ReviewParoxysmal kinesigenic choreoathetosis: From first discovery in 1892 to genetic linkage with benign familial infantile convulsions
Introduction
Paroxysmal kinesigenic choreoathetosis (PKC), the most frequently described type of paroxysmal dyskinesia, is characterized by recurrent and brief attacks of involuntary movement precipitated by the sudden onset of movement. Among familial, idiopathic, and secondary cases reported thus far, familial cases in which the condition is inherited as an autosomal dominant trait are more common (Boel and Casaer, 1984). More males are known to be affected than females, and familial cases are more common in Asians than in Caucasians (Fahn, 1994, Kertesz, 1967).
Paroxysmal dyskinesias have been clinically divided into several forms. Among those, PKC and paroxysmal dystonic choreoathetosis (PDC) are the most well known and common. PKC and PDC are, though sometimes confused and misdiagnosed, clinically distinguished by certain features. PKC attacks occur more frequently, last from seconds to less than 2 min, and are induced by sudden voluntary movements, while PDC attacks last an hour or more, occur less frequently, and are precipitated by fatigue, alcohol or caffeine (Goodenough et al., 1978, Sadamatsu et al., 1999).
Although the clinical features of PKC are well described, the pathophysiology still remains a matter of controversy. Historically PKC has been ascribed to a peculiar form of reflex epilepsy. This is further substantiated by evidence that a history of afebrile infantile convulsions of benign nature is frequently noted in the same pedigree with PKC or even co-morbidly in the same individuals. Independently, a cluster of idiopathic epilepsy syndrome occurring between 3 and 12 months is now defined as benign familial infantile convulsions (BFIC), since the mode of inheritance is autosomal dominant (Vigevano et al., 1992; Caraballo et al., 2002). Consequently infantile convulsions with paroxysmal choreoathetosis (ICCA) was defined for families in which BFIC and PKC occurred within the same family (Szepetowski et al., 1997, Swoboda et al., 2000).
In this paper, we present a historical overview of the first description of PKC, and then discuss the controversial issue of the pathophysiological basis of PKC; reflex epilepsy versus dysfunction of the basal ganglia. We identified a family in which 5 of 18 members (at the time of publication in 1999) were affected with PKC, and performed video-EEG monitoring of 2 patients with PKC during attacks elicited by movements of the lower extremities (Sadamatsu et al., 1999). A further extended follow-up observation of this family revealed that 6 out of 23 members of the same family were found to be affected and 4 of the 6 affected members had a history of infantile convulsions, as reported in this paper.
Finally our results of genome-wide linkage analysis are described. Our haplotype analysis of the eight Japanese families affected by PKC defined, for the first time, the locus of PKC within the pericentromeric region of chromosome 16 (Tomita et al., 1999). Furthermore, an extraordinary story is introduced; a personal impression of the mother of a proband in our PKC family and her insistence that we follow it up led us to the mapping of the wet/dry earwax locus to the closely linked region of chromosome 16 (Tomita et al., 2000), and to the subsequent discovery of the earwax gene (Yoshiura et al., 2006).
Section snippets
The first case of PKC was identified in Japan
It is generally thought that the first detailed description of paroxysmal choreoathetosis was achieved by Mount and Reback (1940). In some literatures the first discovery of choreoathetotic or dystonic attacks triggered by movements is attributed to a brief description in a book written by Gower (1901). In Japan, Fukuyama and Okada, 1967, Fukuyama and Okada, 1968 accomplished a thorough description of the clinical manifestations of five families with peculiar seizures induced by sudden
Is the sudden choreoathetosis in PKC an epilepsy or not?: our evidence
We previously reported a clinical and genetic study of a family of PKC with infantile convulsions (Sadamatsu et al., 1999). At the time of the present study several members of the same family had grown up and moved away from home, so a telephone interview was conducted to obtain supplementary data.
The family pedigree of proband (III-3) is shown in Fig. 3. Altogether 23 members are alive and 6 members are found to be affected. Among the six affected members, only four; Case III-3, Case III-9,
Genome-wide linkage analysis of Japanese families with PKC
PKC (OMIM: 128200) generally occurs as a familial disorder inherited in an autosomal dominant fashion with incomplete penetrance (Valente et al., 2000). Genetic heterogeneity is less likely, and sporadic cases and familial PKC with seemingly autosomal recessive inheritance may be explained by reduced penetrance and variable expressivity. We first performed genome-wide linkage analysis on eight Japanese families with autosomal dominant type PKC (Tomita et al., 1999). Haplotype analysis following
Association between earwax (cerumen) type and PKC
Human earwax is a dimorphic Mendelian trait consisting of wet and dry types, and the wet earwax phenotype is completely dominant to the dry type. A member of a PKC family we studied (Tomita et al., 1999) suggested to us that the wet earwax-type co-segregates with PKC in the family. According to her suggestion, we performed linkage and haplotype analyses for this trait in the PKC family as well as seven other families, and successfully mapped its locus to a ∼7.42 cM region at 16p11.2-q12.1
Conclusion
Shuzo Kure (1865–1932) was appointed to the professorship and Head of Department of Neuropsychiatry of the University of Tokyo, the first Department of Psychiatry in Japan, in 1901 and remained in that position until 1925. He is well known among Japanese psychiatrists, partly because he founded the Japanese Psychiatric Association (1902), but also because he led the first era of psychiatric revolution to liberate psychotic patients from the traditional system of seclusion in private homes where
Acknowledgement
The work was supported by Research Grant on Mental Health, H16schi-3-09, from the Ministry of Health, Labor and Welfare, Tokyo, Japan.
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