia, Huntington's disease, neuroacanthocytosis, myoclonus-dystonia, Tourette syndrome, orthostatic and Holmes' tremor. Expert commentary: The data referenced and discussed showed potential effectiveness for DBS in these disabling and refractory diseases. On the other hand, these disorders are quite complex and multifaceted, often composed of different movement disorders, as well as other motor and non-motor symptoms. Therefore, the possible contribution of DBS in improving patients' quality of life should be weighted in a strictly individual basis, keeping in mind the progressive nature of most of these disorders, as well as risk/benefit ratio.

SGCZ mutations are unlikely to be associated with myoclonus dystonia.

BACKGROUND: Myoclonus dystonia syndrome (MDS) is a hyperkinetic movement disorder caused, in a proportion of cases, by mutations of the maternally imprinted epsilon-sarcoglycan gene (SGCE). SGCE mutation rates vary between cohorts, suggesting genetic heterogeneity. E- and ζ-sarcoglycan are both expressed in brain tissue. In this study we tested whether zeta-sarcoglycan gene (SGCZ) mutations also contribute to this disorder. METHODS: Patients with clinically suspected MDS and no SGCE mutation were recruited and classified, according to previously published criteria, as to their likelihood of the movement disorder. All SGCZ exons and intron/exon boundaries were screened by direct sequencing. RESULTS: Fifty-four SGCE mutation-negative patients were recruited from the UK and the Netherlands. Subdivided according to the likelihood of the movement disorder resulted in 17 'definite', 16 'probable' and 21 'possible' cases. No pathogenic SGCZ mutations were identified. CONCLUSIONS: SGCZ mutations are unlikely to contribute to the genetic heterogeneity in MDS.

A point mutation in ε-sarcoglycan induces inherited myoclonus dystonia syndrome in a Chinese family.

Myoclonus dystonia syndrome is a rare movement disorder featured by myoclonic jerks and dystonia. We identified here a point mutation in ε-sarcoglycan gene exon 6 associating with inherited myoclonus dystonia syndrome in a Chinese Han family. The mutation identified induces a stop codon and terminates the transcription of ε-sarcoglycan mRNA. This in turn results in a large truncation of ε-sarcoglycan protein. The further investigation is required to understand physiological and pathological functions of ε-sarcoglycan.