Onset Of Dystonia Research Articles

Focused Ultrasound Pallidothalamic Tractotomy in Cervical Dystonia: A Pilot Study.

No clinical trials have been reported on the use of focused ultrasound (FUS) for treating cervical dystonia. We aimed to confirm the efficacy and safety of FUS pallidothalamic tractotomy for cervical dystonia. This was a prospective, open-label, non-controlled pilot study. The primary outcome was defined as a change in the score for the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to 6 months after FUS pallidothalamic tractotomy. The secondary outcomes included a change in the neck scale for the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), mood scales including Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Apathy Evaluating Scale (AES), and adverse events. Patients were assessed for TWSTRS, BFMDRS, and adverse events at baseline, 1 week, 1 month, 3 months, and 6 months after treatment. BDI, BAI, and AES were assessed at baseline and 6 months after treatment. Ten patients were enrolled in this study. The mean age of onset of dystonia was 51.6 ± 10.2 years. The TWSTRS at 6 months (29.9 ± 16.0, range: 3-55) was significantly improved by 43.4% (P < 0.001) from baseline. The BFMDRS-Neck scales at 6 months (4.2 ± 2.8) were significantly improved by 38.2% (P < 0.001) from baseline. The BDI, BAI, and AES at 6 months were improved by 23.2%, 10.9%, and 30.3%, respectively from baseline. Reduced hand dexterity in three patients and weight gain in two patients were confirmed at the last evaluation. This study suggests that FUS pallidothalamic tractotomy may be an effective treatment option for patients with cervical dystonia. © 2024 International Parkinson and Movement Disorder Society.

The clinical spectrum and pathogenesis associated with KMT2B variants in Chinese pediatric patients

ObjectiveTo evaluate the clinical spectrum and pathogenesis associated with KMT2B variants in Chinese children with dystonia or developmental delay. MethodsWe reported twenty-seven (fourteen males and thirteen females) pediatric patients with KMT2B variants identified via next-generation sequencing from a single Chinese center. Moreover, transcriptomics and proteomics assays were performed on fibroblasts from patients with different genotypes to investigate the pathogenic mechanisms involved. ResultsTwenty-six patients had dystonia including generalized dystonia (n = 19), multifocal dystonia (n = 6), and segmental dystonia (n = 1), and one patient had nondystonic severe-developmental delay (DD). All the twenty-six patients had complex dystonia compounded with other manifestations of movement disorders (tremor (n = 6), myoclonus (n = 5), status dystonicus (n = 2), and tic (n = 1)) or dysmorphic features and developmental delay. The onset of dystonia was between 1 month and 13 years 8 months (median 4 years 4 months). Dystonia was aggravated by fever (n = 11), and diurnal and climate fluctuations (n = 4). Eleven patients underwent deep brain stimulation and experienced significant improvements in motor function and disability. We identified twenty-six intragenic heterozygous KMT2B pathogenic variants and one Chr:19q13.12 contiguous gene deletion. Sixteen variants were novel. Differentially expressed genes induced by KMT2B variants were significantly enriched for mitochondria-related biological processes in patient fibroblasts. As a result, mitochondrial morphology of mitochondria was altered, and aerobic respiration was impaired. ConclusionOur study reports the pediatric cases of KMT2B-related disorder from a single center in China. Additionally, our study highlights the role of KMT2B variants in mitochondrial dysfunction.

Spinocerebellar ataxia type 49 presenting with ataxia, early onset dystonia, and bradykinesia in an Indian female patient

Spinocerebellar ataxia type 49 presenting with ataxia, early onset dystonia, and bradykinesia in an Indian female patient

Does sex influence the natural history of idiopathic adult-onset dystonia?

BackgroundSeveral earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias...

Expanding the phenotypic and genotypic spectrum of DYT-TUBB4A with seven patients from India

BackgroundVariants in the TUBB4A gene are associated with dystonia (DYT-TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation. CasesAmong these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT-TUBB4A, other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn. ConclusionsWe report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment.

Understanding Anxiety in Cervical Dystonia: An Imaging Study.

