ε-sarcoglycan myoclonus-dystonia—overview of neurophysiological, behavioral, and imaging characteristics

Myoclonus-Dystonia is a rare, neurological movement disorder, clinically characterized by myoclonic jerks and dystonic symptoms, such as cervical dystonia and writer’s cramp. Psychiatric symptoms, like anxiety, depression, and addiction, are frequently reported. Monogenic Myoclonus-Dystonia is mostly caused by pathogenic variants in the ε-sarcoglycan gene, which is among other regions highly expressed in the cerebellum. The current pharmacological treatment is not satisfactory. Neurophysiological and imaging studies in this patient population are scarce with partly heterogeneous results and sometimes important limitations. However, some studies point towards subcortical alterations, e.g., of the cerebellum and its connections. Further studies addressing previous limitations are important for a better understanding of the underlying pathology of Myoclonus-Dystonia and might build a bridge for the development of future treatment

Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia

In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ε-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ε-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D

Interrater reliability of motor severity scales for hemifacial spasm

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants\u27 motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee\u27s scale), clinical grading of spasm intensity (Chen\u27s scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc\u27s scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from poor to moderate ; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee\u27s, Chen\u27s, and Tunc\u27s scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc\u27s scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc\u27s scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training

Functional Characterization of Rare RAB12 Variants and Their Role in Musician's and Other Dystonias

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician's dystonia (MD) and writer's dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A> G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson's disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias

Complex dystonias: an update on diagnosis and care

Complex dystonias are defined as dystonias that are accompanied by neurologic or systemic manifestations beyond movement disorders. Many syndromes or diseases can present with complex dystonia, either as the cardinal sign or as part of a multi-systemic manifestation. Complex dystonia often gradually develops in the disease course, but can also be present from the outset. If available, the diagnostic workup, disease-specific treatment, and management of patients with complex dystonias require a multi-disciplinary approach. This article summarizes current knowledge on complex dystonias with a particular view of recent developments with respect to advances in diagnosis and management, including causative treatments

Prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus-dystonia.

BACKGROUND: Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. METHOD: We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. RESULTS: Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. CONCLUSION: About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed

Temporal discrimination threshold and blink reflex recovery cycle in cervical dystonia – two sides of the same coin?

IntroductionElevated temporal discrimination thresholds (TDT) have been found in cervical dystonia (CD) and unaffected first-degree relatives, indicating autosomal dominant inheritance with reduced penetrance, serving as an endophenotype and being indicative of abnormal inhibitory processing within the brainstem-basal ganglia circuits. The blink reflex R2 recovery cycle (BRRC) is also a measure of excitability of brainstem-basal ganglia circuits, and inconsistent findings are reported in CD. The aim was to investigate TDT and BRRC in CD and evaluate its reliability as an endophenotype.Methods29 patients with isolated cervical dystonia (mean age: 56.1 ± 14.3, female n = 18) and 29 age- and gender-matched healthy controls (mean age: 56.0 ± 14.2, female n = 18) were evaluated using a TDT-paradigm, performed as previously described by testing visual, tactile and visual-tactile temporal discrimination thresholds, and the BRRC, investigated with electrical and air puff stimulation.ResultsMean visual-tactile (p = 0.001) and visual TDTs (p = 0.015) differed between CD and controls; tactile TDTs revealed no group differences (p = 0.232). No between group differences were found for BRRC using either electrical or air puff stimulation (p = 0.117). There was no correlation between the elevation of TDTs and the degree of BRRC-inhibition in CD.ConclusionOur findings support the hypothesis that the TDT is an endophenotype in CD. BRRC testing did not demonstrate disinhibition of brainstem-basal ganglia circuits in CD. In contrast to TDT, the BRRC seems not to represent an endophenotype in cervical dystonia

Predictors of alcohol responsiveness in dystonia

Objective To determine predictors of alcohol responsiveness in a large cohort of patients with dystonia. Methods A total of 2,159 participants with dystonia were prospectively enrolled in the cross-sectional Dystonia Coalition multicenter study. Patients with secondary, combined, or confirmed genetic dystonia (total n = 164) or unknown alcohol responsiveness (n = 737) were excluded. Patients answered a standardized questionnaire and were clinically examined using a standardized video protocol and the Burke-Fahn-Marsden Dystonia Rating Scale. Alcohol responsiveness was determined by patients\u27 self-report. Results A total of 1,258 patientswith isolated dystonia (mean age: 59.5 ± 12.2 years; 898 women) met the inclusion criteria; 369 patients (29.3%) reported improvement of dystonia after alcohol consumption. Alcohol responsiveness was not related to sex (p = 0.742), age (p = 0.715), or severity of dystonia (p = 0.623). Age at onset was lower in patients who responded to alcohol (p \u3c 0.001). Alcohol responsiveness differed across dystonia subgroups (multifocal/generalized \u3e segmental [p = 0.014]; cervical and laryngeal \u3e cranial and limb [p \u3c 0.001]) and was related to a positive family history of movement disorders (p = 0.001), and presence of tremor (p \u3c 0.001). Conclusion The association of alcohol responsiveness with a positive family history for movement disorders, generalized dystonia, and an earlier age at onset suggests that patients with dystonia who have an underlying genetic contribution may be more likely to respond beneficially to alcohol. The fact that dystonic tremor may respond to alcohol is in keeping with the observation that the intake of GABAergic drugs may have a beneficial effect in a proportion of patients

Associative plasticity in supplementary motor area - motor cortex pathways in Tourette syndrome

The important role of the supplementary motor area (SMA) in the generation of tics and urges in Gilles de la Tourette syndrome (GTS) is underscored by an increased SMA-motor cortex (M1) connectivity. However, whether plasticity is also altered in SMA-M1 pathways is unclear. We explored whether SMA-M1 plasticity is altered in patients with Tourette syndrome. 15 patients with GTS (mean age of 33.4 years, SD = 9.9) and 19 age and sex matched healthy controls were investigated with a paired association stimulation (PAS) protocol using three transcranial magnetic stimulation (TMS) coils stimulating both M1 and the SMA. Standard clinical measures for GTS symptoms were collected. There was a significant PAS effect showing that MEP amplitudes measured in blocks during and after PAS were significantly higher compared to those in the first block. However, the degree of PAS was not differentially modulated between patients and controls as shown by a Bayesian data analysis. PAS effects in GTS correlated positively with the YGTSS motor tic severity. Plasticity previously reported to be altered in sensorimotor pathways in GTS is normal in SMA-M1 projections suggesting that the dysfunction of the SMA in GTS is not primarily related to altered plasticity in SMA-M1 connections