Dystonia manifests as slow twisting movements (pure dystonia) or repetitive, jerky motions (jerky dystonia). Dystonia can coexist with myoclonus (myoclonus dystonia) or tremor (tremor dystonia). Each of these presentations can have distinct etiology, can involve discrete sensorimotor networks, and may have characteristic neurophysiological signature. This study reports distinct neurophysiological signatures corresponding to the phenomenological subcategories and associations of dystonia. We studied 17 dystonia patients undergoing deep brain stimulation surgery. Video-based movement tracking classified them into four phenomenological subcategories: myoclonus dystonia, pure dystonia, jerky dystonia, and tremor dystonia. Microelectrode recordings from the globus pallidus interna (GPi) and externa (GPe) were analyzed to characterize single-neuron activity reflecting underlying physiology. Analysis of 1038 neurons revealed distinct patterns of burst, pause, and tonic activity across subtypes. Myoclonus dystonia had the highest prevalence of burst neurons in the GPi, while tremor dystonia showed a balanced distribution of burst and pause neurons. Myoclonus and pure dystonia had higher firing rates compared to tremor and jerky dystonia. Tremor dystonia showed the most irregular and bursty firing patterns. Overall, myoclonus and tremor dystonia had higher burst rates and lower interburst intervals than pure and jerky dystonia, highlighting distinct neuronal activity patterns across the different dystonia types. The differences in pallidal neuron activity across the phenoemenological subtypes and associations of dystonia depict distinct neural mechanisms. These findings offer crucial physiological insights into the diverse phenomenology of different dystonia types.

SGCE myoclonus-dystonia is a monogenic form of dystonia with an autosomal dominant mode of inheritance that co-occurs with a myoclonic jerk. In this study, we present 12 Japanese patients from nine families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified nine distinct SGCE mutations from each of the families: three nonsense, two frameshift, two missense, one in-frame 15 bp deletion, and one splice donor site mutations, of which four were previously unreported. One missense mutation (c.662G>T, p.Gly221Val) was located at the 3' end of exon 5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays performed together with the c.825+1G>C mutation demonstrated complete skipping of exon 5 and 6, respectively, in their transcripts. The other missense (c.1345A>G, p.Met449Val) and 15 bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed a significant reduction in cell membrane expression via HiBiT bioluminescence assay. Therefore, we concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only isoform 3 (NP_001092870 encoded by NM_001099400) among the variously known isoforms of SGCE. This isoform is brain-specific and is mostly expressed in the cerebellum, which supports recent studies showing that cerebellar dysfunction is a key element in the pathophysiology of SGCE myoclonus-dystonia.

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. 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). 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. 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.

Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in SGCE, a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of SGCE-linked M-D is unknown, the pathogenicity of SGCE variants identified in patients with M-D may be indeterminant, and SGCE variants predicted to be deleterious by in silico analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies. SGCE variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated SGCE variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated SGCE pathogenic variants. Within gnomAD v2, there were 56, 408, and 1250 alleles harboring SGCE variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an SGCE variant with a CADD score ≥ 25. SGCE M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious SGCE variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees. In silico analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious SGCE variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.

Myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with M-D. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M-D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways.