Posterior Interosseous Neuropathy with Peripheral Dystonia: A Case Report.

Background: Posterior interosseous neuropathy is an uncommon cause of peripheral dystonia. Case Report: A 62-year-old man awakened and noticed right finger drop. A neurological examination revealed posterior interosseous neuropathy with dystonia-like finger movements. Abnormal movements were predominantly observed in the right thumb, ring finger, and little finger. Within 2 weeks, the muscle weakness in the right fingers had completely improved. However, a brief abnormal posture of the right thumb was persistent. Discussion: The residual abnormal posture of the right thumb may reflect pre-existing motor control abnormalities, which may have contributed to the onset of posterior interosseous neuropathy-associated peripheral dystonia.

CHD8-related disorders redefined: an expanding spectrum of dystonic phenotypes.

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

Interdisciplinary insights into tremor in dystonia: Navigating clinical controversies, definitional challenges, and pathophysiological complexities.

This review delves into the historical evolution and ongoing controversy surrounding the relationship between tremor and dystonia. The Dystonia Consensus Panel and the International Parkinson's and Movement Disorders Society's Tremor Taskforce have attempted to define these entities, but the complexity arises when patients have a combination of both dystonia and tremor. The term "dystonic tremor" has sparked diverse interpretations, with debates over its clinical features and the need for more objectively defined characteristics. Logistic regression analyses in a large cohort of dystonia patients identified determinants such as body region affected by dystonia, dystonia severity, age, and recruitment site, with unexpected associations emphasizing the subjectivity in detecting and classifying tremor. The study further discovered diverse prevalence of "dystonic tremor" based on different definitions, revealing substantial variability among investigators. The recently convened Dystonia-Tremor panel aimed to address these challenges by proposing a more uniform nomenclature, emphasizing precise and descriptive terms. Despite the complexity, instrumented measures, such as electromyography, temporal discrimination threshold, blink reflex, and trajectory shape analysis, seem to be useful in distinguishing between tremor and dystonia. The pathophysiology debate centers around the involvement of the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits. Evidence supports the role of both circuits in driving the pathophysiology of dystonic tremor, challenging the notion of a clear dichotomy. The review concludes by emphasizing the need for a nuanced understanding, highlighting the intricate interplay between tremor and dystonia, and the potential of instrumental measures in advancing diagnostic accuracy.

Gender Differences in Task Specific Dystonia: What Can we Learn from Musician's Dystonia?

BACKGROUND: Musician's Dystonia (MD) is a task specific, focal dystonia which usually occurs only at the instrument. The pathophysiology is not fully understood, but several risk factors like over-practice and genetic predisposition are known. Interestingly, 80% of those affected are men, which stands in contrast to the gender distribution in other focal dystonias, such as cervical dystonia. OBJECTIVES: Our aim was to evaluate the difference in women and men with regard to risk factors leading to MD. METHODS: We investigated known risk factors for MD in a large cohort of 364 MD patients by retrospectively collecting data on practice behavior and family history. RESULTS: In line with previous studies, we found a ratio of ~4:1 men to women. Age at onset of MD was significantly lower in women; however, subsequent analysis revealed that it was a positive family history (FH+) and not gender that was associated with a lower age at onset. Furthermore, we found that those with negative family history had accumulated more practice time until onset of MD. CONCLUSIONS: These results imply that the earlier age at onset in women did not depend on gender but was due to the higher proportion of a positive family history. In contrast, men were less likely to have a positive family history, suggesting that genetic factors may not be the primary reason for the higher prevalence of MD in men. Instead, differences in practice behaviors between men and women may contribute to this gender disparity.

Neuroenergetic Changes in Patients with X-Linked Dystonia-Parkinsonism and Female Carriers.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored. OBJECTIVES: To investigate the bioenergetic state in male patients with XDP and female carriers using 31phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations. METHODS: We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls. RESULTS: HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers. CONCLUSIONS: Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers.

Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature.

BACKGROUND: IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein. OBJECTIVE: To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis. METHODS: We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1). RESULTS: All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12). CONCLUSIONS: Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

R233H mutation in patients with tyrosine hydroxylase deficiency and corresponding phenotypes: a study of four cases and literature review.

Owing to the small number of patients with tyrosine hydroxylase (TH) deficiency, no genotype-phenotype correlations have yet been identified. To investigate the genotype-phenotype correlation of R233H mutation in TH deficiency, we analyzed the clinical manifestations and treatment responses of four patients with the R233H homozygous mutation. Thirty-eight additional patients, available from the literature, known to be homozygous or heterozygous for the R233H mutation, were combined with the four cases from our hospital. Data for a total of 42 patients were retrieved. Our four patients showed clinical presentation consistent with Type A TH deficiency, and responded well to levodopa therapy, with an improvement in clinical symptoms within 1-2 weeks. In the 42 patients, 20 of 42 patients (48%) were homozygous and 22 (52%) were heterozygous for the R233H mutation. Of the 20 patients who were homozygous for the R233H mutation, a majority (80%) suffered from Type A TH deficiency. Of the 8 patients that were heterozygous for the R233H/the mutation located downstream of exon 11, 7 patients (86%) suffered from Type B TH deficiency. Of the 7 patients who were heterozygous for the R233H/nonsense mutation, 6 (86%) suffered from Type B TH deficiency. Genotype-phenotype correlation of R233H mutation was observed in TH deficiency. The homozygous R233H mutation frequently manifests as Type A TH deficiency, whereas R233H/nonsense mutation or any mutation located downstream of exon 11 manifests as Type B TH deficiency.

