Dystonia Research Articles

Challenging Case: A Multidisciplinary Approach to Demystifying Chronic Sleep Impairment in an Infant with a Complex Medical and Behavioral Profile.

Challenging Case: A Multidisciplinary Approach to Demystifying Chronic Sleep Impairment in an Infant with a Complex Medical and Behavioral Profile.

Atypical case of hypermanganesemia with dystonia type 1: a treatable primary dystonia caused by inborn error of manganese metabolism

Dystonia is one of the most common movement disorders in the pediatric age group. Dystonia with hypermanganesemia have polycythemia with deranged iron profile, chronic liver disease and basal ganglia hyperintensity on T1 weighted MRI brain image as characteristic finding. We are reporting one case of dystonia, lower limb weakness, polycythemia, and characteristic basal ganglia hyperintensity with a normal iron profile without liver involvement which diagnosed as inherited manganese (Mn) transporter defect due to homozygous mutations of SLC30A10 gene. Most of the reported cases of this mutation have reported decreased iron profile in their blood report and liver involvement contrary to our case. Intravenous disodium calcium edetate chelation and oral iron therapy led to a decrease in whole blood Mn level as well as clinical improvement in the patient. This is a rare disorder and is one of the potentially treatable inherited metal storage disorders and fatal if left untreated.

Acute Dystonia Associated with Low-Dose Aripiprazole in a Male Child: A Case Report

Aripiprazole is a newer anti-psychotic agent with low liability for Extrapyramidal Symptoms (EPS). Acute dystonia develops due to a lack of dopamine, resulting in a relative overactivity of cholinergic neurons. In the past, cases of Aripiprazole-induced acute dystonia have been reported more frequently among adults than children. Here, the authors present a case in which acute dystonia developed at a very low dose (2 mg) of Aripiprazole. The case involves a 10-year-old boy diagnosed with Oppositional Defiant Disorder (ODD) who exhibited aggressive behaviour and irritability. Aripiprazole (2 mg) was initiated for treatment, but after five days, the patient developed excessive sleepiness, slurred speech, oculogyric crisis, and torticollis, indicative of acute dystonia. To rule out any organic causes, a detailed assessment and investigations were conducted, including complete blood counts, liver and kidney function tests, serum calcium, electrolytes, ceruloplasmin, blood copper levels, slit-lamp examination for Kayser-Fleischer ring, and electroencephalography, which did not reveal any significant organic conditions. Aripiprazole was discontinued, and Promethazine was administered. The dystonia score on the Unified Dystonia Rating Scale (UDRS) decreased from 10 to 0 in 5 days, indicating complete resolution of dystonia. Naranjo’s causality assessment score was seven, reflecting the probable association of aripiprazole with acute dystonia. This case emphasises the importance of monitoring for adverse reactions to anti-psychotic medications, particularly in paediatric patients, and the need for prompt recognition and management of adverse effects to ensure patient safety and treatment efficacy. To the best of our knowledge, this is the first case report of acute dystonia in a child at such a low dose of Aripiprazole. Clinicians should be vigilant for the emergence of such significant adverse effects of commonly used drugs.

Stereotactic Awake Basal Ganglia Electrophysiological Recording and Stimulation (SABERS): A Novel Staged Procedure for Personalized Targeting of Deep Brain Stimulation in Pediatric Movement and Neuropsychiatric Disorders.

