Limitations Of Our Study
Our model suffers from a number of caveats one of which is the suitability of rodents as an accurate model of human neurological or behavioral disorders. In this context it is likely that motor control in quadrupeds is different from that of primates including humans. This concern, however, is balanced by the preceding discussions which highlight consistency of our findings with many prior observations in patients.
Concurrent Perfusion Of The Basal Ganglia And The Cerebellum
For concurrent perfusion of the basal ganglia and the cerebellum we used the same coordinates delineated above. The procedure for perfusion of the cerebellum was identical. However, because mice can maximally carry only two osmotic pumps, perfusion of the basal ganglia required the use of a Y bifurcation canula which was connected to a single pump filled with double the concentration of ouabain used for cerebellum.
Terms Used To Describe Rapid
The classic features of RDP include involuntary dystonic spasms in the limbs, prominent involvement of the speech and swallowing muscles, slowness of movement, and poor balance. Onset of the combined dystonic and parkinsonian symptoms can be sudden, occurring over hours to days. Some people experience seizures. RDP often follows a fever, prolonged exposure to heat or exercise, childbirth, or emotional stress. Symptoms usually stabilize in less than four weeks, after which, it is reported, there is little progression and symptoms may improve slightly. RDP usually occurs in adolescence or young adulthood , but onset of mild dystonia-parkinsonism has been reported in individuals up to the age of 58.
Several mutations in the ATP1A3 gene are associated with RDP and inherited autosomal dominantly with reduced penetrance. This means that only one parents needs to have the gene mutation for a child to inherit the disease, but not everyone who inherits the gene mutation will develop symptoms.
Diagnosis is based on neurological examination. A family history is required to distinguish the mild limb dystonia of RDP from early-onset dystonia.
Dystonia Is Associated With Aberrant Cerebellar Activity
The results presented demonstrate that concurrent perfusion of low concentrations of ouabain into the cerebellum and basal ganglia replicates the salient features of RDP the mice have few motor symptoms prior to a stressful event and stress rapidly triggers persistent dystonia. Since perfusion of higher concentrations of ouabain into the cerebellum alone causes dystonia, we initially used this paradigm to explore the mechanism by which dysfunction of cerebellar sodium pumps can cause dystonia. Because several lines of evidence suggest that aberrant cerebellar activity can cause dystonia ,,, we examined whether the dystonic postures in our animals were accompanied with abnormal cerebellar activity.
Dystonic postures correlate with abnormal cerebellar activity
EEG recordings from the motor cortex and the cerebellum of a mouse whose cerebellum was chronically perfused with 36 ng/h ouabain. The first pair of traces was obtained before any noticeable dystonic postures. Neither the cerebellar EEG nor the motor cortex EEG show abnormal activity. The second pair of traces was recorded concurrent with a dystonic posture in the mouse and shows an abnormal cerebellar EEG signal whereas the motor cortex EEG was unremarkable.
Abnormal electrical activity in both the cerebellum and the motor cortex of the same mouse during status epilepticus induced by 300 mg/kg pilocarpine.
Could Rdp Phenotype Be Broader Similar To Atp1a2 Mutations
While RDP is the first human disease to be associated with mutations of ATP1A3, three neurological diseases have been associated with mutations in the ATP1A2 subunit: infantile seizures, familial hemiplegic migraine and more recently familial common migraine . The dominant characteristics of patients presenting with diseases caused by mutations in ATP1A3 and ATP1A2 are consistent with what is known about the major cell-type distribution of 3 and 2 in the brain . The Na,K-ATPase converts metabolic energy by moving Na out of the cell and K into the cell, restoring the ion gradients of the cell reduced by the activity of ion channels and Na+-dependent carriers . The Na,K-ATPase has three subunits, , , with the representing the catalytic component of the enzyme. The 3 isoform is expressed exclusively in neurons in the CNS and given the highly regulated structure of 3 is reasonable to postulate that defects in ATP1A3 would cause neurological disease beyond dystonia. The phenotype of ATP1A2 mutations continues to broaden with the recent report of Todt et al., implicating mutations in the ATP1A2 gene in familial common migraine . The broad and varied phenotype of ATP1A2 mutations is important to consider when evaluating the non-motor findings in patients with ATP1A3 mutations.
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Evaluation Of Relatives At Risk
It is appropriate to evaluate the at-risk family members of an affected individual in order to identify as early as possible those who should avoid triggers such as alcohol and excessive exercise .
Evaluations can include the following:
- Molecular genetic testing if the in the family is known
- Neurologic evaluation if the in the family is not known
See for issues related to testing of at-risk relatives for purposes.
Potential Implications For Treatment Of Rdp
Two sets of observations made here have potential implications for treatment of RDP. First, our data suggest that lesions or deep brain stimulation of structures that mediate adverse interactions between the basal ganglia and the cerebellum might be of some therapeutic value. Second, our data also suggests that aberrant activity of the cerebellum might be a major contributing factor to dystonia in RDP. Accordingly, pharmacological approaches that restore cerebellar activity to normalcy, or lesions/deep brain stimulation of its output nuclei might also lessen associated symptoms in patients. Obviously both of these approaches require rigorous scrutiny.