Pathophysiological mechanisms of oromandibular dystonia.

Oromandibular dystonia (OMD) is a rare form of focal idiopathic dystonia. OMD was clinically identified at the beginning of the 20th century, and the main clinical features have been progressively described over the years. However, OMD has several peculiarities that still remain unexplained, including the high rate of oral trauma, which is often related to the onset of motor symptoms. The purpose of this paper was to formulate a hypothesis regarding the pathophysiology of OMD, starting from the neuroanatomical basis of the masticatory and facial systems and highlighting the features that differentiate this condition from other forms of focal idiopathic dystonia. We provide a brief review of the clinical and etiological features of OMD as well as neurophysiological and neuroimaging findings obtained from studies in patients with OMD. We discuss possible pathophysiological mechanisms underlying OMD and suggest that abnormalities in sensory input processing may play a prominent role in OMD pathophysiology, possibly triggering a cascade of events that results in sensorimotor cortex network dysfunction. Finally, we identify open questions that future studies should address, including the effect of abnormal sensory input processing and oral trauma on the peculiar neurophysiological abnormalities observed in OMD.

Never too little: Grip and lift forces following probabilistic weight cues in patients with writer's cramp.

OBJECTIVE: Planning of voluntary object-related movements requires the estimation of the most probable object properties. We investigated how 14 writer's cramp (WC) patients compared to 14 controls use probabilistic weight cues in a serial grip-lift task. METHODS: In every grip-lift trial, an object of either light, medium or heavy weight had to be grasped and lifted after a visual cue gave a probabilistic prediction of the object weights (e.g. 32.5% light, 67.5% medium, 0 % heavy). We determined peak (1) grip force GF, (2) load force LF, (3) grip force rate GFR, (4) load force rate LFR, while we registered brain activity with functional magnetic resonance imaging. RESULTS: In both groups, GFR, LFR and GF increased when a higher probability of heavy weights was announced. When a higher probability of light weights was indicated, controls reduced GFR, LFR and GF, while WC patients did not downscale their forces. There were no inter-group differences in blood oxygenation level dependent activation. CONCLUSIONS: WC patients could not utilize the decision range in motor planning and adjust their force in a probabilistic cued fine motor task. SIGNIFICANCE: The results support the pathophysiological model of a hyperfunctional dopamine dependent direct basal ganglia pathway in WC.

Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?

One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.

Splice-variant specific effects of a CACNA1H mutation associated with writer's cramp.

The CACNA1H gene encodes the α1 subunit of the low voltage-activated Cav3.2 T-type calcium channel, an important regulator of neuronal excitability. Alternative mRNA splicing can generate multiple channel variants with distinct biophysical properties and expression patterns. Two major splice variants, containing or lacking exon 26 (± 26) have been found in different human tissues. In this study, we report splice variant specific effects of a Cav3.2 mutation found in patients with autosomal dominant writer's cramp, a specific type of focal dystonia. We had previously reported that the R481C missense mutation caused a gain of function effect when expressed in Cav3.2 (+ 26) by accelerating its recovery from inactivation. Here, we show that when the mutation is expressed in the short variant of the channel (- 26), we observe a significant increase in current density when compared to wild-type Cav3.2 (- 26) but the effect on the recovery from inactivation is lost. Our data add to growing evidence that the functional expression of calcium channel mutations depends on which splice variant is being examined.

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.

BACKGROUND: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. RESULTS: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the "episignature" associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. CONCLUSIONS: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.

Childhood-onset progressive dystonia associated with pathogenic truncating variants in CHD8.

Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystonia-dominant phenotypes.

Speech and swallowing deficits in X-Linked Dystonia-Parkinsonism.

INTRODUCTION: X-linked Dystonia-Parkinsonism (XDP) is a progressive, disabling disease characterized by the devastating impairment of bulbar function, including speech and swallowing. Despite these detrimental impacts, bulbar impairments in this population are not well characterized. OBJECTIVES: To identify impairments in the bulbar system measured by oromotor performance in individuals with XDP relative to healthy controls. Secondarily, to detect diagnostic bulbar markers that are sensitive and specific to the initial years of XDP. METHODS: This case-control study included 25 healthy controls and 30 participants with XDP, divided into two subgroups based on the median of their disease length. Multiple clinical and instrumental oromotor tasks and measures were used to evaluate bulbar motor function. RESULTS: Differences were found between both the subgroups with XDP and healthy controls on almost all measures, including maximum performance tasks such as tongue strength, alternating motion rate (AMR), and sequential motion rate (SMR) (p < 0.05). Differences were found between the XDP subgroups and the control group for the percentage of pause time during the speech, a rating of speech severity, and a swallowing task (ps < 0.05). Scores on self-reported questionnaires, tongue strength, the number of repetitions produced during an AMR, percent pause, and speech severity demonstrated good sensitivity and specificity to differentiate the initial years of XDP onset from healthy controls. CONCLUSIONS: Our findings revealed impairments across bulbar functions in participants within the first 7 years of the XDP onset. Highly sensitive and specific bulbar impairment measures were detected in instrumental and self-reported measures that are fundamental for monitoring disease.

Low-frequency oscillations in cortical level to help diagnose task-specific dystonia.

Task-specific dystonia is a neurological movement disorder that abnormal contractions of muscles result in the twisting of fixed postures or muscle spasm during specific tasks. Due to the rareness and the pathophysiology of the disease, there is no test to confirm the diagnosis of task-specific dystonia, except comprehensive observations by the experts. Evidence from neural electrophysiological data suggests that enhanced low frequency (4-12 Hz) oscillations in the subcortical structure of the globus pallidus were associated with the pathological abnormalities concerning ß and γ rhythms in motor areas and motor cortical network in patients with task-specific dystonia. However, whether patients with task-specific dystonia have any low-frequency abnormalities in motor cortical areas remains unclear. In this study, we hypothesized that low-frequency abnormalities are present in core motor areas and motor cortical networks in patients with task-specific dystonia during performing the non-symptomatic movements and those low-frequency abnormalities can help the diagnosis of this disease. We tested this hypothesis by using EEG, effective connectivity analysis, and a machine learning method. Fifteen patients with task-specific dystonia and 15 healthy controls were recruited. The machine learning method identified 8 aberrant movement-related network connections concerning low frequency, ß and γ frequencies, which enabled the separation of the data of patients from those of controls with an accuracy of 90%. Importantly, 7 of the 8 aberrant connections engaged the premotor area contralateral to the affected hand, suggesting an important role of the premotor area in the pathological abnormities. The patients exhibited significantly lower low frequency activities during the movement preparation and significantly lower ß rhythms during movements compared with healthy controls in the core motor areas. Our findings of low frequency- and ß-related abnormalities at the cortical level and aberrant motor network could help diagnose task-specific dystonia in the clinical setting, and the importance of the contralesional premotor area suggests its diagnostic potential for task-specific dystonia.

Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders.

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although dysfunction of the basal ganglia, a brain region that mediates movement, is implicated in many forms of dystonia, the underlying mechanisms are unclear. The inherited metabolic disorder DOPA-responsive dystonia is considered a prototype for understanding basal ganglia dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of the neurotransmitter dopamine, which mediates the activity of the basal ganglia. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented and proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated striatal proteins identified in our screen are associated with pathogenic variants that cause inherited disorders with dystonia as a sign in humans suggesting shared mechanisms across many different forms of dystonia.

The development and use of an anatomy-based retraining program (MusAARP) to assess and treat focal hand dystonia in musicians-A pilot study.

BACKGROUND: Movement dysfunctions are commonly reported in musicians, and in extreme cases may result in a persisting loss of motor control. This condition, whereby motor control of the hand during previously highly trained movements on the instrument is lost, is termed focal hand dystonia. It is widely considered to be a consequence of prolonged repetitive daily practice, often in combination with exposure to a range of other risk factors. Current literature recommends retraining as a promising treatment intervention, although only scant scientific evidence exists on which components should be included in a retraining program, and how these may be best administered. METHODS: A progressive muscle activation and movement exercise program was devised by one of the authors applying a series of anatomy-based off-instrument movement tasks. This series of fine motor control exercises, was used to both assess and retrain focal hand dystonia in a population of musicians. The standardized approach aimed to provide a systematic method of retraining musically relevant muscular synergies that could later be applied to the instrument, while still allowing individual modifications. Retraining sessions were mostly run online as a consequence of the coronavirus pandemic, although some early sessions were also able to be undertaken face to face. Both qualitative and quantitative measures were used in this case series to evaluate program efficacy, due to the typical heterogeneity of the focal hand dystonia participants. This included: blinded external neurological evaluation of video footage using the Tubiana grading system, written subjective feedback, exercise progressions, and performance outcomes. RESULTS: Pilot testing of 4 patients indicated the utility of the program over approximately a 12- month time period. All subjects improved, 2 of whom have returned to pre-dystonia performance levels. These patients reported the importance of patience and persistence with daily exercise sessions in their recovery. CONCLUSION: Using off-instrument playing-relevant exercises to enhance fine motor control and muscle activation can be effective in retraining focal hand dystonia, regardless of additional treatments or level of performance. They should be regularly practiced and progressed in order for effects to be best progressed to instrumental applications. Further research may elucidate whether there are optimal outcomes with single or particular combinations of treatment approaches.

Subthalamic deep brain stimulation in lingual dystonia: A case series study.

Lingual dystonia is a rare disease, which often interferes with daily activities severely. The efficacy of GPi-DBS on patients with refractory lingual symptoms has been previously reported, while high-level evidence is inadequate. Uniquely, we retrospect six lingual dystonia patients treating with subthalamic DBS, showing its immediate, and long-lasting efficacy.