Anxiety may precede motor symptoms in cervical dystonia (CD) and is associated with an earlier onset of dystonia. Our understanding of anxiety in CD is inadequate. To investigate brain networks associated with anxiety in CD. Twenty-six subjects with idiopathic CD underwent MRI Brain without contrast. Correlational tractography was derived using Diffusion MRI connectometry. Quantitative Anisotropy (QA) was used in deterministic diffusion fiber tracking. Correlational tractography was then used to correlate QA with State-Trait Anxiety Inventory (STAI) state (STAI-S) and trait (STAI-T) subscales. Connectometry analysis showed direct correlation between state anxiety and QA in tracts from amygdala to thalamus/ pulvinar bilaterally, and trait anxiety and QA in tracts from amygdala to motor cortex, sensorimotor cortex and parietal association area bilaterally (FDR ≤0.05). Our efforts to map anxiety to brain networks in CD highlight the role of the amygdala in the pathophysiology of anxiety in CD.

Moving across disorders: A cross-sectional study of cognition in early onset ataxia and dystonia

BackgroundEarly onset ataxia (EOA) and Early Onset Dystonia (EOD) are movement disorders developing in young people (age <25 per definition). These disorders result from dysfunctional networks involving the cerebellum and basal ganglia. As these structures are also important for cognition, cognitive deficits can be expected in EOA and EOD. EOA and EOD sometimes co-occur, but in those cases the predominant phenotype is determining. A pending question is whether predominantly EOA and EOD have different profiles of cognitive impairment. ObjectivesWe investigated whether cognitive functions were impaired in patients with either predominant EOA or predominant EOD and whether cognitive profiles differed between both patient groups. MethodsThe sample consisted of 26 EOA and 26 EOD patients with varying etiology but similar duration and severity of the disorder. Patient samples were compared to a group of 26 healthy controls, all matched on age and gender. All participants underwent neuropsychological testing for verbal intelligence, memory, working memory, attention/cognitive speed, executive functions, emotion recognition and language. ResultsEOA and EOD patients both performed significantly worse than healthy controls on tests of verbal intelligence, working memory and executive functions. Additionally, attention/cognitive speed and emotion recognition were impaired in the EOA group. Compared to EOD, EOA patients performed worse on attention/cognitive speed and verbal intelligence. ConclusionsOur results show overall similar profiles of cognitive deficits in both patient groups, but deficits were more pronounced in the patients with EOA. This suggests that more severe cognitive impairment is related to more severe cerebellar network dysfunction.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Adult-onset idiopathic dystonia: phenotype and mechanism changes “as time goes by”

Adult-onset idiopathic dystonia is thought to be an autosomal dominant disorder with markedly reduced penetrance and heterogeneous clinical presentation. It has been known for a long time that age may affect the clinical phenomenology of the condition, at least in terms of the site of dystonia onset. The aim of this paper is to understand whether age and aging may play a role in the natural history of adult-onset idiopathic dystonia and in the mechanisms underlying its development and progression. Aging may increase abnormalities in cortical/subcortical excitability manifested by patients with different forms of adult-onset idiopathic dystonia, thus enhancing susceptibility to dystonia development, worsening spasm severity, at least in blepharospasm, and favoring perhaps the spread of dystonia to near body sites. The relationship between age of onset and site of onset in adult-onset idiopathic dystonia (AOID) might reflect age- and body-site-specific environmental risk factors that would drive the variable clinical expression of individuals carrying dystonia-susceptibility gene(s).

Case Series: Dystonia with multiple sclerosis and neuromyelitis optica

Dystonia is an uncommon complication of relapsing-remitting multiple sclerosis (MS) and related disorders. The types of dystonia described associated with MS are heterogenous, and the relationship between dystonia and MS remains unclear. Moreover, the anatomical correspondence between MS lesions and the site of dystonia has not been determined. Onset, treatment response, and outcomes of dystonia associated with MS still remain largely uncharacterized. Here, we report a case series of 14 patients with dystonia affecting different body parts in people with MS and neuromyelitis optica (NMO). We characterize the brain regions associated with this form of secondary dystonia and the response to botulinum toxin injections.

