Publications by authors named "Robert Jech"

145 Publications

Genetic overlap between dystonia and other neurologic disorders: A study of 1,100 exomes.

Parkinsonism Relat Disord 2022 Jul 18;102:1-6. Epub 2022 Jul 18.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address:

Introduction: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia.

Methods: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability.

Results: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia.

Conclusions: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.
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http://dx.doi.org/10.1016/j.parkreldis.2022.07.003DOI Listing
July 2022

The Instrumental Activities of Daily Living in Parkinson's Disease Patients Treated by Subthalamic Deep Brain Stimulation.

Front Aging Neurosci 2022 17;14:886491. Epub 2022 Jun 17.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czechia.

Background: Everyday functioning and instrumental activities of daily living (IADL) play a vital role in preserving the quality of life in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS).

Objective: The main goal of the current study was to examine IADL change in pre-and post-surgery of the STN-DBS. We also analyzed the influence of the levodopa equivalent daily dose (LEDD) and global cognitive performance (Dementia Rating Scale; DRS-2) as covariates in relation to IADL.

Methods: Thirty-two non-demented PD patients were administered before and after STN-DBS neurosurgery the Penn Parkinson's Daily Activities Questionnaire (PDAQ; self-report), the DRS-2 and Beck Depression Inventory (BDI-II) to assess IADL change, global cognition, and depression.

Results: We found a positive effect of STN-DBS on IADL in the post-surgery phase. Moreover, lower global cognition and lower LEDD are predictive of lower IADL in both pre-surgery and post-surgery examinations.

Summary/conclusion: STN-DBS in PD is a safe method for improvement of everyday functioning and IADL. In the post-surgery phase, we show a relation of IADL to the severity of cognitive impairment in PD and to LEDD.
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http://dx.doi.org/10.3389/fnagi.2022.886491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247575PMC
June 2022

Multi-centre classification of functional neurological disorders based on resting-state functional connectivity.

Neuroimage Clin 2022 Jun 17;35:103090. Epub 2022 Jun 17.

Psychosomatic Medicine, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Background: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting.

Methods: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation).

Results: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%).

Conclusions: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms.
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http://dx.doi.org/10.1016/j.nicl.2022.103090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240866PMC
June 2022

Bridging structural and functional biomarkers in functional movement disorder using network mapping.

Brain Behav 2022 05 16;12(5):e2576. Epub 2022 Apr 16.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

Background: There are gaps in our neurobiological understanding of functional movement disorder (FMD).

Objectives: We investigated gray matter volumetric profiles in FMD, and related findings to resting-state functional connectivity (rsFC) profiles using Human Connectome Project data.

Methods: Volumetric differences between 53 FMD patients and 50 controls were examined, as well as relationships between individual differences in FMD symptom severity and volumetric profiles. Atrophy network mapping was also used to probe whether FMD-related structural alterations preferentially impacted brain areas with dense rsFC.

Results: Compared to controls without neurological comorbidities (albeit with mild depression and anxiety as a group), the FMD cohort did not show any volumetric differences. Across patients with FMD, individual differences in symptom severity negatively correlated with right supramarginal and bilateral superior temporal gyri volumes. These findings remained significant adjusting for FMD subtype or antidepressant use, but did not remain statistically significant adjusting for depression and anxiety scores. Symptom severity-related structural alterations mapped onto regions with dense rsFC-identifying several disease epicenters in default mode, ventral attention, and salience networks.

Conclusions: This study supports that FMD is a multinetwork disorder with an important role for the temporoparietal junction and its related connectivity in the pathophysiology of this condition. More research is needed to explore the intersection of functional neurological symptoms and mood.
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http://dx.doi.org/10.1002/brb3.2576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120728PMC
May 2022

Symptom-severity-related brain connectivity alterations in functional movement disorders.

Neuroimage Clin 2022 3;34:102981. Epub 2022 Mar 3.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital in Prague, Czech Republic. Electronic address:

Background: Functional movement disorders, a common cause of neurological disabilities, can occur with heterogeneous motor manifestations including functional weakness. However, the underlying mechanisms related to brain function and connectivity are unknown.

Objective: To identify brain connectivity alterations related to functional weakness we assessed network centrality changes in a group of patients with heterogeneous motor manifestations using task-free functional MRI in combination with different network centrality approaches.

Methods: Task-free functional MRI was performed in 48 patients with heterogeneous motor manifestations including 28 patients showing functional weakness and 65 age- and sex-matched healthy controls. Functional connectivity differences were assessed using different network centrality approaches, i.e. global correlation, eigenvector centrality, and intrinsic connectivity. Motor symptom severity was assessed using The Simplified Functional Movement Disorders Rating Scale and correlated with network centrality.