Selection of targets for deep brain stimulation (DBS) has been based on clinical experience, but inconsistent and unpredictable outcomes have limited its use in patients with heterogeneous or rare disorders. In this large case series, a novel staged procedure for neurophysiological assessment from 8 to 12 temporary depth electrodes is used to select targets for neuromodulation that are tailored to each patient's functional needs. Thirty children and young adults underwent deep brain stimulation target evaluation with the new procedure: Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation (SABERS). Testing is performed in an inpatient neuromodulation monitoring unit over 5-7 days, and results guide the decision to proceed and the choice of targets for permanent deep brain stimulation implantation. Results were evaluated 3-6 months postoperatively with the Burke-Fahn-Marsden Dystonia Rating Scale and the Barry-Albright Dystonia Scale. Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation testing allowed modulation to be tailored to specific neurologic deficits in a heterogeneous population, including subjects with primary dystonia, secondary dystonia, and Tourette syndrome. All but one subject were implanted with 4 permanent deep brain stimulation leads. Results showed significant improvement on both scales at postoperative follow-up. No significant adverse events occurred. Use of the Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation protocol with evaluation in the neuromodulation monitoring unit is feasible and results in significant patient benefit compared with previously published results in these populations. This new technique supports a significant expansion of functional neurosurgery to predict effective stimulation targets in a wide range of disorders of brain function, including those for which the optimal target is not yet known.

Methodology of Botulinum Therapy in the Treatment of Dystonic Scoliosis in Generalized Dystonia (clinical case)

Methodology of Botulinum Therapy in the Treatment of Dystonic Scoliosis in Generalized Dystonia (clinical case)

Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias.

Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad "dystonia network" encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the "geste antagoniste" or "sensory trick" to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.

Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia.

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild-type ANO3 and cells expressing anoctamin variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wild-type ANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.

Task-Specific Lingual Dystonia During Japanese Religious Services.

Lingual dystonia is a subtype of oromandibular dystonia characterized by involuntary contractions of the tongue muscles, often provoked by speaking or eating. This study reports six Japanese cases (four female and two male, mean age at onset of 49.5 years) with task-specific lingual dystonia during praying. In the early phase, all patients experienced lingual protrusion exclusively during Japanese religious services. When the patients start speaking, the tongues protrude forward, making it difficult to pronounce words. The patients were treated with multimodal treatment, including muscle afferent block (MAB) therapy comprising local anesthetic injection, botulinum toxin (onabotulinumtoxinA) injection, and a sensory trick splint. MAB therapy was conducted in five patients (mean time: 5.8), and botulinum toxin injection was administered in four patients (mean time: 8). The injected muscles were the genioglossal muscles and, in one case, the lateral pterygoid muscle. Sensory trick splints were inserted in three patients. After the multimodal therapy, the patients were able to pronounce words smoothly and clearly. Oromandibular Dystonia Rating Scale scores improved significantly (P<0.005) from baseline (187 points) to endpoint (47 points) with a mean follow-up of 4.7 years. Although this entity is rare, medical and dental professionals should be aware of this peculiar symptom. Multimodal therapy is required to ensure effective treatment of praying-induced lingual dystonia.

Exploring the predictive factors for DYT gene and non-DYT-mediated primary dystonia: Insights from a tertiary centre of India

Exploring the predictive factors for DYT gene and non-DYT-mediated primary dystonia: Insights from a tertiary centre of India

A Rare and Unusual Case of Ataxia Telangiectasia with Cervical Dystonia from India

We reported a rare and unusual case ATM gene variant responsible of familial Ataxia-Telangiectasia (A-T) with cervical dystonia rather than ataxia as hall mark clinical manifestations in 18-year-old male patient from India. Patient was presented with clinical indications of neck rotatory movements in the last 2 years. Initially intermittent, slowly become constant with more backwards turning and painful movements with severe disability. Examination findings revealed no conjunctival telangiectasia and neurological examination findings suggestive of cervical dystonia with severe retro collis. The patient has a family history of dystonia, his sister started noticing involuntary neck movement in the last 1.5 years with gradual progression. Her physical examination revealed no evidence of conjunctival lesions and neurological examination suggestive of cervical dystonia with lateral collis. MRI findings of patient were normal. Both the patient and her sister are siblings of a consanguineous product. Patient has been referred for whole exome sequencing. The exome data analysis identified a novel homozygous missense variant c.5751A&gt;T, p.Arg1917Ser (chr11:108307973A&gt;T) in ATM gene responsible for familial A-T with cervical dystonia without chorea as hall mark clinical manifestations. In conclusion, to the best of our literature knowledge this is the rare and unusual case from India wherein we are reporting a novel homozygous missense variant c.5751A&gt;T, p.Arg1917Ser (chr11:108307973A&gt;T) in ATM gene responsible for familial A-T with cervical dystonia rather than ataxia as hall mark clinical manifestations affecting both brother and sister in the same family. Thus, early onset of cervical dystonia should be taken into account as a key characteristic of variant A-T, which can manifest without general ataxia and may cause adults with primary dystonia to receive an incorrect diagnosis.

