Myoclonus and Dystonia as Recurrent Presenting Features in Patients with the SCA21-Associated TMEM240 p.Pro170Leu Variant.

Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Variants in ATP5F1B are associated with dominantly inherited dystonia.

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation.

Frontal circuits play a critical role in motor, cognitive, and affective processing - and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)function remains largely elusive. Here, we study 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregate the frontal cortex into circuits that became dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to rostral, ranging from interconnections with sensorimotor cortices in dystonia, with the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairment in the human brain.

AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism.

INTRODUCTION: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565). METHODS: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. RESULTS: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). CONCLUSIONS: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches.

Deep brain stimulation in Huntington's disease: a literature review.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients. METHODS: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected. RESULTS: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%. CONCLUSIONS: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.

Clinical Correlates of Functional Motor Disorders: An Italian Multicenter Study.

BACKGROUND: Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases. OBJECTIVE: The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables. METHODS: For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms. RESULTS: Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs. CONCLUSIONS: Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.

Effects of COVID-19 on Parkinson's Disease Clinical Features: A Community-Based Case-Control Study.

The impact of coronavirus disease 2019 (COVID-19) on clinical features of Parkinson's disease (PD) has been poorly characterized so far. Of 141 PD patients resident in Lombardy, we found 12 COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were similar to controls. Changes in clinical features in the period January 2020 to April 2020 were compared with those of 36 PD controls matched for sex, age, and disease duration using the clinical impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale Parts II and IV, and the nonmotor symptoms scale. Motor and nonmotor symptoms significantly worsened in the COVID-19 group, requiring therapy adjustment in one third of cases. Clinical deterioration was explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were marginally involved, whereas none experienced autonomic failure. © 2020 International Parkinson and Movement Disorder Society.

Spatio-temporal structure of single neuron subthalamic activity identifies DBS target for anesthetized Tourette syndrome patients.

OBJECTIVE: Deep brain stimulation (DBS) of basal ganglia effectively tackles motor symptoms of movement disorders such as Tourette syndrome (TS). The precise location of target stimulation site determines the range of clinical outcome in DBS patients, and the occurrence of side-effects of DBS. DBS implant procedures currently localize stimulation target relying on a combination of pre-surgical imaging, standardized brain atlases and on-the-spot clinical tests. Here we show that temporal structure of single unit activity in subthalamic nucleus (STN) of patients affected by pure TS can contribute to identify the optimal target location of DBS. APPROACH: Neural activity was recorded at different depths within STN with microelectrodes during DBS implant surgery. Depth specific neural features were extracted and correlated with the optimal depth for tic control. MAIN RESULTS: We describe for the first time temporal spike patterns of single neurons from sensorimotor STN of anesthetized TS patients. A large fraction of units (31.2%) displayed intense bursting in the delta band (<4 Hz). The highest firing irregularity and hence the higher density of bursting units (42%) were found at the optimal spot for tic control. Discharge patterns irregularity and dominant oscillations frequency (but not firing rate) carried significant information on optimal target. SIGNIFICANCE: We found single unit activity features in the STN of TS patients reliably associated to optimal DBS target site for tic control. In future works measures of firing irregularity could be integrated with current target localization methods leading to a more effective and safer DBS for TS patients.

Deep brain stimulation for dystonia due to cerebral palsy: A review.

Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies.

Idiopathic delayed-onset edema surrounding deep brain stimulation leads: Insights from a case series and systematic literature review.

INTRODUCTION: Deep brain stimulation (DBS) is effective for some neurological and psychiatric conditions. Idiopathic delayed-onset edema (IDE) surrounding the leads has been anecdotally reported. The etiology, predisposing factors and prognosis of this complication are unknown. We present a multicenter case series of patients with IDE, and a systematic literature review, aimed at defining the pathophysiology and identifying appropriate treatment strategies. METHODS: IDE was defined as edema along the DBS lead, occurring ≥72 h postoperatively, in absence of trauma, vascular events or infection. Information on patients with IDE was collected in a standardized way. A systematic search was performed in Pubmed. RESULTS: Twelve new patients presenting with 14 episodes of IDE are described. From the literature, 38 patients were identified. No common surgical aspects or patient-related factors were identified as risk predictors for the onset of IDE. Symptoms included deterioration of the stimulation effect, seizures and focal neurological signs. Although the condition is self-limiting, with symptoms resolution in 28.5 days on average, three patients underwent surgical revision and seven received antibiotics. CONCLUSIONS: IDE is a rare complication of DBS procedures, presenting from few days to months after surgery. Symptoms can be mild and not-specific, and the condition is self-limiting. The diagnosis of IDE is made after exclusion of vascular events or infections. The pathophysiology is still unexplained. The recognition of this complication can help avoiding unnecessary surgical procedures (system explantation) and antibiotic treatment.

Quantitative gait analysis in parkin disease: Possible role of dystonia.

INTRODUCTION: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. METHODS: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. RESULTS: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. CONCLUSION: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society.

Therapeutic advances in dystonia.

Knowledge on dystonia has greatly improved recently, because of a renewed effort in understanding its cause, pathophysiology, and clinical characterization. Different drug classes traditionally have been used for the symptomatic treatment of dystonia, more recently surpassed by the introduction of botulinum neurotoxins and deep brain stimulation. No curative or disease-modifying treatments are available. Recent knowledge regarding the pathophysiology of inherited dystonias is highlighting new potential treatment strategies. We review therapeutic advances in dystonia that have been published over the last 3 years, particularly regarding oral medications, local injections of botulinum neurotoxins, deep brain stimulation, and transcranial or epidural brain stimulations. We discuss evidence of efficacy, highlight recent advances, and focus on key areas under development.