Catnip for MedCAT: Optimizing the Input for Automated SNOMED CT Mapping of Clinical Variables.

Introduction: Mapping local medical data assets to international data standards such as medical ontology SNOMED CT fosters data harmonization and, thereby, global progress in medical research. Since its intense resource requirements often hinder manual SNOMED CT mapping, automated mapping tools such as MedCAT have been developed. We investigated how the formulation of study variable names (VNs) influences the efficacy and accuracy of the SNOMED CT concepts identified by MedCAT.

Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients.

Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remain poorly understood. While numerous genetic etiologies have been implicated, systematic characterization across diverse populations is lacking.

Lesion distribution and network mapping in dyskinetic cerebral palsy.

Dyskinetic cerebral palsy encompasses a group of predominantly perinatally acquired complex motor disorders that present with dystonia and/or choreoathetosis and are frequently associated with brain lesions in neuroimaging. Recently, lesion network mapping provided a tool to redefine neurological disorders as circuitopathies. Elucidating the common networks impacted by lesions in this condition could pave the way to identify new targets for neuromodulatory therapeutic approaches.

Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families.

Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.

Introduction: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B.

Dystonia caused by ANO3 variants is due to attenuated Ca influx by ORAI1.

Background: Dystonia is a common neurological hyperkinetic movement disorder that can be caused by mutations in anoctamin 3 (ANO3, TMEM16C), a phospholipid scramblase and ion channel. We previously reported patients that were heterozygous for the ANO3 variants S651N, V561L, A599D and S651N, which cause dystonia by unknown mechanisms.

Methods: We applied electrophysiology, Ca measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca signals and defective activation of K channels in patients heterozygous for the ANO3 variants.

Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.

Background: De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.

Methods: Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.

The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons.

A Novel Video-Based Methodology for Automated Classification of Dystonia and Choreoathetosis in Dyskinetic Cerebral Palsy During a Lower Extremity Task.

Background: Movement disorders in children and adolescents with dyskinetic cerebral palsy (CP) are commonly assessed from video recordings, however scoring is time-consuming and expert knowledge is required for an appropriate assessment.

Objective: To explore a machine learning approach for automated classification of amplitude and duration of distal leg dystonia and choreoathetosis within short video sequences.

Methods: Available videos of a heel-toe tapping task were preprocessed to optimize key point extraction using markerless motion analysis.

GNAO1 Mutations Affecting the N-Terminal α-Helix of Gαo Lead to Parkinsonism.

Background: Patients carrying pathogenic variants in GNAO1 present a phenotypic spectrum ranging from severe early-onset epileptic encephalopathy and developmental delay to mild adolescent/adult-onset dystonia. Genotype-phenotype correlation and molecular mechanisms underlying the disease remain understudied.

Methods: We analyzed the clinical course of a child carrying the novel GNAO1 mutation c.

Diffusion tensor imaging in pediatric patients with dystonia.

Background: Childhood-onset dystonia is often progressive and severely impairs a child´s life. The pathophysiology is very heterogeneous and treatment responses vary in patients with dystonia. Factors influencing treatment effects remain to be elucidated.

Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia.

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia.

Novel Genetic and Phenotypic Expansion in -Related Progressive Myoclonus Epilepsy.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene () have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a -related disorder and novel genetic and clinical findings.

Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation.

Background: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare.

Objectives: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP.

Neuroimaging-based analysis of DBS outcomes in pediatric dystonia: Insights from the GEPESTIM registry.

Introduction: Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity to a specific distribution pattern within brain networks. Such information is usually collected using group-level analysis, which relies on the availability of normative imaging resources (atlases and connectomes).

Genotype-phenotype correlation and treatment effects in young patients with -associated disorders.

Background: Patients carrying pathogenic variants in often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations.

Dystonia management across Europe within ERN-RND: current state and future challenges.

Background: Since the first European-wide evaluation of dystonia management in 2016, several efforts have been made to improve dystonia-care. One of these was the development of the Dystonia Disease Group as a part of the European Reference Network for Rare Neurological Diseases (ERN-RND) that implemented several initiatives based on the recommendations made in 2016.

Aim: To evaluate the current state of dystonia management across Europe.

Quality of Life After Deep Brain Stimulation of Pediatric Patients with Dyskinetic Cerebral Palsy: A Prospective, Single-Arm, Multicenter Study with a Subsequent Randomized Double-Blind Crossover (STIM-CP).

Background: Patients with dyskinetic cerebral palsy are often severely impaired with limited treatment options. The effects of deep brain stimulation (DBS) are less pronounced than those in inherited dystonia but can be associated with favorable quality of life outcomes even in patients without changes in dystonia severity.

Objective: The aim is to assess DBS effects in pediatric patients with pharmacorefractory dyskinetic cerebral palsy with focus on quality of life.