Macro- and micro-structural insights into primary dystonia: a UK Biobank study.

Dystonia is a hyperkinetic movement disorder with key motor network dysfunction implicated in pathophysiology. The UK Biobank encompasses > 500,000 participants, of whom 42,565 underwent brain MRI scanning. This study applied an optimized pre-processing pipeline, aimed at better accounting for artifact and improving data reliability, to assess for grey and white matter structural MRI changes between individuals diagnosed with primary dystonia and an unaffected control cohort. Individuals with dystonia (n = 76) were identified from the UK Biobank using published algorithms, alongside an age- and sex-matched unaffected control cohort (n = 311). Grey matter morphometric and diffusion measures were assessed, together with white matter diffusion tensor and diffusion kurtosis metrics using tractography and tractometry. Post-hoc Neurite Orientation and Density Distribution Imaging (NODDI) was also undertaken for tracts in which significant differences were observed. Grey matter tremor-specific striatal differences were observed, with higher radial kurtosis. Tractography identified no white matter differences, however segmental tractometry identified localised differences, particularly in the superior cerebellar peduncles and anterior thalamic radiations, including higher fractional anisotropy and lower orientation distribution index in dystonia, compared to controls. Additional tremor-specific changes included lower neurite density index in the anterior thalamic radiations. Analysis of imaging data from one of the largest dystonia cohorts to date demonstrates microstructural differences in cerebellar and thalamic white matter connections, with architectural differences such as less orientation dispersion potentially being a component of the morphological structural changes implicated in dystonia. Distinct tremor-related imaging features are also implicated in both grey and white matter.

Acute Dystonia Due to Pregabalin Abuse in an Adolescent

Pregabalin is a drug used to treat neuropathic pain, epilepsy, and fibromyalgia. However, the number of reported cases of pregabalin abuse is steadily growing. This case showed dystonia, an effect not previously documented as a consequence of pregabalin administration. A 16-year-old male patient with no known pre-existing medical conditions was admitted to the pediatric emergency department for the first time, complaining of drowsiness caused by pregabalin abuse. During the patient's follow-up, dystonia was observed, and biperiden was administered at a repeating dose. Subsequently, he was moved to the pediatric intensive care unit (PICU) for further tests and treatment. After three days of follow-up, the patient was discharged due to the absence of complaints. This case report presents dystonia resulting from pregabalin abuse, a condition that has not previously been documented in the literature.

Short-term stimulations of the entopeduncular nucleus induce cerebellar changes of c-Fos expression in an animal model of paroxysmal dystonia

Deep brain stimulation (DBS) of the globus pallidus internus (entopeduncular nucleus, EPN, in rodents) is important for the treatment of drug-refractory dystonia. The pathophysiology of this movement disorder and the mechanisms of DBS are largely unknown. Insights into the mechanisms of DBS in animal models of dystonia can be helpful for optimization of DBS and add-on therapeutics. We recently found that short-term EPN-DBS with 130 Hz (50 µA, 60 µs) for 3 h improved dystonia in dtsz hamsters and reduced spontaneous excitatory cortico-striatal activity in brain slices of this model, indicating fast effects on synaptic plasticity. Therefore, in the present study, we examined if these effects are related to changes of c-Fos, a marker of neuronal activity, in brains derived from dtsz hamsters after these short-term DBS or sham stimulations. After DBS vs. sham, c-Fos intensity was increased around the electrode, but the number of c-Fos+ cells was not altered within the whole EPN and projection areas (habenula, thalamus). DBS did not induce changes in striatal and cortical c-Fos+ cells as GABAergic (GAD67+ and parvalbumin-reactive) neurons in motor cortex and striatum. Unexpectedly, c-Fos+ cells were decreased in deep cerebellar nuclei (DCN) after DBS, suggesting that cerebellar changes may be involved in antidystonic effects already during short-term DBS. However, the present results do not exclude functional changes within the basal ganglia–thalamo-cortical network, which will be further investigated by long-term EPN stimulations. The present study indicates that the cerebellum deserves attention in ongoing examinations on the mechanisms of DBS in dystonia.

White matter connectivity of subthalamic nucleus and globus pallidus interna targets for deep brain stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection. The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 μsec for STN; 3.3 V and 90 μsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared. VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex. On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Clinical and genetic analysis of tyrosine hydroxylase deficiency of six cases

The clinical and molecular genetic data of 6 patients with genetically confirmed tyrosine hydroxylase deficiency(THD) diagnosed in Department of Neurology, Qilu Hospital of Shandong University from March 2017 to February 2022 were retrospectively collected and analyzed. The 6 patients were from 5 families. Among them, 5 patients had persistent or paroxysmal abnormal walking posture, 4 patients had dystonia of head and face, including spasm of perioral and oculopharyngeal muscles, hyperactivity, and binocular upvision, 4 patients showed obvious morning light and evening heavy phenomenon, 2 patients had postural tremor of limbs, 2 patients had psychomotor retardation from childhood, 1 patient only had limb and cervical muscle weakness, 1 patient had epileptic seizures. Of the 6 patients, only 1 was adult-onset, and the rest were child-onset. Four patients had good response to low-dose dopa preparation, 2 patients from the same family had poor response to dopamine treatment, requiring extremely low dose initiation and multi-frequency titration treatment. However, the long-term treatment effect was poor with obvious abnormalities. Gene testing of 5 families revealed 8 mutations in the TH gene, with c.698G>A (p.R233H) being the hot spot mutation site. The clinical manifestations of THD are complex. Besides paroxysmal or persistent dystonia, it can also be accompanied by eye movement crisis, muscle weakness, epilepsy, and delayed mental and motor development. Most patients respond well to low-dose dopamine preparations, but a small number of patients require titration treatment with extremely low-dose dopamine preparations, and the long-term effect is not satisfactory.

Psychometric Evaluation of the Misophonia Impact Questionnaire (MIQ) Using a Clinical Population of Patients Seeking Help for Tinnitus, Hyperacusis and/or Misophonia.

Misophonia is a decreased tolerance of certain sounds related to eating noises, lip smacking, sniffing, breathing, clicking sounds, and tapping. While several validated self-report misophonia questionnaires exist, none focus solely on the impact of misophonia on the patient's life. Additionally, there are no available validated pediatric self-report measures of misophonia. Therefore, a tool was needed to assess the impact of misophonia on both adult and pediatric patients. To evaluate the psychometric properties of the 8-item Misophonia Impact Questionnaire (MIQ). This was a retrospective cross-sectional study. Patients who attended the Tinnitus and Hyperacusis Therapy Specialist Clinic (THTSC) in the UK seeking help for tinnitus, hyperacusis and/or misophonia (n = 256). A subsample of children aged 16 years or younger (n=15) was included for preliminary analyses of a version of the MIQ to be filled in by a parent (MIQ-P). Data were collected retrospectively from the records of patients held at the audiology department. These included demographic data, audiological measures and self-report questionnaires taken as part of routine care. Descriptive statistics and psychometric analyses were conducted. The MIQ was analyzed for item difficulty, factor structure, reliability, and construct validity. Confirmatory factor analysis revealed that a one-factor model for the MIQ gave an excellent fit and its estimated reliability was excellent, with Cronbach's α = 0.94. The total MIQ scores were highly correlated with scores for the Hyperacusis Impact Questionnaire (HIQ) and Sound Sensitivity Symptoms Questionnaire (SSSQ). MIQ scores were not significantly correlated with scores for the Tinnitus Impact Questionnaire (TIQ) or average hearing thresholds. Preliminary data from the sub-sample indicated excellent internal consistency for the MIQ-P, with Cronbach's α = 0.92. The MIQ is a promising questionnaire for assessing the impact of misophonia. Future studies should focus on establishing test/re-test reliability, identifying clinically significant change in MIQ scores, defining the severity of misophonia impact categories, and further exploring the psychometric properties of the MIQ-P.

Economic Evaluations Comparing Deep Brain Stimulation to Best Medical Therapy for Movement Disorders: A Meta-Analysis.

Movement disorders (Parkinson's disease, essential tremor, primary dystonia) are a debilitating group of conditions that are progressive in nature. The mainstay of treatment is best medical therapy; however, a number of surgical therapies are available, including deep brain stimulation. Economic evaluations are an important aspect of evidence to inform decision makers regarding funding allocated to these therapies. This systematic review and meta-analysis evaluated the cost effectiveness of including deep brain stimulation compared with best medical therapy for movement disorder indications in the adult population. Ovid Medical Literature Analysis and Retrieval System Online, Embase, and Cochrane Central Register of Controlled Trials were queried. Only economic evaluations reporting incremental cost-effectiveness ratios for including deep brain stimulation versus best medical therapy for movement disorders were included. Studies were reviewed in duplicate for inclusion and data abstraction. Data were harmonized using the Consumer Price Index and Purchasing Power Parity to standardize values to 2022 US dollars. For inclusion in meta-analyses, studies were required to have sufficient data available to calculate an estimate of the incremental net benefit. Meta-analyses of pooled incremental net benefit based on the time horizon were performed. The study was registered at PROSPERO (CRD42022335436). There were 2190 studies reviewed, with 14 economic evaluations included following a title/abstract and full-text review. Only studies considering Parkinson's disease were available for the meta-analysis. Quality of the identified studies was low, with moderate transferability to the American Healthcare System, and certainty of evidence was low. However, studies with a longer time horizon (15 years to lifetime) were found to have significant positive incremental net benefit (indicating cost effectiveness) for including deep brain stimulation with a mean difference of US$40,504.81 (95% confidence interval 2422.42-78,587.19). Deep brain stimulation was cost effective for Parkinson's disease when considered over the course of the patient's remaining life after implantation. Clinical Trial Registration: PROSPERO (CRD42022335436).

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.

SERAC1 Deficiency- A New Phenotype.

Introduction - SERAC1 deficiency phenotype range from MEGD(H)EL syndrome, the most severe, to juvenile complicated spastic paraplegia, to adult-onset dystonic features (in only one patient). The MEGD(H)EL syndrome is characterized by (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome). Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum. Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found. Brain MRI: basal ganglia lesions and generalized atrophy. Results/Case report - A 30-year-old patient with a moderate intellectual disability, developed, since the age of 25, a progressive loss of previous capacities (hand dexterity, oral language), and later subacute generalized dystonic features. Currently he has spastic tetraparesis, dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI. Genetic study revealed biallelic pathogenic variants in SERAC1 gene, confirm MEGD(H)EL. A 73 years old patient with cognitive impairment and progressive spastic tetraparesis had multiple periventricular T2 hyperintense lesions. She has a homozygotic SERAC1 variant NM_032861: exon4:c.T139A: p.F471 (rs112780453), considered benign. Biochemical study revealed elevated plasmatic alanine and urinary3-metilglutaconic and 3-metilglutaric acid. This profile is concordant with mitochondrial dysfunction and SERAC1 Deficit. Conclusion - The first patient has the clinical symptoms associated to the MEGD(H)EL syndrome, and the biochemical and genetic confirmation of the diagnosis, without reservations. However, in the second patient, the progressive paraparesis and cognitive impairment did not appear to be caused by multiple sclerosis nor subcortical vascular leukoencephalopathy (without vascular risk factors). The abnormal biochemical profile is suggestive of SERAC1 Deficiency, even without genetic confirmation. In what should we believe?

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.