Hyperkinetic Involuntary Movements Research Articles

Mitochondrial targeted antioxidants as potential therapy for huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development.

Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report

BackgroundThis case report presents a patient with progressive memory loss and choreiform movements.Case presentationNeuropsychological tests indicated multi-domain amnestic mild cognitive impairment (aMCI), and neurological examination revealed asymmetrical involuntary hyperkinetic movements. Imaging studies showed severe left-sided atrophy and hypometabolism in the left frontal and temporoparietal cortex. [18F]Flortaucipir PET exhibited moderately increased tracer uptake in hypometabolic areas. The diagnosis initially considered Alzheimer’s disease (AD), frontotemporal degeneration (FTD), and corticobasal degeneration (CBD), cerebral hemiatrophy syndrome, but imaging and cerebrospinal fluid analysis excluded AD and suggested fused-in-sarcoma-associated FTD (FTLD-FUS), a subtype of the behavioural variant of FTD.ConclusionsOur case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case. Imaging in particular allowed an accurate measure of the topography and severity of neurodegeneration and the exclusion of AD-related pathology.

Atypical Neurological Presentation in a Patient with Uncontrolled Diabetes

Chorea is a disorder characterized by irregular and involuntary hyperkinetic movements associated with malfunctioning the basal ganglia. One of the rarest acquired causes of unilateral or bilateral chorea is hyperglycemia. This is a case of an elderly female diabetic who presented With 3 days history of unilateral involuntary movements of the upper limb and lower limb, irrelevant talk, and altered sensorium. She had a random blood glucose level of 418 mg/dl with hemoglobin A1C (HbA1c) of 15% and normal ketones. Magnetic resonance imaging brain demonstrated T1 hyperintense and T2 flair hypointense right basal ganglia. Diagnosis of nonketotic hyperglycemic chorea was considered. The patient was treated with insulin, antipsychotics, and benzodiazepines and the chorea resolved after proper control of glucose levels. This condition can be reversible with early identification and treatment. This disorder can be prevented with good glycemic control.

Idiopathic (Oral) and Tardive Dyskinesia: Pathogenesis, Epidemiology, and Treatment

Etymologically, dyskinesia is a combination of the prefix "dys-," which means 'abnormality' and the suffix "-kinesia," which means 'movement.' In a broad sense, dyskinesia indicates hyperkinetic involuntary movements. In a narrow sense, as a general term, dyskinesia refers to combinations of one or more of the following movements: chorea, dystonia, tremor, ballism, athetosis, tics, and myoclonus. In this article, we describe the pathogenesis, epidemiology, and treatment of idiopathic (oral) and tardive dyskinesia.

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist-induced orofacial dyskinesia.

Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.

An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease.

Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

HEMICHOREA-HEMIBALLISM IN VARIOUS CONDITIONS: SERIAL CASE REPORTS

Introduction: Hemichorea-hemiballism (HCHB) is an uncommon movement disorder involved unilateral extremities characterized by irregular, poorly patterned, a continual hyperkinetic involuntary movement disorder in the proximal or distal parts of the body. The acute development of HCHB depends on focal lesions on the contralateral basal ganglia and subthalamic nuclei. Various conditions such as cerebrovascular, neurodegenerative, neoplastic, immunologic, infectious, and metabolic diseases are known as secondary causes of HCHB. This paper aims to compare and discuss the HCHB in various etiologies. Case Reports: Here, we reported 5 cases of HCHB induced by non-ketotic hyperosmolar hyperglycemia (NKKH), thrombotic stroke, and toxoplasmosis cerebral. We compare the admission data, clinical course, imaging, treatment, and outcome of every case. Conclusion: Various hypotheses have been proposed to explain the pathophysiology of HCHB due to these conditions. Principally, the main management for these cases is to determine the etiology and correct the underlying disorder

Clinical features, neuroimaging findings and treatment outcomes in non ketotic hyperglycemic hemichorea-hemiballismus