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.

Adult Onset of Pyruvate Dehydrogenase Deficiency Presenting with Dystonia and Chorea in Female Patient from India - A Very Rare Case

We reported a very rare case of pyruvate dehydrogenase complex E1α (PDHA1) gene deficiency presenting as cervical dystonia and chorea in an adult female patient from India. Patient was presented with a history of involuntary rhythmic repetitive movements of both hands, legs, and head, lips and stammering of speech with tilting of neck to one side along with orofacial dyskinetic movements since past 6 years and gait changes since past 4 years. Her symptoms were progressive in nature. Her physical examination and systemic examinations were normal. Neurological examinations suggestive of cervical dystonia with chorea form movements. Brain MRI investigations revealed marked atrophy of bilateral caudate nuclei and putamina. Patient had a familial history of father and second brother had mild hand tremors. Patient has been referred for whole exome sequencing. The exome data analysis identified a very rare and unusual heterozygous indel variant c.-20_-19delinsCT, (chrX:19344018_19344019delinsCT) in 5’UTR region of PDHA1 gene caused late phenotypic onset of cervical dystonia as major clinical manifestation of PDHA1 deficiency along with chorea form movement disorders at the age of 24 year. In conclusion, to the best of our literature knowledge this is the novel and unusual case of adult female patient wherein we are reporting a novel heterozygous indel variant c.-20_-19delinsCT, (chrX:19344018_19344019delinsCT) in 5’UTR region of PDHA1 gene responsible for PDHA1 deficiency presenting with cervical dystonia and chorea as major clinical manifestations. Hence, dystonia and chorea as major clinical manifestations of PDH deficiency could be considered in adult patients also rather than only in paediatric patients.

Demographics and Clinical Characteristics Associated with the Spread of New-Onset Laryngeal Dystonia.

Adult-onset idiopathic laryngeal dystonia (LD) can be associated with the risk of spread to muscles in the body. Subjects with extralaryngeal onset of dystonia have exhibited spread to the larynx. Previous studies analyze the spread of other dystonias but emphasis has not been placed on LD. The objective was to identify demographic and clinical factors contributing to the spread of dystonia to and from the larynx. Data were obtained from the Dystonia Coalition (DC)-patients from 49 international clinical centers. Clinical and demographic data was taken from 143 out of 409 patients with diagnosed LD. Patient criteria included adult-onset LD diagnosed on exam with no co-morbid neurologic conditions and no dystonia in other locations. Among the 143 patients, 94 (65.7%) patients were diagnosed with focal laryngeal onset, with the remainder having extralaryngeal onset. Family history and age at study were statistically significant indicators of a patient developing laryngeal versus extralaryngeal onset of dystonia. Among the laryngeal onset group, 21 cases (22.3%) had an average time of 5.81 ± 5.79 years to spread from diagnosis, most commonly to neck (61.9%). Among extralaryngeal onset patients, mean time of larynx spread was 7.92 ± 7.737 years, most commonly to neck (22.7%). Our data indicates approximately a quarter of patients with laryngeal-onset dystonia will exhibit spread. There were no demographic or clinical factors that were statistically predictive of the likelihood of spread from larynx. Patients with dystonia elsewhere in the body should be counseled on the possibility of spread to larynx, and vice versa. 4 Laryngoscope, 134:2295-2299, 2024.

