Myoclonus characteristics, namely, lack of stimulus sensitivity, a negative C-reflex finding, absence of premyoclonic cortical potential, and absence of giant somatosensory evoked potential, indicate subcortical origin.
This finding is in keeping with the high expression level of the main brain-specific SGCE isoform in the cerebellum. Comprehensive neurophysiological investigation is a potent approach to understand the underlying pathophysiology of movement disorders. However, neurophysiological studies in M-D are scarce and involve small groups of patients, often belonging to a single family, 7 , 17 , 18 or patients with heterogeneous genetic backgrounds.
The aim of this study was to clarify the neurophysiological characteristics of M-D, thereby gaining further insight into the pathophysiological features of the disease. We studied 12 M-D patients mean [SD] age, Patients with severe myoclonus or dystonia that interfered with recording were not included in the study. To ensure that the treatment would not interfere with the recordings, all pharmacological treatment was interrupted for at least 1 week before the beginning of the study.
All variables were also recorded in 12 age- and sex-matched healthy volunteers controls. The local ethics board approved the study. All participants gave written informed consent. Subjects came for 3 visits, separated by at least 1 week.
Visit 1 included the clinical examination and rating, magnetic resonance imaging of the anatomical brain, and a battery of electrophysiological variables, including resting motor threshold RMT active motor threshold AMT , short-interval intracortical inhibition SICI , and short-interval intracortical facilitation SICF.
All electrophysiological variables were measured using a commercially available stimulator BiStim 2 ; Magstim Company Ltd that induces monophasic electrical pulses in the brain and a 7-cm figure-of-eight coil.
Visit 3 included the eye-blink classic conditioning EBCC. Participants underwent evaluation of their dominant hemisphere. The EMG activity was continuously monitored during the recordings to ensure muscle relaxation. Trials contaminated by EMG activity anywhere within milliseconds around each motor evoked potential MEP were discarded from the offline analysis. Transcranial magnetic stimulation was conducted with a 7-cm figure-of-eight coil connected to the BiStim 2 module or the SuperRapid 2 magnetic stimulator.
All stimulations were performed using a neuronavigation device eXimia; Nextim Ltd with individual anatomical magnetic resonance images. This process allowed maintaining the same placement and tilt of the stimulator coil throughout each session and from one session to the next in the same participant.
The coil handle was oriented backward and laterally so that the first wave of the TMS pulse induced a posterior-anterior—directed current in the brain. The plasticity-inducing protocol was a 5-Hz RPAS, 25 which consisted of repeatedly pairing a peripheral electrical stimulation of the median nerve intensity, 2. The pulse pairs were repeated every milliseconds 5 Hz for 2 minutes pairs. Each peripheral pulse was triggered 25 milliseconds before the TMS pulse.
The paired associative stimulation with millisecond pairing delay has been shown to induce a lasting increase in M1 excitability through hebbian-like associative plasticity that relies on mechanisms similar to long-term potentiation.
The intensity of the test TMS pulses was set to evoke 0. The EBCC protocol is an associative learning paradigm, dependent on the cerebellum for acquisition.
The CS was a tone millisecond duration, 2-kHz pitch, and to dB intensity above the individual hearing threshold played via binaural headphones, and the unconditioned stimulus US was an electrical stimulation microsecond pulse width of the right supraorbital nerve that evoked a stable reflex response R2 bilaterally in the orbicularis oculi muscles.
The CS inconsistently produces an acoustic startle response alpha blink occurring within milliseconds after CS onset. The EBCC sessions consist of 6 learning blocks followed by 1 extinction block. The extinction block consisted of 11 CS-only trials. We used unpaired t tests for post hoc analysis. To analyze CRs, we used rANOVA with block blocks as the repeated factor and group patients and controls as the between-subject factor. We explored correlations between clinical scores and physiological variables by linear regression analysis.
Action myoclonus in the upper limbs constituted the main symptom. Dystonia was absent in 3 patients and minimal in 4. The global disability score scored on a visual analog scale ranging from normal [0] to severe disability [4] had discrepant results between the patient self-rating and the neurologist rating Table 1.
This analysis showed that RPAS-induced plastic changes were similar in patients and controls until the peak at 20 minutes after the end of the intervention, after which M1 excitability returned to baseline levels in the controls at 30 minutes and remained at peak levels in patients Figure 2 A and B.
We found no correlation with any other clinical score or for the ADM muscles. Ten patients and 8 healthy controls acquired the CR, and we analyzed their extinction phases. We conducted a controlled study investigating in detail the neurophysiological characteristics of 12 untreated M-D patients from 11 families with a proven SGCE defect. Similarly to patients with other forms of dystonia, the M-D patients demonstrated the enhanced propensity of the motor cortex to develop plasticity and cerebellar dysfunction.
