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Since the very first descriptions of the paroxysmal movement disorders, there has been much controversy regarding their pathophysiology. Many authors regard these to be a form of reflex epilepsy, perhaps involving the thalamus or the basal ganglia, particularly with reference to PKD/PKC as an example [51,52]. Their main arguments are the paroxysmal nature of the attacks, the aura at onset, the nonprogressive (often remitting) character of the disorder, and the excellent response to anticonvulsants [51]. The absence of seizure discharges on EEG in the majority of cases, the absence of evolution of the attacks into generalized or focal convulsions, and the lack of an associated loss of consciousness or amnesia is said to fit in with the possibility of a subcortical, rather than cortical, focus. Also in support of this are cases in which both epilepsy and paroxysmal dyskinesia are present, both aspects responding to antiepileptics [12,13,53].

On the other hand, a basal ganglia disorder is a view favored by some authors based on the clinical characteristics of the involuntary movements, the absence of EEG abnormalities during attacks, the occurrence of symptomatic PKC due to lesions, or conditions known to affect basal ganglia [10]. There has been support for this extrapyramidal theory based on special electrophysiological studies known to be abnormal in basal ganglia disorders. Abnormalities of contingent negative variation (CNV), which, normalized with phenytoin therapy in PKC, have been reported [54], as well as abnormalities of the premotor (Bereitschafts) potential in the same disorder [11]. Abnormally decreased choline/creatine ratios in the basal ganglia were found on magnetic resonance spectroscopy in PKC [55], and increased perfusion of the thalamus was noted on SPECT scans [56]. Furthermore, increased CSF dopamine metabolites have been noted following an attack in both PNKD and PED [21,57], and decreased presynaptic dopamine decarboxylase activity with increased D2 post-synaptic receptors has been suggested by 18 fluorodopa and raclopride scan changes, respectively, in PNKD [58].

Although this debate is still inconclusive, what is clear is that the paroxysmal dyskinesias have many similarities to other episodic disorders of the nervous system, such as episodic ataxias and periodic paralysis, thus suggesting a common pathophysiological mechanism [9]. More and more paroxysmal neurological disorders are now being discovered to be caused by gene mutations regulating ion channels [59-64] called channelopathies. The periodic paralyses were found to be caused by mutations in voltage-gated sodium [61] and calcium [62] channels. Subsequently, the two forms of episodic ataxias (EA1 and EA2) were shown to be caused by mutations of voltage-gated potassium [59] and calcium channels [64]. It is interesting to observe the similarities between PKD and episodic ataxia type 1 (EA1). EA1 is characterized by periodic ataxia, frequently provoked by kinesigenic stimuli similar to the attacks of PKC; the episodes are brief, lasting from seconds to a few minutes, and they can occur several times a day [65]. Both PKC and EA1 have an early age of onset, and both have the tendency to abate in adulthood. Although EA1 typically responds to acetazolamide like PKD does, anticonvulsants may reduce EA1 attacks in some patients and also help the interictal myokymia seen in this disorder [65,66]. Like the paroxysmal dyskinesias, many of these other paroxysmal disorders have similar precipitating factors such as stress, fatigue, and diet. There is also an overlap for many of these disorders with regard to drug treatment. For example, acetazolamide is helpful not only for periodic paralysis, but also for myotonia, episodic ataxias [63], and some paroxysmal dyskinesias [25]. Carbamazepine, an antiepileptic, is also very effective in patients with paroxysmal kinesigenic dyskinesia. There are also reports of families with multiple episodic disorders, for example, paroxysmal dyskinesia in a family with episodic ataxia and association of episodic problems such as migraine and epilepsy in families with paroxysmal dyskinesias [16,26]. Thus, like periodic paralysis and episodic ataxias, the familial paroxysmal dyskinesias may also be caused by defects in genes regulating ion channels [2].


