Molecular genetic analysis of essential tremor

Essential tremor (ET) is the most common extrapyramidal disorder of the central nervous system with autosomal dominant transmission in the majority of cases and age-dependent penetrance of the mutant gene. In a number of cases, it shares some phenotypic features with autosomal dominant idiopathic torsion dystonia (locus DYT1 on chromosome 9q32-34) and is genetically heterogeneous: distinct variants of ET were mapped to chromosomes 3q13 (ETM1) and 2p22-25 (ETM2). We performed studies of candidate loci in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. Mutational analysis of the DYT gene in probands did not reveal the major deletion 946-948delGAG characteristic of idiopathic torsion dystonia, which allows one to genetically distinguish the studied hereditary forms of ET and torsion dystonia. Based on analysis of genetic linkage in informative Tajik pedigrees with ET, linkage to locus ETM1 on chromosome 3q13 was established in four families. Maximum pairwise Lod score was 2.46 at recombination fraction of theta = 0.00; maximum combined multipoint Lod score was 3.35 for marker D3S3720 and a common "mutant" haplotype for markers D3S3620, D3S3576, and D3S3720 allowed us to locate a mutant gene in a relatively narrow chromosome region spanning 2 cM. In one informative pedigree with ET, both candidate loci ETM1 and ETM2 were definitely excluded on the basis of negative Lod scores obtained by linkage estimations, which testifies to the existence of another distinct gene for autosomal dominant ET.     

Discrimination of Parkinsonian tremor from essential tremor by implementation of a wavelet-based soft-decision technique on EMG and accelerometer signals

A wavelet-decomposition with soft-decision algorithm is used to estimate an approximate power-spectral density (PSD) of both accelerometer and surface EMG signals for the purpose of discrimination of Parkinson tremor from essential tremor. A soft-decision wavelet-based PSD estimation is used with 256 bands for a signal sampled at 800 Hz. The sum of the entropy of the PSD in band 6 (7.8125–9.375 Hz) and band 11 (15.625–17.1875 Hz) is used as a classification factor. The data has been recorded for diagnostic purposes in the Department of Neurology of the University of Kiel, Germany. Two sets of data are used. The training set, which consists of 21 essential-tremor (ET) subjects and 19 Parkinson-disease (PD) subjects, is used to obtain the threshold value of the classification factor differentiating between the two subjects. The test data set, which consists of 20 ET and 20 PD subjects, is used to test the technique and evaluate its performance. A “voting” between three results obtained from accelerometer signal and two EMG signals is applied to obtain the final discrimination. A total accuracy of discrimination of 85% is obtained.     

Gait variability magnitude but not structure is altered in essential tremor

Essential tremor (ET) is a common tremor disorder affecting postural/action tremor of the upper extremities and midline. Recent research revealed a cerebellar-like deficit during tandem gait in persons with ET, though spatiotemporal variability during normal gait in ET has been relatively ignored. The first purpose of this study was to investigate gait variability magnitude and structure in ET as compared to healthy older adults (HOA). To address this issue, 11 ET and 11 age-matched HOAs walked on a treadmill for 5 min at preferred walking speeds. HOAs walked for an additional minute while speed-matched to an ET participant. The second purpose was to describe the clinical correlates of gait variability in this population. To address this aim, 31 persons with ET walked on a treadmill for 5 min and completed the Fahn–Tolosa–Marin Tremor Rating Scale. Gait variability magnitude was derived by calculating coefficients of variation in stride length, stride time, step length, step time, and step width. Gait variability structure was derived using a detrended fluctuation analysis technique. At preferred walking speeds, ET participants walked significantly slower with significantly increased variability magnitude in all five spatiotemporal gait parameters. At speed-matched walking, ET participants exhibited significantly higher step width variability. Gait variability structure was not different between groups. We also observed that gait variability magnitude was predicted by severity of upper extremity and midline tremors. This study revealed that self-selected gait in ET is characterized by high variability that is associated with tremor severity in the upper extremity and midline.     

The approximate entropy of the electromyographic signals of tremor correlates with the osmotic fragility of human erythrocytes

Background  

The main problem of tremor is the damage caused to the quality of the life of patients, especially those at more advanced ages. There is not a consensus yet about the origins of this disorder, but it can be examined in the correlations between the biological signs of aging and the tremor characteristics.     

Cerebral toxoplasmosis in Acquired Immunodeficiency Syndrome (AIDS) patients also provides unifying pathophysiologic hypotheses for Holmes tremor

Background  

Holmes tremor is a rare symptomatic movement disorder. Currently suggested pathophysiological mechanisms of the disease are mostly derived from stroke cases. Although rare, cerebral toxoplasmosis may strengthen the pathophysiologic mechanism of disease.     

Molecular Genetic Analysis of Essential Tremor

Essential tremor (ET) is the most common extrapyramidal disorder of the central nervous system with autosomal dominant transmission in the majority of cases and age-dependent penetrance of the mutant gene. In a number of cases, it shares some phenotypic features with autosomal dominant idiopathic torsion dystonia (locusDYT1on chromosome 9q32–34) and is genetically heterogeneous: distinct variants of ET were mapped to chromosomes 3q13 (ETM1) and 2p22–25 (ETM2). We performed studies of candidate loci in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. Mutational analysis of the DYT1 gene in probands did not reveal the major deletion 946–948delGAG characteristic of idiopathic torsion dystonia, which allows one to genetically distinguish the studied hereditary forms of ET and torsion dystonia. Based on analysis of genetic linkage in informative Tajik pedigrees with ET, linkage to locus ETM1 on chromosome 3q13 was established in four families. Maximum pairwise Lod score was 2.46 at recombination fraction of = 0.00; maximum combined multipoint Lod score was 3.35 for marker D3S3515 and a common mutant haplotype for markers D3S3620, D3S3576, and D3S3720 allowed us to locate a mutant gene in a relatively narrow chromosome region spanning 2 cM. In one informative pedigree with ET, both candidate loci ETM1 and ETM2 were definitely excluded on the basis of negative Lod scores obtained by linkage estimations, which testifies to the existence of another distinct gene for autosomal dominant ET.     

Neuroanatomical Heterogeneity of Essential Tremor According to Propranolol Response

Background

Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET.

Methods

A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18) and a non-responder group (n = 14). We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters.

Results

There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration.

Conclusions

The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity.     

The nature of essential tremor

The literature concerning essential tremor is confusing. Some accounts describe tremor of a resting type and its accompaniment by other neurological abnormalities. Critical analysis of the pertinent literature leaves some question as to the validity of these observations.Clinical analysis of 34 patients with essential tremor, personally observed during a four-year period, reveals this to be a monosymptomatic condition. The tremor was usually of both a postural and action type and resting tremor was not observed. There were no other neurological abnormalities. Serious disability was infrequent and, when present, was related to upper limb tremor. Essential tremor should be readily distinguishable from other central nervous system diseases but it may be confused with Parkinson''s disease or cerebellar ataxia.     

Analysis of Nuclear Export Sequence Regions of FUS-Related RNA-Binding Proteins in Essential Tremor

Background and Objective

Genes encoding RNA-binding proteins, including FUS and TDP43, play a central role in different neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recently, a mutation located in the nuclear export signal (NES) of the FUS gene has been reported to cause an autosomal dominant form of familial Essential tremor.

Material and Methods

We sequenced the exons coding the NES domains of five RNA-binding proteins (TARDBP, hnRNPA2B1, hnRNPA1, TAF15 and EWSR1) that have been previously implicated in neurodegeneration in a series of 257 essential tremor (ET) cases and 376 healthy controls. We genotyped 404 additional ET subjects and 510 healthy controls to assess the frequency of the EWSR1 p.R471C substitution.

Results

We identified a rare EWSR1 p.R471C substitution, which is highly conserved, in a single subject with familial ET. The pathogenicity of this substitution remains equivocal, as DNA samples from relatives were not available and the genotyping of 404 additional ET subjects did not reveal any further carriers. No other variants were observed with significant allele frequency differences compared to controls in the NES coding regions.

Conclusions

The present study demonstrates that the NES domains of RNA-binding proteins are highly conserved. The role of the EWSR1 p.R471C substitution needs to be further evaluated in future studies.     

Excitability decreasing central motor plasticity is retained in multiple sclerosis patients

Background

Essential tremor (ET) is one of the commonest movement disorders though the prevalence varies globally. There is paucity of data on ET prevalence in sub-Saharan Africa. The study aimed to determine the prevalence of ET in a Nigerian community.