Our findings indicate that specific underlying dysfunctions are associated with the very particular clinical phenotype of M-D and make it a unique entity that stands apart from other primary dystonias. We found an enhanced motor threshold, commonly associated with abnormal membrane excitability of the cortical neurons. The present study was performed in a large number of unrelated M-D patients, thereby excluding the possibility of a family trait.
A different methodological approach might explain the discrepancy between the studies. The RMT is a function of membrane potentials and of postsynaptic excitability levels at all the synapses en route to the spinal motoneurons. The AMT is closer to measuring membrane excitability, because synapses in the corticospinal chain are already activated by the voluntary contraction, and the membrane potentials are more homogeneous close to the discharging threshold.
Tentative explanation for the exclusive AMT increase after biphasic TMS stimulation is that biphasic pulses excite a more heterogeneous population of interneurons than monophasic ones that might be more susceptible to minute alterations of membrane excitability.
Augmented biphasic AMT correlated with the self-rated but not the neurologist-rated global disability score of the Unified Myoclonus Rating Scale. This finding was unexpected. The self-rated score might provide a better estimation of disease severity, because M-D symptoms vary throughout the day and the Unified Myoclonus Rating Scale scoring by a neurologist may fail to evaluate in its entirety the real impact of myoclonus in daily life.
The bilateral decrease of SICI in focal hand dystonia despite unilateral symptoms 29 may reflect a primary dysfunction of the dystonic brain. However, decreased SICI in psychogenic dystonia 31 suggested the opposite; it may be the consequence of dystonic movements per se.
We found abnormal plasticity of the motor cortex in M-D patients, which is a core feature of dystonia. When testing the sensorimotor associative plasticity, the RPAS triggered an increase in M1 excitability, which was not higher but outlasted the effect observed in controls. This profile was strikingly similarly to the profile triggered by RPAS in focal hand dystonia. A possible explanation is that enhanced M1 responsiveness to the RPAS is a true endophenotypic trait that is detected only in less severely affected patients ie, who rarely have myoclonus jerks at rest and concealed by the subjacent myoclonic jerks in more severely affected patients.
Indeed, muscle activity preceding the application of a plasticity-inducing protocol can interfere with or even suppress the plasticity-inducing process.
When testing the integrity of cerebellar mechanisms controlling associative learning, we found that the EBCC was acquired similarly in patients and controls but failed to be extinguished efficiently in M-D patients, who maintained higher rates of CR compared with controls. This finding differs from the severe impairment of acquisition and extinction of conditioning in focal dystonia, 27 , 38 pointing to different subjacent mechanisms. Although acquisition and extinction of CR involve the cerebellum, their underlying neuronal substrates are likely different.
The lack of cerebellar cardinal signs in dystonia despite neurophysiological evidence of cerebellar dysfunction might reflect a distortion of the cerebellar output. In contrast, a reduction of the cerebellar output would lead to a loss of function and overt cerebellar clinical manifestations. In keeping with this model, the severity and location of cerebellar dysfunction might account for the different phenotypes.
Published Online: March 17, Although less common, chorea, dystonia, myoclonus, and tremor are not rare in children. Therefore, it is important for the pediatric clinician to be able to recognize and distinguish these movement disorders. The first step in diagnosis and treatment is to identify and classify the disorders.
In this article, we review these and drug-induced movement disorders. Drug-induced movement disorders fall into the same phenomenologic categories chorea, dystonia, myoclonus, and tremor but often are considered as Advertising Disclaimer ».
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Previous Article Next Article. Article Navigation. Articles July 01 Mink, MD, PhD. This Site. People normally inherit one copy of each gene from their mother and one copy from their father. For most genes, both copies are active, or "turned on," in all cells. For a small subset of genes, however, only one of the two copies is active. For some of these genes, only the copy inherited from a person's father the paternal copy is active, while for other genes, only the copy inherited from a person's mother the maternal copy is active.
These differences in gene activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting. Mutations in the maternal copy of the gene typically do not cause any health problems.
Rarely, individuals who inherit an SGCE gene mutation from their mothers will develop features of myoclonus-dystonia. It is unclear why a gene that is supposed to be turned off is active in these rare cases.
Other genes associated with myoclonus-dystonia are not imprinted, and mutations that cause the condition can be inherited from either parent. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. From Genetics Home Reference. Description Myoclonus-dystonia is a movement disorder that typically affects the neck, torso, and arms.
Frequency The prevalence of myoclonus-dystonia in Europe is estimated to be 1 in , individuals. Inheritance In cases in which the genetic cause is known, myoclonus-dystonia is inherited in an autosomal dominant pattern , which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Research Studies from ClinicalTrials. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA.
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