Introduction: Nonketotic hyperglycemic hemichorea-hemiballism (NKHH) is an uncommon hyperkinetic movement disorder. It is the second most common etiology after stroke affecting basal ganglion. Only a few hundred cases are reported so far in literature. Objectives: The study attempts to systematically highlight clinical profile and neuroimaging findings in 15 patients of Nonketotic hyperglycemic hemichorea-hemiballism. Materials and Methods: Patients with hemichorea/ hemiballism associated with hyperglycemia were included in the study. The period of the study was from January 2008 to September 2018. Neurological examination, Demographic data, clinical, biochemical, and neuroimaging findings were captured from the medical records. Details of the involuntary hyperkinetic movements such as type and side(s) involved were noted. Treatment was aimed to control glycemic status and neuroleptic drugs. Descriptive statistics were used wherever necessary. Results: During the study period, 52 patients had hemichorea/ hemiballismus.27 patients had stroke affecting basal ganglia.6 patients had granuloma affecting basal ganglia. 4 patients had Wilson’s disease.15 patients had NKHH. Among 15 patients of NKHH, 9 patients were females and 6 were males. (Female to male 1.5:1).The mean age at the onset was 70.2 years (Range 58 -85). The mean serum glucose levels measured after the onset of NKHH was 439.93 mg/dL (Range 342-532).The mean glycated haemoglobin was 10.98% (Range 9.1-18.5.Neuroimaging showed involvement of striatum in 13 patients. Conclusion: NKHH is a rare hyperkinetic movement disorder. Elderly poorly controlled diabetics and female sex are most commonly affected. Neuroimaging findings are distinct. Further studies are needed to elucidate pathogenesis of this disease and for determining prognosticating factors. Keywords: Non ketotic, hyperglycemia, Hemichorea-hemiballism, Putamen, Striatum.

Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements.

To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

Phenotypic characterization of paroxysmal dyskinesia in Maltese dogs.

BackgroundParoxysmal dyskinesias (PDs) are a group of central nervous system diseases characterized by episodes of abnormal involuntary hyperkinetic movement without altered consciousness that increasingly have been recognized in dogs.ObjectivesTo present the phenotypical characterization, treatment, and outcome of a PD observed in Maltese dogs.AnimalsClient‐owned Maltese dogs (n = 19) with presumed diagnosis of PD.MethodsData were collected retrospectively from medical records (2014‐2019), and supporting information was added prospectively by using a questionnaire directed to the owners of the affected dogs.ResultsThe episodes were characterized mainly by sudden dystonia of ≥1 limbs and generalized body tremors with preserved consciousness. The mean age of clinical onset was 5.4 years. Episode frequency varied widely both among and within individuals. Median episode duration was 4.5 minutes. Most episodes were stress‐ or exercise‐induced. Acetazolamide was administered to 6 dogs, and 4 dogs experienced a decrease in episode frequency. In 7 dogs that received a gluten‐free diet, 6 dogs became episode‐free. In 4 dogs, the episodes stopped spontaneously and in 2 dogs no medication or specific diet was given and the episodes continued at the same frequency.Conclusions and Clinical ImportanceGiven the breed predisposition and regional distribution of the disease, additional research should focus on elucidating the underlying genetic cause doing so might advance both our understanding of the pathophysiology and treatment of this disease, not only in dogs, but also in humans. Regardless of the treatment protocol selected, prognosis appears fair to good.

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone.

Neurodevelopmental disorder with involuntary movements (Online Mendelian Inheritance in Man: 617493) is a severe, early onset neurologic condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause neurodevelopmental disorder with involuntary movements. Gα o, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G proteins. Go is found abundantly throughout the brain, but the pathophysiological mechanisms linking Gα o functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1 +/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the neurodevelopmental disorder with involuntary movements clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1 +/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from wild-type (WT) mice, but the nucleotide exchange rate of mutant R209H Gα o was 6.2× faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1 +/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent. SIGNIFICANCE STATEMENT: Children with de novo mutations in the GNAO1 gene may present with movement disorders with limited effective therapeutic options. The most common mutant variant seen in children with GNAO1-associated movement disorder is R209H. Here we show, using a novel Gnao1 +/R209H mouse, that there is a clear behavioral phenotype that is suppressed by risperidone. However, risperidone also affects wild-type mouse activity, so its effects are not selective for the GNAO1-associated movement disorder.

The Rodent Models of Dyskinesia and Their Behavioral Assessment.

Dyskinesia, a major motor complication resulting from dopamine replacement treatment, manifests as involuntary hyperkinetic or dystonic movements. This condition poses a challenge to the treatment of Parkinson's disease. So far, several behavioral models based on rodent with dyskinesia have been established. These models have provided an important platform for evaluating the curative effect of drugs at the preclinical research level over the past two decades. However, there are differences in the modeling and behavioral testing procedures among various laboratories that adversely affect the rat and mouse models as credible experimental tools in this field. This article systematically reviews the history, the pros and cons, and the controversies surrounding rodent models of dyskinesia as well as their behavioral assessment protocols. A summary of factors that influence the behavioral assessment in the rodent dyskinesia models is also presented, including the degree of dopamine denervation, stereotaxic lesion sites, drug regimen, monitoring styles, priming effect, and individual and strain differences. Besides, recent breakthroughs like the genetic mouse models and the bilateral intoxication models for dyskinesia are also discussed.