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Curbing Aberrant Cerebellar Output Alleviates Dystonia
If ouabain-induced aberrant cerebellar activity is the main cause of dystonia then reducing aberrant activity or eliminating cerebellar output should lessen dystonia. The sodium pump is electrogenic and contributes to the resting membrane potential. We reasoned that the main cause of the aberrant cerebellar activity when sodium pumps were partially blocked was depolarization of cerebellar neurons. If this were the case, pharmacologically hyperpolarizing the cells with GABA should partially restore their activity to normalcy and thus one would predict that acute perfusion of GABA into the cerebellum of ouabain-perfused animals might lessen dystonia. To test this hypothesis we induced dystonia in mice by chronic cerebellar perfusion of ouabain using a canula which also permitted acute perfusions using a secondary port. Acute perfusion of GABA into the cerebellum of dystonic mice lessened the frequency and severity of dystonic postures and significantly improved their performance on a treadmill .
Reducing aberrant cerebellar activity or silencing cerebellar output lessons dystonia
Deep cerebellar nuclei were electrically lesioned in both cerebellar hemispheres at either at one or two sites . Comparable data was obtained with both approaches. Scale bar corresponds to 1 mm.
Chronic perfusion of 36ng/h ouabain into the cerebellum of DCN-lesioned mice did not produce dystonia.
Studies Of The Variable Phenotypic Presentations Of Rapid
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
|Recruitment Status : Active, not recruitingFirst Posted : May 22, 2008Last Update Posted : June 3, 2021
Rapid-onset dystonia-parkinsonism is a rare, movement disorder with variable characteristics ranging from sudden onset of severe dystonic spasms to gradual onset of writer’s cramp. RDP has elements of both dystonia and Parkinson’s disease-two neurological diseases with motor and neuropsychological symptoms that hinder the quality of life. An internal trigger associated with extreme physiological stress has been reported prior to abrupt symptom onset of RDP.
This study, which is a continuation of an earlier study begun by Dr. Allison Brashear, aims to more clearly identify the characteristics associated with RDP and to explore whether mutations in the RDP gene are associated with atypical dystonias, Parkinson’s disease, and other movement disorders.
The study involves in-person or remote neurological assessments and blood samples for genetic analysis.
Acute Injections Of Ouabain Into The Cerebellum And Select Basal Ganglia Nuclei
For acute injections, guide canula were stereotaxically implanted at the target location and 2.5 or 5 l of the desired solution was injected over a period of 15 minutes using an automated pump. The same coordinate used for chronic perfusion were used in the acute injection of 5 l of solution into the midline cerebellum. To target select basal ganglia output nuclei guide canula were bilaterally positioned and 2.5 l of the solution was independently injected to each side using the following coordinates: the entopeduncular nucleus , the globus pallidus , and the substantia nigra .
Cb Sodium Pump Dysfunction Produces Ataxia And Dystonia
We next examined the potential role of the cerebellum in RDP since i) a role for the cerebellum in producing dystonia is not unprecedented ,, and ii) its principal neurons, the Purkinje cells, exclusively express the 3 isoform of the sodium pumps that is mutated in RDP . Without affecting the neighboring brain regions, cerebellar sodium pumps were selectively targeted by midline chronic perfusion of ouabain in vivo . Cerebellar perfusion of ouabain resulted in ataxia and clear dystonic-like postures in a time and concentration-dependent manner. This was quantitatively reflected as reduced locomotion , and as high dystonia scores . The motor symptoms appeared initially as ataxia which in time transformed to dystonic-like postures and to generalized dystonia . Electromyogram recordings in agonist and antagonist muscles of the hind limb and examination of the corresponding cross-correlations of the EMG signals confirmed that the dystonic-like postures were caused by prolonged co-contraction of the opposing muscle groups . These dystonic episodes were not caused by seizures since electroencephalogram recordings showed that they were not accompanied with epileptic activity in the motor cortex . Moreover, targeting perfusion of ouabain to only one of the cerebellar hemispheres generated comparable but unilateral symptoms.
Chronic partial blockade of cerebellar sodium pumps results in ataxia and dystonic-like postures
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Modest Role Of Motor Cortex In Cerebellar
The small increase in the amplitude of the cortical EEG signal during cerebellar-induced dystonic postures could, in part, be accounted for by feedback within the cortico-cerebellar and cortico-striatal loops and it is therefore plausible that motor cortex plays only a modest role in the generation of dystonia. To directly test this possibility we bilaterally silenced motor cortex by blocking voltage-gated sodium channels with TTX and examined the consequences for cerebellar-induced dystonia. The efficacy of TTX in silencing the motor cortex was ascertained by EEG recordings . In all 8 mice examined silencing the motor cortex made the animals flaccid, and reduced the occurrence of spontaneous dystonia. However, sometimes spontaneously, and more often with physical perturbation the mice showed clear dystonia although the severity was reduced . These findings suggest that while cortical activity clearly contributes to the severity and frequency of cerebellar-induced dystonic postures, dystonia can nonetheless manifest in the absence of overt cortical activity.
