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Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology. Epilepsies are common brain disorders and are classified based on clinical phenotyping, imaging and genetics. Here, the authors perform genome-wide association studies for 3 broad and 7 subtypes of epilepsy and identify 16 loci - 11 novel - that are further annotated by eQTL and partitioned heritability analyses.

Myasthenic syndromes are typically characterized by muscle weakness and increased fatigability due to an impaired transmission at the neuromuscular junction (NMJ). Most cases are caused by acquired autoimmune conditions such as myasthenia gravis (MG), typically with antibodies against the acetylcholine receptor (AChR). Different drugs are among the major factors that may complicate pre-existing autoimmune myasthenic conditions by further impairing transmission at the NMJ. Some clinical observations are substantiated by experimental data, indicating that presynaptic, postsynaptic or more complex pathomechanisms at the NMJ may be involved, depending on the individual compound. Most robust data exist for the risks associated with some antibiotics (e.g., aminoglycosides, ketolides, fluoroquinolones) and cardiovascular medications (e.g., class Ia antiarrhythmics, beta blockers). Apart from primarily autoimmune-mediated disorders of the NMJ, myasthenic manifestations may also be triggered by medical treatments that induce an autoimmune reaction. Most notably, there is growing evidence that the immune checkpoint inhibitors (ICI), a modern class of drugs to treat various malignancies, represent a relevant risk factor to develop severe and progressive medication-induced myasthenia via an immune-mediated mechanism. From a clinical perspective, it is of utmost importance for the treating physicians to be aware of such adverse treatment effects and their consequences. In this article, we aim to summarize existing evidence regarding the key molecular and immunological mechanisms as well as the clinical implications of medication-aggravated and medication-induced myasthenic syndromes.

This study investigated treatment characteristics of Guillain-Barré syndrome (GBS) in a real-world setting between 2000 and 2019. We analyzed clinical improvement between nadir and last follow-up in patients with severe GBS (defined as having a GBS disability scale > 2 at nadir) and aimed to detect clinical factors associated with multiple treatments. We included 121 patients (74 male; median age 48 [IQR 35–60]) with sensorimotor (63%), pure motor (15%), pure sensory (10%) and localized GBS (6%) as well as Miller Fisher syndrome (6%). 44% of patients were severely affected. All but one patient received at least one immunomodulatory treatment with initially either intravenous immunoglobulins (88%), plasma exchange (10%) or corticosteroids (1%), and 25% of patients received more than one treatment. Severe GBS but not age, sex, GBS subtype or date of diagnosis was associated with higher odds to receive more than one treatment (OR 4.22; 95%CI 1.36–13.10; p  = 0.01). Receiving multiple treatments had no adjusted effect (OR 1.30, 95%CI 0.31–5.40, p  = 0.72) on clinical improvement between nadir and last follow-up in patients with severe GBS. This treatment practice did not change over the last 20 years.

BackgroundThe genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.Methods112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE.ResultsES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants.ConclusionThis study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.

Background Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. Methods We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. Results Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0–4.3) in Austria. The most frequent genetic etiology was CHRNE ( n  = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 ( n  = 4), RAPSN ( n  = 3), COLQ ( n  = 2), GMPPB ( n  = 2), CHAT ( n  = 1), COL13A1 ( n  = 1), MUSK ( n  = 1) and AGRN ( n  = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. Conclusions Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype–phenotype correlations that may help to improve the diagnostic approach and patient management.

PurposeARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Background Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. The diagnosis typically relies on clinical features, serologic testing, and neurophysiological assessment but provocation tests such as the edrophonium test can provide rapid supportive information; however, data on its diagnostic performance are limited. Thus, we aimed to evaluate the diagnostic performance and safety of the edrophonium test in MG. Methods We conducted a retrospective case–control study of patients who underwent an edrophonium test at the Department of Neurology of the Medical University of Vienna between January 1991 and January 2024. We calculated sensitivity, specificity, and likelihood ratios and performed a multivariable logistic regression analysis to identify variables associated with a positive edrophonium test. Additionally, we assessed the safety of the edrophonium test. Results We included 182 patients with MG (41.2% female; mean age 55.8 years) and 324 controls (55.2% female; mean age 53.6 years). The edrophonium test had a sensitivity of 83.5% and a specificity of 87.7% in diagnosing MG. Patients with a decrement after repetitive nerve stimulation had higher odds of a positive response to the edrophonium test (OR 3.79, 95% CI 1.48–10.33, p  = 0.0067), while odds were lower in patients with MuSK-MG compared to patients with AChR-MG (OR 0.08, 95% CI 0.01–0.82, p  = 0.0254). Adverse events were reported in 58 patients (11.5%), in most of whom (53 patients, 91.4%) they were mild. Conclusions We provide data on the diagnostic performance and safety of the edrophonium test, supporting its use as an adjunctive diagnostic test for the diagnosis of MG.

Objective To investigate whether the rs10191329 risk allele in the DYSF–ZNF638 locus, which is implicated in central nervous system resilience rather than immune‐mediated pathology, is associated with retinal layer thinning, a biomarker of neuroaxonal damage in relapsing multiple sclerosis (RMS). Methods From a prospective observational study, we included RMS patients with ≥ 2 optical coherence tomography (OCT) scans, excluding eyes with optic neuritis during the observation period. DNA samples were genotyped using the Illumina Infinium Global Screening Array‐24 and variants imputed using the Haplotype Reference Consortium panel and Minimac4. Multivariable linear regression models were used to assess the association between rs10191329 risk allele number (rs10191329*A) and annualized rates of peripapillary retinal nerve fiber layer (aLpRNFL) and macular ganglion‐cell‐and‐inner‐plexiform‐layer (aLGCIPL) atrophy, adjusting for age, sex, MS‐specific variables, and 10 ancestry components. Results We included 183 RMS patients (mean age 35.9 years [SD 9.6], 74.9% female, median EDSS 2.0 [range 0–6.5], median observation 25 months [12–73], median OCT scans 3 [2–5]). Multivariable analyses revealed that each rs10191329*A allele was associated with a 0.10%/year increase in aLpRNFL (95% confidence interval [CI] 0.05–0.19, p < 0.001) and a 0.11%/year increase in aLGCIPL (95% CI 0.07–0.19, p < 0.001). The rs10191329 variant explained 8.9% of GCIPL atrophy and 8.2% of pRNFL atrophy variance. Interpretation Carriers of the rs10191329 risk allele show accelerated retinal atrophy, suggesting heightened neuroaxonal vulnerability in MS. While clinical implications are currently unclear, genetic stratification may be reasonable in clinical trials targeting neuroprotection.

Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.