Defining the spectrum of spasticity-associated involuntary movements

BackgroundSpasticity can be associated with several hyperkinetic involuntary movements generally referred to as “spasms” despite different phenomenology and clinical characteristics. ObjectiveTo better characterize the phenomenology and clinical characteristics of spasticity-associated involuntary movements. MethodsWe performed a cross-sectional study of a consecutive patient sample from the spasticity clinic. Each patient was interviewed by a movement-disorder neurologist who conducted a standardized movement-disorder survey and a focused exam. Patients with involuntary movements were video-recorded and videos were independently rated by a separate blinded movement-disorder neurologist. ResultsSixty-one patients were included (54% female, mean age 49.7 ± 13.9 years). Of the entire cohort, 11.5% had spinal, 44.3% had cerebral, and 44.3% had mixed-origin spasticity. Fifty-eight patients (95%) reported one or more involuntary movements: 75% tonic spasms (63% extensor, 58% isometric, 41% flexor/adductor), 52% spontaneous clonus, 34% myoclonus, 33% focal dystonia, and 28% action tremor. One third of the involuntary movements were painful. Only 53% of patients reported that their involuntary movements were much or very-much improved with their current anti-spasticity management. Patients treated with intrathecal baclofen therapy were more likely to report much or very-much improvement compared to patients receiving oral and/or botulinum therapy (P = 0.0061 and 0.0069 respectively). ConclusionMost spastic patients experience spasticity-associated involuntary movements of variable phenomenology and impact. However, only half of these patients experience significant improvement with the current management strategies. More research is needed to explore better treatment options for spasticity-associated involuntary movements with focus on phenomenology-specific approaches.

Overcoming barriers to effective management of tardive dyskinesia.

Tardive dyskinesia (TD) is a heterogeneous syndrome of involuntary hyperkinetic movements that is often persistent and occurs belatedly during treatment with antipsychotics. Recent approval of two dopamine-depleting analogs of tetrabenazine based on randomized controlled trials offers an evidence-based therapeutic approach to TD for the first time. These agents are optimally used within the context of a comprehensive approach to patient management that includes a practical screening and monitoring program, sensitive and specific criteria for the diagnosis of TD, awareness of the severity and impact of the disorder, informed discussions with patients and caregivers, and a rational basis for prescribing decisions about continued antipsychotic and adjunctive agents. Areas of limited or inconclusive data, bias and misunderstandings about key aspects, and neglect of training about TD in recent years contribute to barriers in providing effective care and promoting patient safety.

Parkinsonism in Huntington's disease.

Huntington's disease (HD) is usually characterized by involuntary hyperkinetic movements, called chorea. The intensity of chorea exhibits a peak in middle stages of HD and then decreases as HD progresses. In contrast, Pakinsonian signs of HD are often less appreciated. They typically progress in a fairly linear pattern over time. In fact, bradykinesia is detectable early on in premanifest gene carriers up to two decades prior to the clinical manifestation of HD symptoms using quantitative motor (Q-Motor) assessments such as finger tapping (digitomotography). Other Parkinsonian symptoms besides bradykinesia are rigidity and postural instability. They typically results in falls and injuries in advanced stages of HD. A primarily Parkinsonian motor phenotype, often seen with little to no chorea, is characteristically observed in older, late manifesting patients and in pediatric HD subjects. Establishing a diagnosis of HD is difficult in these groups and patients are often misdiagnosed in early stages.

Клиническая и лабораторно-инструментальная характеристика ревматической хореи у детей