What Are The Causes Of Adult
- Adult-Onset Dystonia-Parkinsonism is caused by mutations in the PLA2G6 gene
- This gene codes for an enzyme, A2 phospholipase, which catalyzes the breakdown of phospholipids
- PLA2G6 gene mutations are inherited in an autosomal recessive manner
Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant , a 50% chance of being heterozygous , and a 25% chance of being homozygous recessive .
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Potential Benefit Of Criteria: Positive Family History Not Required
The benefits of using the suggested criteria of abrupt onset, a rostrocaudal gradient, and prominent bulbar findings broaden the suggestive diagnostic criteria for RDP. In prior reports, we considered a positive family history necessary for diagnosis. Using these criteria and testing for ATP1A3 mutations, we now report four patients with mutation positive RDP and normal results of mutation analysis in one or both parents. Based upon lack of a family history and the absence of ATP1A3 mutations in one or both parents, the mutations found in these four individuals most likely represent spontaneous mutations in ATP1A3. Our finding of four individuals with de novo mutations underscores the need to consider RDP in patients with atypical presentations of dystonia or parkinsonism, and the potential usefulness of genetic testing.
Emg And Eeg Recordings
For EMG recordings electrodes were surgically inserted into the gastronemius and cranial tibial muscle respectively. Thin Teflon-coated EMG wires were routed underneath the skin and connected to a connector secured on the skull. For field EMG recordings a wire underneath the skin on the back of the animal was positioned to terminate 2/3 of the way between the neck and the tail. The low impedance of the exposed end of the wire permitted pick up of electrical signals over relatively long distances. Additionally, also as a consequence of its very low impedance, the wire only registered large electrical changes and thus a detectable signal correlated with concerted activity of large groups of excitable elements . This technique is analogous to extracellular field recordings in the CNS where a low impedance electrode is positioned above a region and registers concurrent activity of a large number of neurons.
To induce seizures animals were injected subcutaneously with 300 mg/kg pilocarpine hydrochloride . Methyl scopolamine nitrate 1mg/kg was injected subcutaneously 30 minutes prior to pilocarpine to minimize peripheral cholinergic effects.
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What Are The Signs And Symptoms Of Adult
The signs and symptoms of Adult-Onset Dystonia-Parkinsonism may vary among the affected individuals in type and severity, and may include:
- Rigidity of muscles
- Slowing down of movements
- Abnormal posture
- Imaging studies
- Biopsy studies, if necessary
Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.
What Are The Risk Factors For Adult
- A positive family history may be an important risk factor, since Adult-Onset Dystonia-Parkinsonism can be inherited
- Children born to consanguineous parents may bear an increased risk for developing the disorder
It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.
Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.
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A Role For Both The Basal Ganglia And The Cerebellum In Rdp
Our data implicate two structures in the pathophysiology of RDP: the basal ganglia and the cerebellum. A role for the basal ganglia in RDP was not unexpected RDP patients show Parkinsonism-like symptoms, a hallmark of basal ganglia dysfunction. Our data clearly corroborate the hypothesis that a reduction in the overall function of sodium pumps in the basal ganglia, as is likely to occur in RDP, may be the cause of the Parkinsonism-like symptoms seen in patients. Considering a wider context, the crouched posture, akinesia, and tremor seen in mice following partial blockade of basal ganglia sodium pumps closely resemble the actual symptoms of patients that suffer from Parkinsonism and provide an attractive animal model of this disorder.
Our studies also implicate cerebellar dysfunction in RDP and suggest that it makes a major contribution to dystonia. There are a number of patient case reports that implicate cerebellar dysfunction in dystonia . Surgically lesioning the dentate cerebellar nuclei in some of these patients improved dystonia ,, suggesting that in these and some other cases the cerebellum might have been a major contributing factor to dystonia. Indeed, abnormal cerebellar activity has been noted frequently in dystonic patients although these observations have routinely been interpreted in the context of cerebellar compensation of dysfunctional basal ganglia .
What Is The Prognosis Of Adult
- The prognosis of Adult-Onset Dystonia-Parkinsonism is dependent upon the severity of the signs and symptoms and associated complications, if any
- Individuals with mild conditions have better prognosis than those with severe symptoms and complications
- Typically, the prognosis may be assessed on a case-by-case basis
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Related Genetic Counseling Issues
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the ATP1A3 in the family.
Issues unique to RDP. Because of the sudden onset of RDP, at-risk individuals may become hypervigilant about symptoms. Serious psychological issues have been observed in families .
Considerations in families with an apparent . When neither parent of a with an condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including or maternity and undisclosed adoption could also be explored.
- The optimal time for determination of genetic risk and discussion of the availability of prenatal/ is before pregnancy.
- It is appropriate to offer to young adults who are affected or at risk.
DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed .