Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based ...on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.
Background
Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) ...are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1β (IL-1β), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1β and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses.
Results
Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1β and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1β was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called ‘conditioned medium’) that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1β or NO augmented the evoked release of CGRP by trigeminal neurons.
Conclusion
These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1β and NO). The responsiveness of IL-1β to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine.
GNAO1 variants were recently discovered as causes of epileptic encephalopathies and heterogeneous syndromes presenting with movement disorders (MDs), whose phenomenology and clinical course are yet ...undefined. We herein focused on GNAO1-related MD, providing an analytical review of existing data to outline the main MD phenomenology and management, clinical evolution and genotype-phenotype correlations.
Reviewing 41 previously published patients and assessing 5 novel cases, a comprehensive cohort of 46 patients was analyzed, reassuming knowledge about genotypes, phenotypes, disease course and treatment of this condition. GNAO1-related MD consisted of a severe early-onset hyperkinetic syndrome, with prominent chorea, dystonia and orofacial dyskinesia. Symptoms are poorly responsive to medical therapy and fluctuate, with critical and life-threatening exacerbations, such as status dystonicus. The presence of a choreiform MD appears to be predictive of a higher risk of movement disorder emergency. Surgical treatments are sometimes effective, although severe disabilities persist. Differently from the early infantile epileptic encephalopathy phenotype (associated with loss of function variants), no clear correlation between genotype and MD phenotype emerged, although some variants recurred more frequently, mainly affecting exons 6 and 7.
•A comprehensive review of MD features in GNAO1-encephalopathy is provided.•Movement disorder is a core feature of GNAO1-encephalopathy.•Choreiform movement disorder is a risk factor for movement disorder emergencies.•Variants affecting the Arg 209 residue cause a prominent movement disorder phenotype.•Loss of function variants cause more frequently early onset epileptic encephalopathy.
GNAO1 gene mutations are associated with a neurodevelopmental disorder characterized by developmental delay, epilepsy, and movement disorder. Eye tracking and eye movement analysis are an intriguing ...method to assess cognitive and language function and, to the best of our knowledge, it has never been tested in a standardized way in GNAO1. GNAO1 children are usually wheelchair-bound and with numerous motor constrains, including dystonic movements and postures, heterotropia, and hypotonia, making the cognitive assessment arduous. These contribute to the burden and disability, with a high level of frustration of caregivers and patients. We have herein demonstrated that, through an eye tracking system, six GNAO1 patients evaluated showed variable degrees of communicative intent through intentionally directed gaze. Moreover, three of these were able to complete a cognitive evaluation, and showed normal fluid intelligence and lexical comprehension. In conclusion, in GNAO1-related disorders, the degree of cognitive development is underestimated; eye tracking technologies may help in overcome these boundaries.
In recent years, genetic techniques of diagnosis have shown rapid development, resulting in a modified clinical approach to many diseases, including neurological disorders. Movement disorders, in ...particular those arising in childhood, pose a diagnostic challenge. First, from a purely phenomenological point of view, the correct clinical classification of signs and symptoms may be difficult and require expert evaluation. This is because the clinical picture is often a mixture of hyperkinetic and hypokinetic disorders, and within hyperkinetic movement disorders, combined phenotypes are not unusual. Second, although several genes that cause movement disorders in children are now well-known, many of them have only been described in adult populations or discovered in patients after many years of disease. Furthermore, diseases that alter their mechanisms from childhood to adulthood are still little known, and many phenotypes in children are the result of a disruption of normal neurodevelopment. High-throughput gene screening addresses these difficulties and has modified the approach to genetic diagnosis. In the exome-sequencing era, customized genetic panels now offer the ability to perform fast and low-cost screening of the genes commonly involved in the pathogenesis of the disease. Here, we describe a 3-year study using a customized gene panel for pediatric-onset movement disorders in a selected cohort of children and adolescents. We report a satisfying diagnostic yield, further confirming the usefulness of gene panel analysis.
We aimed to conduct a state-of-the-art review of the current literature and offer further insights into the methodological aspects concerning induced sputum. The increasing popularity of sputum ...induction as a non-invasive and cost-effective method for obtaining lower airway secretions from patients who cannot produce sputum naturally has led to extensive research and applications in respiratory conditions like asthma and COPD. This technique allows for analysis of the cellular and biochemical components of the sputum to take place, providing insights into airway inflammation, immune cells, and help in predicting treatment response. Furthermore, induced sputum enables various analyses, including microRNA and gene expression studies and immunophenotyping. The procedure is generally safe and well tolerated, even in patients with airflow limitations; however, monitoring lung function is essential, especially in those with airway hyperresponsiveness. Optimal saline solution concentration and inhalation duration have been investigated, recommending a 15–20 min induction with hypertonic saline. Expectoration involves coughing at the end of each inhalation time. Careful handling during sputum processing is necessary for obtaining accurate results in cell cytology, immunocytochemistry, and in situ hybridization. Overall, induced sputum offers significant advantages as a preferred alternative for large-scale and repeated airway sampling, despite some technical demands and limitations.
Acute Movement Disorders in Childhood Garone, Giacomo; Graziola, Federica; Grasso, Melissa ...
Journal of clinical medicine,
06/2021, Letnik:
10, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Acute-onset movement disorders (MDs) are an increasingly recognized neurological emergency in both adults and children. The spectrum of possible causes is wide, and diagnostic work-up is challenging. ...In their acute presentation, MDs may represent the prominent symptom or an important diagnostic clue in a broader constellation of neurological and extraneurological signs. The diagnostic approach relies on the definition of the overall clinical syndrome and on the recognition of the prominent MD phenomenology. The recognition of the underlying disorder is crucial since many causes are treatable. In this review, we summarize common and uncommon causes of acute-onset movement disorders, focusing on clinical presentation and appropriate diagnostic investigations. Both acquired (immune-mediated, infectious, vascular, toxic, metabolic) and genetic disorders causing acute MDs are reviewed, in order to provide a useful clinician’s guide to this expanding field of pediatric neurology.
ATP1A3
mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and ...cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in
ATP1A3-
related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different
ATP1A3
variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of
ATP1A3
mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of
ATP1A3-
related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.
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