Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

[Conclusion instead of exclusion-The clinical diagnosis of functional movement disorders]. / Abschluss statt Ausschluss ­ die klinische Diagnosesicherung funktioneller Bewegungsstörungen.

Functional neurological movement disorders are common in neurological practice and lead to a high degree of impairment and chronification. Affected patients usually receive a diagnosis with considerable delay and often do not get disease-specific treatment. The reasons for this delay are related to extensive diagnostic measures to exclude other nonfunctional neurological diseases. As a consequence, functional movement disorders are typically communicated as diagnoses of exclusion, which makes it difficult for patients to understand and accept the diagnosis. This is particularly unfortunate, because in the majority of patients the diagnosis can be made with confidence based on clinical features, i.e., inconsistency and incongruence. The clarification of the symptoms and the resulting treatment options should be supplemented by patient-friendly explanations of the pathophysiological basis of the disease. In this way, patients are enabled to understand and accept the diagnosis. Moreover, it can put an end to the search for a diagnosis, which can sometimes take decades, and paves the way for treatment. Thus, the diagnosis by exclusion itself becomes the starting point for treatment and can itself have a therapeutic effect.

Impaired Metacognition of Voluntary Movement in Functional Movement Disorder.

BACKGROUND: Motor symptoms in functional movement disorders (FMDs) are experienced as involuntary but share characteristics of voluntary action. Clinical and experimental evidence indicate alterations in monitoring, control, and subjective experience of self-performed movements. OBJECTIVE: The objective of this study was to test the prediction that FMDs are associated with a reduced ability to make accurate (metacognitive) judgments about self-performed movements. METHODS: We compared 24 patients with FMD (including functional gait disturbance, functional tremor, and functional tics) with 24 age- and sex-matched healthy control subjects in a novel visuomotor-metacognitive paradigm. Participants performed target-directed movements on a graphics tablet with restricted visual feedback, decided which of two visually presented trajectories was closer to their preceding movement, and reported their confidence in the visuomotor decision. We quantified individual metacognitive performance as participants' ability to assign high confidence preferentially to correct visuomotor decisions. RESULTS: Patients and control subjects showed comparable motor performance, response accuracy, and use of the confidence scale. However, visuomotor sensitivity in the trajectory judgment was reduced in patients with FMD compared with healthy control subjects. Moreover, metacognitive performance was impaired in patients, that is, their confidence ratings were less predictive of the correctness of visuomotor decisions. Exploratory subgroup analyses suggest metacognitive deficits to be most pronounced in patients with a functional gait disturbance or functional tremor. CONCLUSIONS: Patients with FMD exhibited deficits both when making visuomotor decisions about their own movements and in the metacognitive evaluation of these decisions. Reduced metacognitive insight into voluntary motor control may play a role in FMD pathophysiology and could lay the groundwork for new treatment strategies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perception-Action Integration Is Altered in Functional Movement Disorders.

BACKGROUND: Although functional neurological movement disorders (FMD) are characterized by motor symptoms, sensory processing has also been shown to be disturbed. However, how the integration of perception and motor processes, essential for the control of goal-directed behavior, is altered in patients with FMD is less clear. A detailed investigation of these processes is crucial to foster a better understanding of the pathophysiology of FMD and can systematically be achieved in the framework of the theory of event coding (TEC). OBJECTIVE: The aim was to investigate perception-action integration processes on a behavioral and neurophysiological level in patients with FMD. METHODS: A total of 21 patients and 21 controls were investigated with a TEC-related task, including concomitant electroencephalogram (EEG) recording. We focused on EEG correlates established to reflect perception-action integration processes. Temporal decomposition allowed to distinguish between EEG codes reflecting sensory (S-cluster), motor (R-cluster), and integrated sensory-motor processing (C-cluster). We also applied source localization analyses. RESULTS: Behaviorally, patients revealed stronger binding between perception and action, as evidenced by difficulties in reconfiguring previously established stimulus-response associations. Such hyperbinding was paralleled by a modulation of neuronal activity clusters, including reduced C-cluster modulations of the inferior parietal cortex and altered R-cluster modulations in the inferior frontal gyrus. Correlations of these modulations with symptom severity were also evident. CONCLUSIONS: Our study shows that FMD is characterized by altered integration of sensory information with motor processes. Relations between clinical severity and both behavioral performance and neurophysiological abnormalities indicate that perception-action integration processes are central and a promising concept for the understanding of FMD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interrater reliability of motor severity scales for hemifacial spasm.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia: MDSGene Review.

