Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases. © 2019 The Author

Phenotypic insights into ADCY5-associated disease

Background Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. Methods In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole‐exome sequencing. Results Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile‐onset action‐induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. Conclusion We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5‐associated dyskinesia may be under‐recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications

Cost-Effectiveness of IncobotulinumtoxinA in the Treatment of Sialorrhea in Patients with Various Neurological Conditions

Abstract Introduction Sialorrhea is a common and debilitating symptom associated with neurological conditions, which can result in considerable physical and psychosocial complications. In Australia, management options are limited and further impeded by the lack of approved treatments. Whilst there is emerging evidence for the efficacy and tolerability of botulinum toxin (BoNT) for the treatment of sialorrhea in patients with neurological conditions, the cost-effectiveness of the treatment is yet to be established. Objectives To evaluate the cost-effectiveness of incobotulinumtoxinA for the treatment of chronic troublesome sialorrhea caused by various neurological conditions from the Australian healthcare perspective. Methods A Markov state transition model was developed to perform a cost-utility analysis comparing incobotulinumtoxinA with standard of care (SoC). The model consisted of a hypothetical cohort of patients transiting between three severity-based health states, defined according to the Drooling Severity and Frequency Scale (DSFS), in 16-weekly cycles over 5 years. All clinical and utility inputs were sourced from a single placebo-controlled randomised clinical trial. Only direct healthcare costs were considered, and potential indirect costs such as carer’s time and lost productivity were ignored. The primary outcome measure was the incremental cost per quality-adjusted life-year (QALY). Univariate and probabilistic sensitivity analyses were conducted. Results The model demonstrated that proportionally more patients spent time in less severe sialorrhea health states in the incobotulinumtoxinA arm. For example, over the 5-year period, patients receiving incobotulinumtoxinA were estimated to spend 1.6 years with minimal or no sialorrhea, while no patients achieved this level of improvement under SoC. IncobotulinumtoxinA was shown to have an incremental cost per QALY gained of A$23,445 when compared with SoC. Conclusions The quality of life (QoL) of patients with sialorrhea caused by neurological conditions was considerably compromised. IncobotulinumtoxinA was shown to successfully alleviate sialorrhea and it was demonstrated to be a cost-effective intervention when compared with SoC alone

Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.status: publishe

Neurophysiological features Of Hemiballism

Hemiballism is a rare hyperkinetic movement disorder. The pathophysiology of hemiballism is poorly understood, and there have been few reports of neurophysiological recordings. The authors report three cases of hemiballism with associated radiological and neurophysiological findings. In patients 1 and 2, who were studied in the acute phase 4 and 14 days after presentation, irregularly timed and predominantly long-duration electromyographic (EMG) bursts were observed typically ranging from 200 to 1500 milliseconds in duration and occurring asynchronously or alternating in antagonist muscles. In patient 3, who was studied 6 weeks after presentation when the involuntary movements had become choreiform, the EMG bursts were still from 200 to 1000 milliseconds in duration but were more synchronous or co-contracting. The flailing movements of hemiballism appear to occur as a result of prolonged bursts of EMG activity generated in individual muscles unopposed by EMG bursting in the antagonist. During the subacute phase when the movements become more choreiform, the results indicate that EMG activity becomes more synchronous or co-contracting

Resolution of Othello Syndrome after subthalamic nucleus deep brain stimulation in 3 patients with parkinson's disease

Psychiatric symptoms are historically thought a relative contraindication to DBS for advanced Parkinson's disease (PD). However, in the case of drug-induced mental illness, DBS may provide an acceptable alternative for the treatment of motor symptoms. This allows reduction of pharmacological dopaminergic therapy that might otherwise cause negative psychiatric consequences. For example, DBS is increasingly used to ameliorate specific complications of PD treatment, such as impulse control disorders. We present a series of 3 cases of young male patients who developed Othello syndrome (OS) during treatment with dopamine agonists. In each case, the OS resolved with withdrawal of the offending drug. Subsequent treatment with bilateral STN DBS improved motor symptoms and allowed reduction in their dopaminergic drug regimen. We therefore propose that drug-induced psychopathology may be an indication (rather than a contraindication) for DBS in selected cases

Effect of impulse control disorders on disability and quality of life in Parkinson's disease patients

Impulse control and related disorders (ICRD) are not uncommon in patients with idiopathic Parkinson's disease (PD). The present study aimed to investigate the effects of ICRD on quality of life (QoL) and disability in PD. From two movement disorder clinics in Sydney, Australia, 100 consecutive patients with PD were included in the trial. The Unified Parkinson's Disease Rating Scale (UPDRS), Mini Mental State Examination and the Parkinson's Disease Questionnaire-39 were used to measure disease severity, cognition and disease-specific QoL. The diagnosis of ICRD was based on face-to-face structured clinical interviews by three psychiatrists with experience in ICRD using the Expanded Structured Clinical Interview for the Diagnostic and Statistical Manual IV for Obsessive-Compulsive Disorder Related/Spectrum Disorders. ICRD were present in 15% of our patient population, and had a negative impact on QoL and Activity of Daily Living (ADL) scores. After adjusting for the presence of major depressive disorders and PD duration, the effect on emotional wellbeing remained statistically significant (p < 0.004). Disease duration also correlated with worse QoL and ADL scores. Major depression disorders reduced QoL but not ADL. Patients with ICRD tended to suffer more from depression than those without ICRD. There were no statistically significant differences in age, sex, major depressive disorders, PD duration, total levodopa equivalent daily dose, use of dopamine agonists, or UPDRS motor score between patients with and without ICDR