Results: Comparing patients with and without functional weakness showed significant network centrality differences in the left temporoparietal junction and precuneus. Patients with functional weakness showed increased centrality in the same anatomical regions when comparing functional weakness with healthy controls. Moreover, in the same regions, patients with functional weakness showed a positive correlation between motor symptom severity and network centrality. This correlation was shown to be specific to functional weakness with an interaction analysis, confirming a significant difference between patients with and without functional weakness.

Conclusions: We identified the temporoparietal junction and precuneus as key regions involved in brain connectivity alterations related to functional weakness. We propose that both regions may be promising targets for phenotype-specific non-invasive brain stimulation.
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http://dx.doi.org/10.1016/j.nicl.2022.102981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921488PMC
March 2022

Progressive choreodystonia in X-linked hyper-IgM immunodeficiency: a rare but recurrent presentation.

Ann Clin Transl Neurol 2022 04 10;9(4):577-581. Epub 2022 Mar 10.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications.
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http://dx.doi.org/10.1002/acn3.51538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994980PMC
April 2022

SPG11: clinical and genetic features of seven Czech patients and literature review.

Neurol Res 2022 May 7;44(5):379-389. Epub 2022 Mar 7.

Department of Paediatric Neurology, Neurogenetic Laboratory, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague.

SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.
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http://dx.doi.org/10.1080/01616412.2021.1975224DOI Listing
May 2022

Tremor associated with similar structural networks in Parkinson's disease and essential tremor.

Parkinsonism Relat Disord 2022 02 23;95:28-34. Epub 2021 Dec 23.

Central European Institute of Technology (CEITEC), Masaryk University, Neuroscience Centre, Brno, Czech Republic.

Introduction: Despite substantial clinical and pathophysiological differences, the characteristics of tremor in Parkinson's disease (PD) and essential tremor (ET) patients bear certain similarities. The presented study delineates tremor-related structural networks in these two disorders.

Methods: 42 non-advanced PD patients (18 tremor-dominant, 24 without substantial tremor), 17 ET, and 45 healthy controls underwent high-angular resolution diffusion-weighted imaging acquisition to reconstruct their structural motor connectomes as a proxy of the anatomical interconnections between motor network regions, implementing state-of-the-art globally optimised probabilistic tractography.

Results: When compared to healthy controls, ET patients exhibited higher structural connectivity in the cerebello-thalamo-cortical network. Interestingly, the comparison of tremor-dominant PD patients and PD patients without tremor yielded very similar results - higher structural connectivity in tremor-dominant PD sharing multiple nodes with the tremor network detected in ET, despite the generally lower structural connectivity between basal ganglia and frontal cortex in the whole PD group when compared to healthy controls.

Conclusion: The higher structural connectivity of the cerebello-thalamo-cortical network seems to be the dominant tremor driver in both PD and ET. While it appears to be the only tremor-related network in ET, its combination with large scale hypoconnectivity in the frontal cortico-subcortical network in PD may explain different clinical features of tremor in these two disorders.
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http://dx.doi.org/10.1016/j.parkreldis.2021.12.014DOI Listing
February 2022

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes.

Ann Neurol 2022 02 20;91(2):225-237. Epub 2022 Jan 20.

University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.

Objective: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases.

Methods: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients.

Results: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10).

Interpretation: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.
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http://dx.doi.org/10.1002/ana.26293DOI Listing
February 2022

WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.

Parkinsonism Relat Disord 2022 01 2;94:54-61. Epub 2021 Dec 2.

Department of Neurology, Charles University, First Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.

Introduction: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia.

Methods: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed.

Results: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity.

Conclusions: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
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http://dx.doi.org/10.1016/j.parkreldis.2021.11.030DOI Listing
January 2022

Brittle Biballism-Dystonia in a Pediatric Patient with GNAO1 Mutation Managed Using Pallidal Deep Brain Stimulation.

Mov Disord Clin Pract 2021 Jan 4;8(1):153-155. Epub 2021 Jan 4.

Department of Child Neurology Faculty of Medicine of Masaryk University Brno, University Hospital Brno Brno Czech Republic.

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http://dx.doi.org/10.1002/mdc3.13118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607975PMC
January 2021

Expiratory Muscle Strength Training in Patients with Parkinson's Disease: A Pilot Study of Mobile Monitoring Application.

Mov Disord Clin Pract 2021 Oct 4;8(7):1148-1149. Epub 2021 Aug 4.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine Charles University and General University Hospital Prague Czech Republic.

