Original articlesChannelopathy: Hypothesis of a common pathophysiologic mechanism in different forms of paroxysmal dyskinesia
Introduction
Paroxysmal dyskinesias are a rare group of heterogeneous neurologic disorders, characterized by transient sudden attacks of choreoathetosis or dystonia, without loss of consciousness [1], [2], [3], [4], [5], [6]. Various classifications of paroxysmal dyskinesia have been proposed [2], [3], [7]. Paroxysmal dyskinesias are traditionally divided into paroxysmal kinesigenic dystonia/choreoathetosis and nonkinesigenic paroxysmal dystonic choreoathetosis [2], [3], [4]. However, in 1995 Demirkiran and Jankovic proposed a new classification based chiefly on precipitating events, but also on duration of attacks, and etiology [5]. These authors used the generic term dyskinesia because it is difficult to specifically determine the type of hyperkinetic movements (dystonic, choreic, choreoathetoid, ballistic). The term broadly correlates with paroxysmal kinesigenic dystonia/choreoathetosis, paroxysmal dystonic choreoathetosis, and the intermediate variety of the old classification. However, the authors further subclassified patients in each category as having either short or long attacks, depending on whether the episode lasted up to 5 minutes or longer. Each case in each subcategory was also classified as either idiopathic (familial/sporadic) or secondary, depending on the etiology. A recent genetic classification of the dystonic syndromes identified three genetic loci for paroxysmal dyskinesia, DYT8, DYT9, and DYT10 [8], yet the cause of this condition remains uncertain.
This study describes a family (with six affected members in three generations) and two sporadic cases of paroxysmal dyskinesia. Clinical and diagnostic evaluation of these patients suggests an ion channel disorder. The familial cases were affected by idiopathic long-lasting paroxysmal exertion-induced dyskinesia, and the sporadic cases were affected by idiopathic short-lasting paroxysmal kinesigenic dyskinesia. The familial cases also suffered from epilepsy, mental retardation, and impulsivity. One sporadic case is affected by migraine.
Section snippets
Familial cases (paroxysmal exertion-induced dyskinesia)
Six members of a family, in three generations, presented with a syndrome characterized by idiopathic long-lasting paroxysmal exertion-induced dyskinesia, epilepsy, mental retardation, and behavioral disorders. This family has been previously described [9], [10], [11]. The dyskinesia attacks appeared in childhood and were characterized by dystonia and choreoathetosis, with flexion and extension, and by alternate twisting of upper and lower limbs. Two patients also experienced oro-buccal
Discussion
According to Demirkiran and Jankovic’s classification [5], familial cases are affected by idiopathic long-lasting paroxysmal exertion-induced dyskinesia and sporadic cases by idiopathic short-lasting paroxysmal kinesigenic dyskinesia.
Paroxysmal exertion-induced dyskinesia is a rare movement disorder. Only 16 cases reported in the literature are sporadic, the other are familial [2], [5], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Associations between paroxysmal
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2020, NeuroscienceCitation Excerpt :Alternatively, bursts of Purkinje cell activity due to paroxysmal release of glutamate at parallel fiber synapses could drive transient bursting activity in the CbN as described in the dystonic rat and a mouse model of rapid-onset dystonia-parkinsonism (LeDoux et al., 1998; Fremont et al., 2014). Others have suggested that the palliative effects of these drugs point to a channelopathy underlying the pathology of PKD (Margari et al., 2005; Pan et al., 2019), and interaction of PRRT2 with NaV in mice give weight to this model (Fruscione et al., 2018). We have shown that PRRT2 KO changes excitability in cells not expressing PRRT2 (i.e., Purkinje cells), indicating that, in addition to potential channelopathy effects of Prrt2 KO, cellular activity is altered without PRRT2 absence causing changes in cellular channels.
Paroxysmal movement disorders
2015, Neurologic ClinicsCitation Excerpt :EA are channelopathies, or a group of disorders caused by abnormal function of the membrane ion channels or transmembrane transporters. The notion that paroxysmal dyskinesias represent channelopathies100 was not supported by a recent discovery of PRRT2 mutations, presumably resulting in an abnormal protein that does not seem to mediate channel functions. The diagnosis of paroxysmal dyskinesias and other paroxysmal movement disorders may be difficult to make because many patients might not have any paroxysms during their visits with the physician.
PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins
2013, European Journal of Paediatric NeurologyCitation Excerpt :Moreover extensive studies on cellular and animal models have indicated that gene mutations in familial hemiplegic migraine increase neuronal excitability and reduce the threshold for cortical spreading depression.12 It is relevant that haloperidol was effective in the treatment of dyskinetic attacks, in both our patients as previously reported18 but was ineffective for migraine episodes. Besides its known D2 antagonist effect, haloperidol modulates transcription of voltage-gated ion channels the brain of C57BL/6 mice19 and haloperidol derivatives are currently being studied as potent calcium channel blockers and vasodilators.20
Clinical features of paroxysmal kinesigenic dyskinesia: Report of 24 cases
2012, Epilepsy and BehaviorExtended surround inhibition in idiopathic paroxysmal kinesigenic dyskinesia
2010, Clinical NeurophysiologyCitation Excerpt :Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent brief episodes of chorea and dystonia induced by sudden movement (Fahn, 1994). Although PKD is presumed to be an ion channel disorder like other paroxysmal disorders (Margari et al., 2005), the underlying neurophysiologic mechanisms responsible for the paroxysmal attack remains unknown. Further, various defects in cortical and spinal inhibitory mechanisms including spinal reciprocal inhibition (Lee et al., 1999; Mir et al., 2005), short-interval intracortical inhibition (Mir et al., 2005), long-interval intracortical inhibition (Kang et al., 2006), and transcallosal interhemispheric inhibition (Mir et al., 2005), have all been demonstrated in PKD, although these findings are rather non-specific in that they are also commonly observed in various neurological conditions (Berardelli, 1999) as well as under the influence of various drugs (Ziemann, 2004).