The natural history of progressive myoclonus ataxia.

Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild cognitive impairment and infrequent epileptic seizures. This is the first study to describe the natural history of PMA and identify clinical, electrophysiological, and genetic features explaining the variability in disease progression. A Dutch cohort of consecutive patients meeting the criteria of the refined definition of PMA was included.

Conventional and novel anti-seizure medications reveal a particular role for GABA in a North Sea progressive myoclonus Epilepsy Drosophila model.

Objective: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p.

Clinical Characteristics Suggestive of a Genetic Cause in Cerebral Palsy: A Systematic Review.

Background: Cerebral palsy (CP) is a clinical diagnosis and was long categorized as an acquired disorder, but more and more genetic etiologies are being identified. This review aims to identify the clinical characteristics that are associated with genetic CP to aid clinicians in selecting candidates for genetic testing.

Methods: The PubMed database was systematically searched to identify genes associated with CP.

Physician's conceptions of the decision-making process when managing febrile infants ≤ 60 days old: a phenomenographic qualitative study.

Background: The management of febrile infants aged ≤ 60 days and adherence to guidelines vary greatly. Our objective was to describe the process of decision-making when managing febrile infants aged ≤ 60 days and to describe the factors that influenced this decision.

Methods: We conducted 6 focus group discussions with 19 clinically active physicians in the pediatric emergency departments of 2 university hospitals in Skåne region, Sweden.

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.

Early onset ataxia with comorbid myoclonus and epilepsy: A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement.

Objectives: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown.

Gut Microbiome Composition in Dystonia Patients.

Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut-brain axis.

A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism.

Background: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy-to-use clinical screening tool to help recognize movement disorders.

Objective: The aim is to develop a user-friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs.

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms.

Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021.

Methylation of the serotonin reuptake transporter gene and non-motor symptoms in dystonia patients.

Background: Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms.

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients.

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking.

Serotonergic system in vivo with [C]DASB PET scans in GTP-cyclohydrolase deficient dopa-responsive dystonia patients.

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms.

The Mitochondrial Epigenome: An Unexplored Avenue to Explain Unexplained Myopathies?

Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies.

Developmental neurobiology of cerebellar and Basal Ganglia connections.

Background: The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network.

Methods: In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia.

Development and Validation of Decision Rules Models to Stratify Coronary Artery Disease, Diabetes, and Hypertension Risk in Preventive Care: Cohort Study of Returning UK Biobank Participants.

Many predictive models exist that predict risk of common cardiometabolic conditions. However, a vast majority of these models do not include genetic risk scores and do not distinguish between clinical risk requiring medical or pharmacological interventions and pre-clinical risk, where lifestyle interventions could be first-choice therapy. In this study, we developed, validated, and compared the performance of three decision rule algorithms including biomarkers, physical measurements, and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension against commonly used clinical risk scores in 60,782 UK Biobank participants.

Case Report: "Niemann-Pick Disease Type C in a Catatonic Patient Treated With Electroconvulsive Therapy".

We describe a case of an adolescent male with Niemann-Pick Type C (NP-C), a neurodegenerative lysosomal lipid storage disorder, who presented with recurrent catatonia which required repeated treatment with electroconvulsive therapy (ECT). During the ECT-course, seizure threshold increased substantially, leading to questions about the influence of NP-C on neuronal excitability. In this exemplary ECT-patient, NP-C was diagnosed not until after the first ECT-course when initial psychopharmacology for catatonia had failed and antipsychotics and benzodiazepines showed significant .

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients.

Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations.

The neurological and neuropsychiatric spectrum of adults with late-treated phenylketonuria.

Introduction: Phenylketonuria (PKU) is a rare, treatable inborn error of metabolism with frequent neurological and neuropsychiatric complications, especially in undiagnosed or insufficiently treated individuals. Given the wide range of clinical presentations and the importance of treatment implications, we here delineate the neurological and neuropsychiatric symptom spectrum in a large cohort of previously unreported adults with late-treated PKU.

Methods: We consecutively evaluated late-treated PKU cases and pooled clinical and paraclinical data, including video-material, from three centers with expertise in complex movement disorders, inborn errors of metabolism and pediatrics.

Treatment of ARS deficiencies with specific amino acids.

Purpose: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections.

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.

How to detect late-onset inborn errors of metabolism in patients with movement disorders - A modern diagnostic approach.

We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists.

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology.

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD), are still unclear. In 80 EOA-patients, we determined the EOAD-prevalence in association with MRI-abnormalities.