Sydenham's chorea (SC) is a major clinical criterion in acute rheumatic fever (RF). SC is a late neurological manifestation of acute rheumatic fever which occurs 1 to 6 months after pharyngeal infection with group A betahemolytic streptococci. SC is characterized by clinical symptoms: involuntary hyperkinetic movements, muscular hypotonia, hyperreflexia, gait disturbance, emotional lability. Objective: The aim of the study was to identify frequency, clinical manifestations and the treatment of SC. The study included 56 children 4-17 years old, who were hospitalized in the Morozovskaya children’s clinical city hospital in 2001-2015 with RF. Clinical history, laboratory and instrumental methods (electrocardiography, transthoracic echocardiogram, cranial computed tomography scan and/or magnetic resonance imaging, electroencephalography, electroneuromyography). The study revealed frequent errors (66%) in RF diagnosis before hospitalization. Besides chorea, the clinical manifestations of RF were: carditis (89,3%), arthritis (46,4%), erythema marginatum (10,7%), subcutaneous nodule (1,8%). The peculiarity of our study washighfrequency of chorea (42,9%). Isolated chorea wasseen in 12,5%, mixed chorea - in 30,4% of SC. The clinical manifestations of chorea were typical. The nervous system lesion most often occured in children with a neurological history (p < 0,05). The clinical or laboratory evidence of streptococcal infection were seldom found (p = 0,02) in patients withchorea (45,8%) compared with patients without chorea symptoms (69%). RF issue requires attention from the medical community. SC, especially isolated chorea (29%), is the most challenging manifestation of RF for the differential diagnosis.Chronic rheumatic heart disease can be developed even in patients with isolated chorea (12,5%). In the treatment of SC in addition antibiotics and drugs which affect domamine and GABA metabolism, glucocorticoids (Prednisolone) are needed.

Lingual Hyperkinesia as An Initial Manifestation of Wernicke’s Encephalopathy: Evidence for Localization of Involuntary Hyperkinetic Movement of the Tongue

Background: Movement disorders caused by Wernicke’s encephalopathy (WE) are very rarely reported, and involuntary hyperkinesia of the tongue as an initial manifestation of WE have not yet been reported. The study aimed to investigate the path mechanism and localization of involuntary lingual movement symptoms. Methods: We present a patient with lingual hyperkinesia as an initial manifestation of WE, who had lesions of the periaqueductal area of the midbrain tectum and bilaterally medial thalami in Brain MRI. Patient’s lingual symptoms were observed and analyzed sequentially for localization of involuntary hyperkinetic movement of the tongue. Results: Lingual hyperkinesia symptoms of the patient diagnosed in WE, occurred in advance and were more earlier improved by thiamine treatment before other brainstem symptoms. Conclusion: The clinical and neuro-radiological results discussed here may provide support for the localization of lingual hyperkinetic movement disorders. In addition to brainstem lesion, thalamic lesion should be considered in cases of acute or subacute-onset, involuntary hyperkinetic movement of the tongue.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.

What is new in tics, dystonia and chorea?

Movement disorders comprise hyperkinetic involuntary movements (eg tremor, myoclonus, tics, dystonia and chorea) and hypokinetic (parkinsonism) disorders. Tics are cardinal features of primary tic disorders encompassing Tourette syndrome (TS), but are also found in some neurodegenerative conditions and may be induced by psychoactive substances. The first line treatment for tics is pharmacological (mainly dopamine receptor blockers or alpha-2 adrenergic agonists) and behavioural. Dystonia and chorea syndromes are considerably heterogeneous in aetiology, and age at onset, body distribution of the movement disorder, accompanying neurological motor and non-motor features, and systemic manifestations are all important to reach a correct aetiological diagnosis. While symptomatic pharmacological treatment remains the mainstay of treatment for choreas, deep brain stimulation surgery has a well-defined place in the management of medically refractory dystonia.

Delineation of the movement disorders associated with FOXG1 mutations

Objective:The primary objective of this research was to characterize the movement disorders associated with FOXG1 mutations.Methods:We identified patients with FOXG1 mutations who were referred to either a tertiary movement disorder clinic or tertiary epilepsy service and retrospectively reviewed medical records, clinical investigations, neuroimaging, and available video footage. We administered a telephone-based questionnaire regarding the functional impact of the movement disorders and perceived efficacy of treatment to the caregivers of one cohort of participants.Results:We identified 28 patients with FOXG1 mutations, of whom 6 had previously unreported mutations. A wide variety of movement disorders were identified, with dystonia, choreoathetosis, and orolingual/facial dyskinesias most commonly present. Ninety-three percent of patients had a mixed movement disorder phenotype. In contrast to the phenotype classically described with FOXG1 mutations, 4 patients with missense mutations had a milder phenotype, with independent ambulation, spoken language, and normocephaly. Hyperkinetic involuntary movements were a major clinical feature in these patients. Of the symptomatic treatments targeted to control abnormal involuntary movements, most did not emerge as clearly beneficial, although 4 patients had a caregiver-reported response to levodopa.Conclusions:Abnormal involuntary movements are a major feature of FOXG1 mutations. Our study delineates the spectrum of movement disorders and confirms an expanding clinical phenotype. Symptomatic treatment may be considered for severe or disabling cases, although further research regarding potential treatment strategies is necessary.