Methods

This door-to-door survey was conducted in two stages. In Stage 1, 3000 randomly selected residents of an urban centre in Lagos, Nigeria, were screened using a questionnaire to detect symptoms of movement disorder. 234 participants who responded positively regarding presence of tremors were rescreened using an ET-specific questionnaire, a face-to-face interview and neurological examination. Diagnosis of ET was based on the Movement Disorders Society (MDS) consensus diagnostic criteria for ET.

Results

Of the 3000 participants, forty responded positively to the ET screening questionnaire, of which 36 (19 females and 17 males) had a final diagnosis of ET, giving a crude prevalence of 12 per 1000 (95% CI?=?8.1- 15.9). Gender specific prevalence was 10.3 /1000 in males and 14.3/1000 in females. Age specific prevalence increased with advancing age in both sexes. Age adjusted prevalence (WHO New world population) was 23.8 per 1000.

Conclusions

We documented a high prevalence of ET in this study, with typical increasing prevalence with advancing age as previously reported in other populations.     

Effect of mental fatigue on induced tremor in human knee extensors

In this study, the effects of mental fatigue on mechanically induced tremor at both a low (3–6 Hz) and high (8–12 Hz) frequency were investigated. The two distinct tremor frequencies were evoked using two springs of different stiffness, during 20 s sustained contractions of the knee extensor muscles at 30% maximum voluntary contraction (MVC) before and after 100 min of a mental fatigue task, in 12 healthy (29 ± 3.7 years) participants. Mental fatigue resulted in a 6.9% decrease in MVC and in a 9.4% decrease in the amplitude of the agonist muscle EMG during sustained 30% MVC contractions in the induced high frequency only. Following the mental fatigue task, the coefficient of variation and standard deviation of the force signal decreased at 8–12 Hz induced tremor by 31.7% and 35.2% respectively, but not at 3–6 Hz induced tremor. Similarly, the maximum value and area underneath the peak in the power spectrum of the force signal decreased by 55.5% and 53.1% respectively in the 8–12 Hz range only. In conclusion, mental fatigue decreased mechanically induced 8–12 Hz tremor and had no effect on induced 3–6 Hz tremor. We suggest that the reduction could be attributed to the decreased activation of the agonist muscles.     

Long-term therapy of essential tremor with propranolol.

In a double-blind crossover study 12 patients with essential tremor were treated with propranolol and a placebo; 8 improved with propranolol and 3 with the placebo; the degree of improvement with propranolol was greater. In a similar study with diazepam 5 of 12 improved with diazepam and 4 of 12 with the placebo; the degree of improvement was less than that achieved with propranolol. Response in 21 patients to treatment with propranolol for 2 to 4 years was excellent in 4, good in 4 and fair in 10; the condition of 1 was unchanged and that of 2, worse. Excellent response was maintained for as long as 4 years, but response tended to deteriorate with time if initially it was less than excellent. Response decreased with increasing age. No patient 60 years of age or older had an excellent response, and the four with an excellent response were under age 55, three being under age 35; all four had had their tremor less than 12 years. Patients with essential tremor should be given a 3-month trial of propranolol at 120 mg/d; if no significant response is seen the dose should be decreased, then the drug discontinued.     

<Emphasis Type="Italic">Bacillus anthracis</Emphasis>-derived edema toxin (ET) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway

Background  

A common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (PMNs) in infected tissues in the face of abundant circulating PMNs. A major virulence determinant of anthrax is edema toxin (ET), which is formed by the combination of two proteins produced by the organism, edema factor (EF), which is an adenyl cyclase, and protective antigen (PA). Since cAMP, a product of adenyl cyclase, is known to enhance endothelial barrier integrity, we asked whether ET might decrease extravasation of PMNs into tissues through closure of the paracellular pathway through which PMNs traverse.     