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http://dx.doi.org/10.1002/mdc3.13313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485587PMC
October 2021

Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Brain 2022 04;145(2):644-654

Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
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http://dx.doi.org/10.1093/brain/awab360DOI Listing
April 2022

Asymmetry of the insula-sensorimotor circuit in Parkinson's disease.

Eur J Neurosci 2021 09 6;54(6):6267-6280. Epub 2021 Sep 6.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.

Patients with Parkinson's disease (PD) experience motor and non-motor symptoms, suggesting alterations of the motor and/or limbic system or more probably of their communications. We hypothesized that the communication between the insula (part of the limbic system) and sensorimotor cortex in PD is altered and hemispheric asymmetric. Furthermore, that this asymmetry relates to non-motor symptoms, and specifically, that apathy-related asymmetry is unique to PD. To test these hypotheses, we used a novel multivariate time-frequency analysis method applied to resting-state functional magnetic resonance imaging (MRI) data of 28 controls and 25 participants with PD measured in their OFF medication state. The analysis infers directionality of coupling, that is, afferent or efferent, among four anatomical regions, thus defining directed pathways of information flow, which enables the extension of symmetry measures to include directionality. A major right asymmetry reduction of the dorsal-posterior insula efferent and a slight bilateral increase of insula afferent pathways were observed in participants with PD versus controls. Between-group pathways that correlated with mild cognitive impairments combined the central-executive and default-mode networks through the right insula. Apathy-correlated pathways of the posterior insula in participants with PD versus controls exhibited reduced right efferent and increased left afferent. Because apathy scores were comparable between the groups and effects of the other motor and non-motor symptoms were statistically removed by the analysis, the differences in apathy-correlated pathways were suggested as unique to PD. These pathways could be predictors in the pre-symptomatic phase in patients with apathy.
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http://dx.doi.org/10.1111/ejn.15432DOI Listing
September 2021

The sensitivity of ECG contamination to surgical implantation site in brain computer interfaces.

Brain Stimul 2021 Sep-Oct;14(5):1301-1306. Epub 2021 Aug 21.

MRC Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.

Background: Brain sensing devices are approved today for Parkinson's, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability.

Objectives: Investigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity.

Methods: Electric field modeling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination.

Results: The impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination.

Conclusions: Given the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for "closed-loop" algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration.
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http://dx.doi.org/10.1016/j.brs.2021.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460992PMC
November 2021

Dystonia as a prominent presenting feature in developmental and epileptic encephalopathies: A case series.

Parkinsonism Relat Disord 2021 09 11;90:73-78. Epub 2021 Aug 11.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Technical University of Munich, Munich, Germany; School of Medicine, Institute of Human Genetics. Electronic address:

Introduction: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum.

Methods: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained.

Results: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2.

Conclusions: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.
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http://dx.doi.org/10.1016/j.parkreldis.2021.08.007DOI Listing
September 2021

Severely disabled multiple sclerosis patients can achieve the performance of healthy subjects after expiratory muscle strength training.

Mult Scler Relat Disord 2021 Oct 5;55:103187. Epub 2021 Aug 5.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Katerinska 30, 128 21 Prague 2, Czech Republic.

Background: The efficacy of expiratory muscle strength training (EMST) in patients with multiple sclerosis (MS) is controversial. The current study's primary objective was to test the effects of a progressive and intensive 12 week home based EMST program on expiratory muscle strength and voluntary cough strength. The secondary objective was to determine the retention of EMST benefits.

Methods: Thirty-five severely disabled MS patients (relapsing-remitting MS, n = 15; primary progressive MS, n = 5; secondary progressive MS, n = 15) with Expanded Disability Status Scale (EDSS) 5.0 - 7.0 were included in the study. Within 36 weeks, patients completed 12 weeks of a non-training period, 12 weeks of EMST and 12 weeks of a detraining period. Maximal expiratory pressure (PEmax) and voluntary peak cough flow (vPCF) were assessed 4 times: at week 0 (baseline), week 12 (pre-training), week 24 (post-training), and week 36 (post-detraining). MS patients included in the study were compared to age- and sex-matched healthy subjects. In the healthy controls, the PEmax and vPCF were assessed once to obtain normative data.