A. Paroxysmal Kinesigenic Dyskinesia (PKC/PKD)

Szepetowski and colleagues linked four French families with what was described as the "ICCA syndrome" (infantile convulsions and paroxysmal choreoathetosis) to the peri-centromeric region of chromosome 16 [12]. Linkage to the same locus was further confirmed in a Chinese family said to have a similar disorder [13]. Although description of the paroxysmal dyskinetic episodes in these reports was rather limited, they did seem similar to PKD. Not surprisingly, eight Japanese families [14] and an African-American kindred [15], both with typical PKC, were also linked to the pericentromeric region of chromosome 16. In these Japanese families there was an increased prevalence of afebrile infantile convulsions; therefore, it was suggested that one gene may be responsible for both PKC and ICCA [14]. However, the PKC interval identified in the African-American family in which individuals had PKC alone (and no infantile seizures) overlaps by 3.4 cM with the ICC A region and by 9.8 cM with the PKC region identified in Japanese families. Thus at the moment it is unclear whether there are two genes or a single gene in this interval that could give rise to both ICCA and PKC in these families. Furthermore, an autosomal recessive family with rolandic epilepsy, paroxysmal exercise-induced dyskinesia, and writer's cramp (RE-PED-WC) syndrome (see above in the section on Clinical Features) has also been linked to chromosome 16 within the ICCA region but outside the 3.4cM overlap between ICCA and PKC [31]. Thus, RE-PED-WC is probably allelic to ICCA but not PKC. Furthermore, an Indian family with PKC has been linked to a second locus on chromosome 16q, distinct from the locus of the Japanese families with PKC [16], thus suggesting that there may be a family of genes causing paroxysmal disorders on the pericentromeric region of chromosome 16 [16]. Since the gene is likely to be an ion channel gene, different candidate genes, including the sodium/hydrogen exchanger and other ion channel genes, have been considered and excluded [67] and the gene remains unknown. There are also families with PKC that do not link to chromosome 16 at all [68], thus suggesting at least one more locus and confirming that PKD is genetically heterogeneous.

B. Paroxysmal Non-Kinesigenic Dyskinesia (PNKD)

Two separate groups reported linkage to microsatellite markers on distal 2q (2q31-q36) [20-21]. This was further confirmed in a British family (69) and also other families with typical PNKD and autosomal dominant inhertitance [70-72]. It appears therefore that there is genetic homogeneity for typical familial PNKD/PDC. A variety of candidate genes (mostly ion channels), including the acid-sensing ion channels (ASICs) and others, have been excluded in the area of linkage [70,73-74], but the gene has not been found.

C. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)

In an Australian family, Phillips et al. (1995) mapped an ADNFLE locus on chromosome 20q13.2; the obvious candidate was the alpha 4 subunit of the neuronal acetylcholine receptor (CHRNA4) gene [75]. Two different mutations—a missense mutation and a 3-bp insertion—were then identified in the CHRNA4 gene in the Australian family and in a Norwegian family, respectively [76,77]. However, another family with ADNFLE was linked not to CHRNA4 on chromosome 20q but to a novel locus on chromosome 15q24 close to a CHRNA3/CNRNA5/CHRNB4 nicotinic acetylcholine receptor gene cluster [78]. Also, in seven other families with ADNFLE and in seven sporadic cases, linkage to the ADNFLE loci on chromosome 20q13.2 and 15q24 was excluded, thereby suggesting the existence of at least a third ADNFLE locus and supporting the fact that ADNFLE is a genetically heterogeneous disease [78].

D. Other Paroxysmal Dyskinesias

Benign positional torticollis (BPT) of infancy has been reported in four cases from families with familial hemiplegic migraine, which is linked to a calcium channel gene (CACLNA1) [38]. It is not clear whether there were any functional mutations of the CACLNA1 in these cases and whether this applies to all cases with BPT. Further reports are awaited.

With regard to the startle syndrome, hyperekplexia, as mentioned above, this is due to the defective alpha 1 subunit of the inhibitory glycine receptor (GLRA1) gene [45-46]. The inhibitory glycine receptor is a member of the neuro-transmitter-gated ion channel superfamily that includes GABA, glutamate, and nicotinic acetylcholine receptors. It is a ligand-gated chloride channel, provoking postsynaptic hyperpolarization, which mediates synaptic inhibition in brain stem and spinal cord, where it is primarily expressed. Several missense mutations of GLRA1 gene have been identified in families with autosomal dominant hyperekplexia [47-49]. These missense mutations result in amino acid

TABLE 2 Mapped Loci/Genes for Familial Paroxysmal Dyskinesia Conditions




Ion channel

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