The impact of localized fatigue on contralateral tremor and muscle activity is exacerbated by standing posture

Physiological tremor is an inherent feature of the motor system that is influenced by intrinsic (neuromuscular) and/or extrinsic (task) factors. Given that tremor must be accounted for during the performance of many fine motor skills; there is a requirement to clarify how different factors interact to influence tremor. This study was designed to assess the impact localized fatigue of a single arm and stance position had on bilateral physiological tremor and forearm muscle activity. Results demonstrated that unilateral fatigue produced bilateral increases in tremor and wrist extensor activity. For example, fatigue resulted in increases in extensor activity across both exercised (increased 8–10% MVC) and the non-exercised arm (increased 3–7% MVC). The impact of fatigue was not restricted to changes in tremor/EMG amplitude, with altered hand–finger coupling observed within both arms. Within the exercised arm, cross-correlation values decreased (pre-exercise r = 0.62–0.64; post-exercise r = 0.37–0.43) while coupling increased within the non-exercised arm (pre-exercise r = 0.51–0.55; post-exercise r = 0.62–0.67). While standing posture alone had no significant impact on tremor/EMG dynamics, the tremor and muscle increases seen with fatigue were more pronounced when standing. Together these results demonstrate that the combination of postural and fatigue factors can influence both tremor/EMG outputs and the underlying coordinative coupling dynamics.     

Is There a Role for Combined EMG-fMRI in Exploring the Pathophysiology of Essential Tremor and Improving Functional Neurosurgery?

Background

Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting.

Objective

Aim of the study was to evaluate whether EMG-fMRI could detect blood oxygen level dependent brain activations associated with tremor in patients with Essential Tremor. Second, we explored whether EMG-fMRI could improve the delineation of targets for stereotactic surgery.

Methods

Simultaneous EMG-fMRI was performed in six Essential Tremor patients with unilateral thalamotomy. EMG was recorded from the trembling arm (non-operated side) and from the contralateral arm (operated side). Protocols were designed to study brain activations related to voluntary muscle contractions and postural tremor.

Results

Analysis with the EMG regressor was able to show the association of voluntary movements with activity in the contralateral motor cortex and supplementary motor area, and ipsilateral cerebellum. The EMG tremor frequency regressor showed an association between tremor and activity in the ipsilateral cerebellum and contralateral thalamus. The activation spot in the thalamus varied across patients and did not correspond to the thalamic nucleus ventralis intermedius.

Conclusion

EMG-fMRI is potentially useful in detecting brain activations associated with tremor in patients with Essential Tremor. The technique must be further developed before being useful in supporting targeting for stereotactic surgery.     

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background  

Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback.     

Detection of viral sequence fragments of HIV-1 subfamilies yet unknown

Background  

Methods of determining whether or not any particular HIV-1 sequence stems - completely or in part - from some unknown HIV-1 subtype are important for the design of vaccines and molecular detection systems, as well as for epidemiological monitoring. Nevertheless, a single algorithm only, the Branching Index (BI), has been developed for this task so far. Moving along the genome of a query sequence in a sliding window, the BI computes a ratio quantifying how closely the query sequence clusters with a subtype clade. In its current version, however, the BI does not provide predicted boundaries of unknown fragments.     

Carpal Tunnel Syndrome in Patients with Tremor Dominant Parkinson’s Disease

Background

Unilateral hand tremor is one of the cardinal symptoms of Parkinson’s disease. Additionally, mechanical traumatic hand movement is one of the risk factors for carpal tunnel syndrome. Our objective in this study was to examine whether repetitive mechanical movement may be related to the development of carpal tunnel syndrome in Parkinson’s disease with unilateral hand tremor using neurophysiological methods.

Methods

The study participants included 33 de novo Parkinson’s disease patients with unilateral hand tremor, and we compared the tremor hand and non-tremor hand within the same patients.

Results

Seven (21.2%) of the 33 patients had carpal tunnel syndrome. All of carpal tunnel syndrome patients showed neurophysiological abnormalities in both the hand without tremor and the hand with tremor. In addition, in patients without carpal tunnel syndrome, the sensory nerve action potential was lower in the hand without tremor than in the hand with tremor, although there were no significant differences.

Conclusions

We concluded that hand tremor in de novo Parkinson’s disease patients was not directly related to the development of carpal tunnel syndrome. In contrast, more frequent use of hand without tremor may induce mechanical loading and may be associated with CTS in the hand without tremor. Early diagnosis of Parkinson’s disease and proper education in hand use may be essential for preventing carpal tunnel syndrome in Parkinson’s disease tremor patients.     

Tremor suppression in ECG

Background  

Electrocardiogram recordings are very often contaminated by high-frequency noise usually power-line interference and EMG disturbances (tremor). Specific method for interference cancellation without affecting the proper ECG components, called subtraction procedure, was developed some two decades ago. Filtering out the tremor remains a priori partially successful since it has a relatively wide spectrum, which overlaps the useful ECG frequency band.