Results: Twenty-six patients completed the training period (mean age 52.7 ± 10.2, EDSS 5.9 ± 0.6) and were compared to 26 sex- and age-matched healthy subjects (mean age 53.5 ± 5.8). Patients with MS had a lower PEmax (p = 0.002) and vPCF (p = 0.022) at baseline than the healthy control group. In training period, the PEmax and vPCF increased (p = 0.0000; effect size: d = 0.94 and p = 0.0036; d = 0.57 respectively) in comparison with the non-training period (p = 0.0692; d = -0.36 and p = 0.5810; d = 0.11 respectively). Following the 12 weeks detraining period, the PEmax and vPCF declined but remained 16.7% and 5.5% respectively above the pre-training values. No differences were observed in the PEmax and vPCF between the MS group at the post-training and post-detraining timepoint and the healthy control group normative values.

Conclusions: EMST improves expiratory muscle strength and voluntary cough strength in severely disabled MS patients.
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http://dx.doi.org/10.1016/j.msard.2021.103187DOI Listing
October 2021

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Nat Genet 2021 07 1;53(7):1006-1021. Epub 2021 Jul 1.

McMaster University, Hamilton, Ontario, Canada.

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.
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http://dx.doi.org/10.1038/s41588-021-00886-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273149PMC
July 2021

Dystonia Management: What to Expect From the Future? The Perspectives of Patients and Clinicians Within DystoniaNet Europe.

Front Neurol 2021 3;12:646841. Epub 2021 Jun 3.

Expertise Centre Movement Disorders Groningen, Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands.

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the , the which however only existed for a limited time), and the Dutch project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.
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http://dx.doi.org/10.3389/fneur.2021.646841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211212PMC
June 2021

Guided Self-rehabilitation Contracts Combined With AbobotulinumtoxinA in Adults With Spastic Paresis.

J Neurol Phys Ther 2021 07;45(3):203-213

UR 7377 BIOTN, Université Paris-Est Créteil, Albert Chenevier-Henri Mondor Hospital, Department of Neurorehabilitation, Créteil, France (J.M.G.); Department of Physical Medicine and Rehabilitation, the University of Texas Health Science Center at Houston McGovern Medical School, and the Neurorecovery Research Center at TIRR Memorial Hermann, Houston, Texas (G.E.F.); Department of Neurology, First Faculty of Medicine, Charles University, and General Faculty Hospital, Prague, Czech Republic (R.J.); Neurology Department, Federal State Hospital, Treatments and Rehabilitation, Center of Ministry of Health and Social Development of Russian Federation, Moscow, Russia (S.K.); and Ipsen Pharma, Boulogne- Billancourt, France (C.D.R., P.M).

Background And Purpose: Guided self-rehabilitation contracts (GSCs) are a diary-based rehabilitation strategy, wherein specific muscles are identified for prescription of high-load, home self-stretching techniques. We assessed the effect of GSCs combined with simultaneous upper limb (UL) and lower limb (LL) abobotulinumtoxinA injections on composite active range of motion (CXA) in adults with chronic spastic paresis.

Methods: This was an international, prospective, single-arm, open-label study (ENGAGE, NCT02969356). Personalized GSCs were monitored by phone every other week, alongside 2 consecutive abobotulinumtoxinA injections (1500 U) across UL and LL, over 6 to 9 months. Primary outcomes were responder rates (CXA improvement ≥35° [UL] or ≥5° [LL]) at week 6 cycle 2. Secondary outcomes were active function (UL: Modified Frenchay Scale [MFS]; LL: 10-m barefoot maximal walking speed [WS]) and quality of life (12-item Short Form Health Survey, SF-12).

Results: Of the 153 treated participants, 136 had primary endpoint data; 72.1% (95% confidence interval [CI], 64.0-78.9) were responders. Mean (SD) CXA changes from baseline to last study visit were +49.3° (63.4) for UL and +20.1° (27.6) for LL. Mean (95% CI) changes from baseline to week 12 cycle 2 were +0.55 (0.43-0.66) in MFS, +0.12 m/s (0.09-0.15) for WS, and +4.0 (2.8-5.2) for SF-12 physical scores. In the safety population (n = 157), 49.7% of participants reported treatment-emergent adverse events (AEs); 12.1% reported 25 serious AEs.

Discussion And Conclusions: GSC combined with simultaneous UL and LL abobotulinumtoxinA injections led to improvements in CXA and function in both limbs, and quality-of-life physical scores. These results suggest the beneficial effect of combined GSC and abobotulinumtoxinA therapy in the management of spastic paresis.Video Abstract available for more insight from the authors (see the Supplementary Video, available at: http://links.lww.com/JNPT/A346).
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http://dx.doi.org/10.1097/NPT.0000000000000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191476PMC
July 2021

Trisomy X syndrome with dystonia and a pathogenic SATB1 variant.

Neurol Sci 2021 Sep 24;42(9):3883-3884. Epub 2021 May 24.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

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http://dx.doi.org/10.1007/s10072-021-05320-0DOI Listing
September 2021

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

Mov Disord 2021 08 5;36(8):1959-1964. Epub 2021 May 5.

Klinik für Neurologie, Asklepios Fachklinikum Stadtroda, Stadtroda, Germany.

Background: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications.

Objectives: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity).

Methods: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses.

Results: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81.

Conclusions: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28614DOI Listing
August 2021

Concomitant Medication Usage with Levodopa-Carbidopa Intestinal Gel: Results from the COSMOS Study.

Mov Disord 2021 08 28;36(8):1853-1862. Epub 2021 Apr 28.

Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain.

Background: Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels.

Objective: The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD.

Methods: The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter.

Results: Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment.

Conclusions: LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453961PMC
August 2021

Myoclonic dystonia phenotype related to a novel calmodulin-binding transcription activator 1 sequence variant.

Neurogenetics 2021 05 6;22(2):137-141. Epub 2021 Mar 6.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.
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http://dx.doi.org/10.1007/s10048-021-00637-6DOI Listing
May 2021

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome.

Ann Clin Transl Neurol 2021 04 6;8(4):951-955. Epub 2021 Mar 6.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.
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http://dx.doi.org/10.1002/acn3.51335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045898PMC
April 2021

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Clin Genet 2021 07 1;100(1):14-28. Epub 2021 Mar 1.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
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http://dx.doi.org/10.1111/cge.13946DOI Listing
July 2021

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Parkinsonism Relat Disord 2021 03 12;84:129-134. Epub 2021 Feb 12.

Lehrstuhl für Sozialpädiatrie, Technische Universität München, Munich, Germany; Kbo-Kinderzentrum München, Munich, Germany.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia.

Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource.

Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone.

Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.013DOI Listing
March 2021

When can maximal efficacy occur with repeat botulinum toxin injection in upper limb spastic paresis?

Brain Commun 2021 18;3(1):fcaa201. Epub 2020 Nov 18.

Ipsen Pharma, Les Ulis, France.

Repeated injection cycles with abobotulinumtoxinA, a botulinum toxin type A, are recommended in current clinical guidelines as a treatment option for adults with upper limb spastic paresis. However, the magnitude of the maximal therapeutic effect of repeated abobotulinumtoxinA treatment across different efficacy parameters and the number of injection cycles required to reach maximal effect remain to be elucidated. Here, we present a exploratory analysis of a randomized, double-blind, placebo-controlled trial (12-24 weeks; NCT01313299) and open-label extension study (up to 12 months; NCT0131331), in patients aged 18-80 years with hemiparesis for ≥6 months after stroke/traumatic brain injury. Two inferential methods were used to assess the changes in efficacy parameters after repeat abobotulinumtoxinA treatment cycles: Mixed Model Repeated Measures analysis and Non-Linear Random Coefficients analysis. Using the latter model, the expected maximal effect size (not placebo-controlled) and the number of treatment cycles to reach 90% of this maximal effect were estimated. Treatment responses in terms of passive and perceived parameters (i.e. modified Ashworth scale in primary target muscle group, disability assessment scale for principal target for treatment or limb position, and angle of catch at fast speed) were estimated to reach near-maximal effect in two to three cycles. Near-maximal treatment effect for active parameters (i.e. active range of motion against the resistance of extrinsic finger flexors and active function, assessed by the Modified Frenchay Scale) was estimated to be reached one to two cycles later. In contrast to most parameters, active function showed greater improvements at Week 12 (estimated maximal change from baseline-modified Frenchay Scale overall score: +0.8 (95% confidence interval, 0.6; 1.0) than at Week 4 (+0.6 [95% confidence interval, 0.4; 0.8]). Overall, the analyses suggest that repeated treatment cycles with abobotulinumtoxinA in patients chronically affected with upper limb spastic paresis allow them to relearn how to use the affected arm with now looser antagonists. Future studies should assess active parameters as primary outcome measures over repeated treatment cycles, and assess efficacy at the 12-week time-point of each cycle, as the benefits of abobotulinumtoxinA may be underestimated in the studies of insufficient duration. In this analysis of repeated abobotulinumtoxinA injection cycles in upper limb spastic paresis, Gracies used statistical modelling to elucidate the maximal therapeutic effect of abobotulinumtoxinA. Notably, the number of injections required to reach this maximal effect was higher for active (e.g. active function) compared with passive (e.g. tone) parameters.
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http://dx.doi.org/10.1093/braincomms/fcaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850141PMC
November 2020
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