Diagnostic approach to paediatric movement disorders:a clinical practice guide

Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This can make the diagnostic process time-consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next-generation sequencing, post-sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs.</p

Challenges in Clinicogenetic Correlations:One Phenotype – Many Genes

Background: In the field of movement disorders, what you see (phenotype) is seldom what you get (genotype). Whereas 1 phenotype was previously associated to 1 gene, the advent of next-generation sequencing (NGS) has facilitated an exponential increase in disease-causing genes and genotype-phenotype correlations, and the "one-phenotype-many-genes" paradigm has become prominent.Objectives: To highlight the "one-phenotype-many-genes" paradigm by discussing the main challenges, perspectives on how to address them, and future directions.Methods: We performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype.Results: The notable challenges are (1) the lack of gold standards, overlap in clinical spectrum of different movement disorders, and variability in the interpretation of classification systems; (2) selecting which patients benefit from genetic tests and the choice of genetic testing; (3) problems in the variant interpretation guidelines; (4) the filtering of variants associated with disease; and (5) the lack of standardized, complete, and up-to-date gene lists. Perspectives to address these include (1) deep phenotyping and genotype-phenotype integration, (2) adherence to phenotype-specific diagnostic algorithms, (3) implementation of current and complementary bioinformatic tools, (4) a clinical-molecular diagnosis through close collaboration between clinicians and genetic laboratories, and (5) ongoing curation of gene lists and periodic reanalysis of genetic sequencing data.Conclusions: Despite the rapidly emerging possibilities of NGS, there are still many steps to take to improve the genetic diagnostic yield. Future directions, including post-NGS phenotyping and cohort analyses enriched by genotype-phenotype integration and gene networks, ought to be pursued to accelerate identification of disease-causing genes and further improve our understanding of disease biology

Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells.

The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.Molecular Physiolog

Bilateral Pallidotomy for Dystonia:A Systematic Review

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre-and postoperative Burke-Fahn-Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty-five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median-reported follow-up was 12 months (n = 83; range: 2-180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication-refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Are we on the right track in DBS surgery for dystonic head tremor?:Polymyography is a promising answer

The clinical benefit of Deep Brain Stimulation (DBS) is associated with electrode positioning accuracy. Intraoperative assessment of clinical effect is therefore key. Evaluating this clinical effect in patients with dystonic head tremor, as opposed to limb tremor, is challenging because the head is fixed in a stereotactic frame. To clinically assess head tremor during surgery, surface electromyography (EMG) electrodes were bilaterally applied to the sternocleidomastoid and cervical paraspinal muscles. This case shows that intraoperative polymyography is an easy and useful tool to assess the clinical effect of DBS electrode positioning

Crossing barriers:a multidisciplinary approach to children and adults with young-onset movement disorders

Abstract Background Diagnosis of less common young-onset movement disorders is often challenging, requiring a broad spectrum of skills of clinicians regarding phenotyping, normal and abnormal development and the wide range of possible acquired and genetic etiologies. This complexity often leads to considerable diagnostic delays, paralleled by uncertainty for patients and their families. Therefore, we hypothesized that these patients might benefit from a multidisciplinary approach. We report on the first 100 young-onset movement disorders patients who visited our multidisciplinary outpatient clinic. Methods Clinical data were obtained from the medical records of patients with disease-onset before age 18 years. We investigated whether the multidisciplinary team, consisting of a movement disorder specialist, pediatric neurologist, pediatrician for inborn errors of metabolism and clinical geneticist, revised the movement disorder classification, etiological diagnosis, and/or treatment. Results The 100 referred patients (56 males) had a mean age of 12.5 ± 6.3 years and mean disease duration of 9.2 ± 6.3 years. Movement disorder classification was revised in 58/100 patients. Particularly dystonia and myoclonus were recognized frequently and supported by neurophysiological testing in 24/29 patients. Etiological diagnoses were made in 24/71 (34%) formerly undiagnosed patients, predominantly in the genetic domain. Treatment strategy was adjusted in 60 patients, of whom 43 (72%) reported a subjective positive effect. Conclusions This exploratory study demonstrates that a dedicated tertiary multidisciplinary approach to complex young-onset movement disorders may facilitate phenotyping and improve recognition of rare disorders, with a high diagnostic yield and minimal diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a multidisciplinary approach in comparison to regular subspecialty care

The Effectiveness of Deep Brain Stimulation in Dystonia:A Patient-Centered Approach

Background: To systematically evaluate the effectiveness of deep brain stimulation of the globus pallidus internus (GPi-DBS) in dystonia on pre-operatively set functional priorities in daily living. Methods: Fifteen pediatric and adult dystonia patients (8 male; median age 32y, range 8-65) receiving GPi-DBS were recruited. All patients underwent a multidisciplinary evaluation before and 1-year post DBS implantation. The Canadian Occupational Performance Measure (COPM) first identified and then measured changes in functional priorities. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was used to evaluate dystonia severity. Results: Priorities in daily functioning substantially varied between patients but showed significant improvements on performance and satisfaction after DBS. Clinically significant COPM-score improvements were present in 7/8 motor responders, but also in 4/7 motor non-responders. Discussion: The use of a patient-oriented approach to measure GPi-DBS effectiveness in dystonia provides an unique insight in patients' priorities and demonstrates that tangible improvements can be achieved irrespective of motor response. Highlights: Functional priorities in life of dystonia patients and their caregivers vary greatlyThe effect of DBS on functional priorities did not correlate with motor outcomeHalf of the motor 'non-responder' patients reported important changes in their prioritiesThe effect of DBS in dystonia should not be measured by motor outcome alone