BACKGROUND: Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability. OBJECTIVES: Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information. METHODS: 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs. RESULTS: Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1. CONCLUSIONS: Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[Development and content validation of a questionnaire for functional movement disorders]. / Entwicklung und inhaltliche Validierung eines Fragebogens für funktionelle Bewegungsstörungen.

From shell shock tremors to TikTok tics, functional movement disorders have long been assumed to be motor expressions of emotional turmoil. However, psychodynamic explanations are increasingly complemented by neurophysiological findings, meaning that specialized physiotherapy is gaining in importance alongside psychotherapy. Still, there is no disease-specific outcome measure that adequately assesses patient-relevant aspects of this heterogeneous condition. Such a questionnaire was developed and its content was validated in a multistage development process. The relevance and comprehensibility of the items were first evaluated by a panel of experts and then by affected patients, and questions and possible response categories were adjusted accordingly. The resultant revised questionnaire yields good content-related validity and thus allows, for the first time, a quantification of the subjective complaints and implications associated with functional movement disorders. The next step will be a multicenter study to analyze the psychometric properties and factorial structure of this new instrument.

Neural dynamics of stimulus-response representations during inhibitory control.

The investigation of action control processes is one major field in cognitive neuroscience and several theoretical frameworks have been proposed. One established framework is the "Theory of Event Coding" (TEC). However, only rarely, this framework has been used in the context of response inhibition and how stimulus-response association or binding processes modulate response inhibition performance. Particularly the neural dynamics of stimulus-response representations during inhibitory control are elusive. To address this, we examined n = 40 healthy controls and combined temporal EEG signal decomposition with source localization and temporal generalization multivariate pattern analysis (MVPA). We show that overlaps in features of stimuli used to trigger either response execution or inhibition compromised task performance. According to TEC, this indicates that binding processes in event file representations impact response inhibition through partial repetition costs. In the EEG data, reconfiguration of event files modulated processes in time windows well-known to reflect distinct response inhibition mechanisms. Crucially, event file coding processes were only evident in a specific fraction of neurophysiological activity associated with the inferior parietal cortex (BA40). Within that specific fraction of neurophysiological activity, the decoding of the dynamics of event file representations using temporal generalization MVPA suggested that event file representations are stable across several hundred milliseconds, and that event file coding during inhibitory control is reflected by a sustained activation pattern of neural dynamics.NEW & NOTEWORTHY The "mental representation" of how stimulus input translate into the appropriate response is central for goal-directed behavior. However, little is known about the dynamics of such representations on the neurophysiological level when it comes to the inhibition of motor processes. This dynamic is shown in the current study.

Interhemispheric interactions between the right angular gyrus and the left motor cortex: a transcranial magnetic stimulation study.

The interconnection of the angular gyrus of right posterior parietal cortex (PPC) and the left motor cortex (LM1) is essential for goal-directed hand movements. Previous work with transcranial magnetic stimulation (TMS) showed that right PPC stimulation increases LM1 excitability, but right PPC followed by left PPC-LM1 stimulation (LPPC-LM1) inhibits LM1 corticospinal output compared with LPPC-LM1 alone. It is not clear if right PPC-mediated inhibition of LPPC-LM1 is due to inhibition of left PPC or to combined effects of right and left PPC stimulation on LM1 excitability. We used paired-pulse TMS to study the extent to which combined right and left PPC stimulation, targeting the angular gyri, influences LM1 excitability. We tested 16 healthy subjects in five paired-pulsed TMS experiments using MRI-guided neuronavigation to target the angular gyri within PPC. We tested the effects of different right angular gyrus (RAG) and LM1 stimulation intensities on the influence of RAG on LM1 and on influence of left angular gyrus (LAG) on LM1 (LAG-LM1). We then tested the effects of RAG and LAG stimulation on LM1 short-interval intracortical facilitation (SICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI). The results revealed that RAG facilitated LM1, inhibited SICF, and inhibited LAG-LM1. Combined RAG-LAG stimulation did not affect SICI but increased LICI. These experiments suggest that RAG-mediated inhibition of LAG-LM1 is related to inhibition of early indirect (I)-wave activity and enhancement of GABAB receptor-mediated inhibition in LM1. The influence of RAG on LM1 likely involves ipsilateral connections from LAG to LM1 and heterotopic connections from RAG to LM1.NEW & NOTEWORTHY Goal-directed hand movements rely on the right and left angular gyri (RAG and LAG) and motor cortex (M1), yet how these brain areas functionally interact is unclear. Here, we show that RAG stimulation facilitated right hand motor output from the left M1 but inhibited indirect (I)-waves in M1. Combined RAG and LAG stimulation increased GABAB, but not GABAA, receptor-mediated inhibition in left M1. These findings highlight unique brain interactions between the RAG and left M1.