Excessive psychological stress preceding the onset of idiopathic cervical dystonia

Idiopathic cervical dystonia (ICD) is the largest subgroup of dystonia. Psychological stress as a triggering factor has long been discussed, but detailed descriptions are lacking. We report on a group of 13 patients with ICD and preceding excessive psychological stress (age at ICD onset 39.0 ± 13.9 years, 7 females, 6 males). The observation period was 7.8 ± 5.0 years. Excessive psychological stress included partner conflicts (divorce and separation, domestic violence), special familial burdens, legal disputes and migration. It started 8.3 ± 3.9 months before ICD onset. In 85% of our patients (typical cases), ICD developed within 5.8 ± 4.4 weeks, then lasted 18.5 ± 8.3 months, before it started to remit 2.7 ± 0.8 years after its onset to 54.5 ± 35.3% of its maximal severity. Idiopathic dystonia is thought to be based upon a genetic predisposition triggered by epigenetic factors. Our study suggests that excessive psychological stress could be one of them. Pathophysiologic elements are only vaguely identified, but could include the endoplasmic reticulum stress response, cerebellar 5HT-2A receptors and the metabolism of heat shock proteins. Whilst the clinical presentation of ICD preceded by excessive psychological stress is typical, its course is atypical with rapid onset and fast and substantial remission.

Do cerebrovascular risk factors impact the clinical expression of idiopathic isolated adult-onset dystonia?

BackgroundAlthough acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features. MethodsData were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia). ResultsA total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient. ConclusionsResults of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association.

Whole exome sequencing and clinical investigation of young onset dystonia: What can we learn?

BackgroundDystonia is a heterogeneous movement disorder involving various genetic backgrounds, and the implication of whole exome sequencing (WES) has yet to be clearly elucidated. In this study, we performed WES in Korean patients with young-onset dystonia. MethodsWe recruited patients with young-onset dystonia based on the new MDS dystonia classification at Samsung Medical Centre from 2015 to 2019. We excluded subjects diagnosed by single gene tests (GCH1, TOR1A, PANK2, PRRT2, and SGCE) or levodopa trials and subjects with focal or possible secondary dystonia. We performed WES in all enrolled subjects and confirmed the results with Sanger sequencing. ResultsOf the 43 patients, we detected 11 disease-causing variants, classified as either pathogenic or likely pathogenic, in 9 patients (20.9%). Generalized dystonia, infancy-childhood-onset dystonia, and other combined neurologic manifestations were related with PV/LPV. When we retrospectively reviewed the patients with PV/LPV, brain imaging was diagnostic in 3 subjects (HTRA1, SCL20A, and WDR45), clinical characteristics of paroxysmal presentation were observed in 2 (ADCY5 and ATP1A3), and microcephaly was noted in 1 patient (KMT2B). ConclusionClinical exome sequencing is helpful for the diagnosis of dystonia, especially for that with infancy-childhood onset, and generalized dystonia with other neurologic manifestations. Additionally, careful evaluations and examinations could provide information for selecting candidates for genetic testing.

DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxia.

DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which was thought to be pathogenic. This case describes the latest known symptomatic onset of DMN1L-related disease described in literature. We highlight our approach to a challenging diagnostic workup and interpretation of a specific variant that has not been previously reported. Furthermore, the case highlights the diagnostic importance of utilizing genomic sequencing and research studies for patients with rare disease.

CAFFEINE INDUCED CERVICAL DYSTONIA-A CASE STUDY

Dystonia is a movement disorder characterised by involuntary, extended, patterned, and often repetitive muscle contractions of skeletal muscles, frequently causing twisting movements or abnormal postures. Recent studies have shown that stress and coffee consumption can precipitate dystonic attacks. Many people, due to their diligent life schedules and increased physical inactivity due to less work-life balance, have been identified as the major cause of this neurological movement disorder. The action of caffeine and other CNS stimulants may be related to dystonic episodes in an individual. Cervical dystonia is specifically characterised by involuntary muscle contraction of the trapezius muscle, pain in the cervical region, numbness in one or both arms, and restricted movement. Proper understanding and management of spasmodic torticollis are necessary to avoid discomfort and progress towards a healthy life. The case study aims to highlight the role of physical activity along with proper work-life balance to live a healthy lifestyle and minimise the frequency of muscle spasm attacks caused by spasmodic torticollis. The role of clinicians such as physicians and clinical pharmacists in understanding and managing the disease is critical and crucial for a better quality of life and leading a stress-free life.

Episignature analysis of moderate effects and mosaics

DNA methylation classifiers (“episignatures”) help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.