Pandemic Tic-like Behaviors Following Social Media Consumption.

BACKGROUND: Currently, there is a marked increase of young people with sudden onset of tic-like behaviors (TLBs) resembling movements and vocalizations presented on social media videos as "Tourette's syndrome." OBJECTIVE: To delineate clinical phenomenology of TLBs after social media exposure in comparison with clinical features of Tourette's syndrome. METHODS: We compared demographic and clinical variables between 13 patients with TLBs and 13 age- and sex-related patients with Tourette's syndrome. RESULTS: Patients with TLBs had several characteristics allowing to distinguish them from patients with Tourette's syndrome, some of which discriminated perfectly (ie, abrupt symptom onset, lack of spontaneous symptom fluctuations, symptom deterioration in the presence of others) and some nearly perfectly (ie, predominantly complex movements involving trunk/extremities). Also, symptom onset was significantly later. CONCLUSIONS: TLBs after social media consumption differ from tics in Tourette's syndrome, strongly suggesting that these phenomena are categorically different conditions. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated ("bagged") decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%-86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10-12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57-70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism. © 2021 International Parkinson and Movement Disorder Society.

Complex dystonias: an update on diagnosis and care.

Complex dystonias are defined as dystonias that are accompanied by neurologic or systemic manifestations beyond movement disorders. Many syndromes or diseases can present with complex dystonia, either as the cardinal sign or as part of a multi-systemic manifestation. Complex dystonia often gradually develops in the disease course, but can also be present from the outset. If available, the diagnostic workup, disease-specific treatment, and management of patients with complex dystonias require a multi-disciplinary approach. This article summarizes current knowledge on complex dystonias with a particular view of recent developments with respect to advances in diagnosis and management, including causative treatments.

Combined dystonias: clinical and genetic updates.

The genetic combined dystonias are a clinically and genetically heterogeneous group of neurologic disorders defined by the overlap of dystonia and other movement disorders such as parkinsonism or myoclonus. The number of genes associated with combined dystonia syndromes has been increasing due to the wider recognition of clinical features and broader use of genetic testing. Nevertheless, these diseases are still rare and represent only a small subgroup among all dystonias. Dopa-responsive dystonia (DYT/PARK-GCH1), rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3), X-linked dystonia-parkinsonism (XDP, DYT/PARK-TAF1), and young-onset dystonia-parkinsonism (DYT/PARK-PRKRA) are monogenic combined dystonias accompanied by parkinsonian features. Meanwhile, MYC/DYT-SGCE and MYC/DYT-KCTD17 are characterized by dystonia in combination with myoclonus. In the past, common molecular pathways between these syndromes were the center of interest. Although the encoded proteins rather affect diverse cellular functions, recent neurophysiological evidence suggests similarities in the underlying mechanism in a subset. This review summarizes recent developments in the combined dystonias, focusing on clinico-genetic features and neurophysiologic findings. Disease-modifying therapies remain unavailable to date; an overview of symptomatic therapies for these disorders is also presented.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia.

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.

Alcohol improves cerebellar learning deficit in myoclonus-dystonia: A clinical and electrophysiological investigation.

OBJECTIVE: To characterize neurophysiological subcortical abnormalities in myoclonus-dystonia and their modulation by alcohol administration. METHODS: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8g/l). The alcohol responsiveness of clinical symptoms was evaluated by 3 blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale and the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. Whereas the conditioning response rate decreased under alcohol intake in controls, it increased in patients (analysis of variance: alcohol state × group, p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients. INTERPRETATION: The combination of findings of reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients who improved significantly with alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. Ann Neurol 2017;82:543-553.

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D.

Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases.

Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood-onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.

Premotor-motor excitability is altered in dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia is clinically dominated by a combination of dystonia and parkinsonism, both known to be associated with abnormal activity in premotor-motor circuits. METHODS: To probe premotor-motor excitability, we used a transcranial magnetic stimulation dual pulse conditioning paradigm in 15 genetically confirmed dopa-responsive dystonia patients and 20 controls under different medication states. We also determined silent periods, short-latency afferent inhibition, interhemispheric inhibition, and short-interval intracortical inhibition and facilitation. RESULTS: In contrast to healthy controls, no motor cortex inhibition was seen after premotor conditioning regardless of the dopaminergic state in patients. The duration of the ipsilateral silent period was increased in the OFF state, and short-latency afferent inhibition was reduced in the ON compared with the OFF state. CONCLUSION: Premotor-motor circuits appear hyporesponsive in dopa-responsive dystonia.