Unlocking the genetics of paroxysmal kinesigenic dyskinesia

Abstract

Paroxysmal kinesigenic dyskinesia (PKD, or paroxysmal kinesigenic choreoathetosis) is a rare and remarkable hereditary disorder that was recognized as early as 1892 and defined more precisely during the 20th century (Mount and Reback, 1940; Kertesz, 1967; Richards and Barnett, 1968; Lance, 1977; Kato et al ., 2006). Patients with PKD experience recurrent and brief episodes of dystonic or choreoathetotic involuntary movements that are induced by sudden motion, such as standing up quickly or being startled (Bruno et al ., 2004; Bhatia, 2011). Although this disorder can be very disabling if undiagnosed, its outcome is usually benign when treated with low doses of anti-convulsants such as carbamazepine or phenytoin. Most patients with primary idiopathic forms of PKD report a family history of the disease compatible with autosomal dominant inheritance. The first locus for PKD, identified in 1999 on chromosome 16p11.2-q12.1 (EKD1, Fig. 1) overlaps with another locus identified for infantile convulsions and paroxysmal choreoathetosis (ICCA) (Szepetowski et al ., 1997; Tomita et al ., 1999). ICCA is also inherited in an autosomal dominant fashion and is characterized by benign afebrile infantile convulsions that start within the first year of life and usually stop by 3 years of age, variably associated with paroxysmal dyskinesia (Table 1). Benign familial infantile convulsions, ICCA and PKD have thus been proposed to be different expressions of the same disorder or allelic disorders (Caraballo et al ., 2001). Linkage of families with PKD, ICCA and benign familial infantile convulsions to the same region on chromosome 16 has been confirmed by many groups, but despite the sequencing of the 157 genes contained in the region, the causative one has remained a mystery for more than a decade (Kikuchi et al ., 2007). Figure 1 Schematic representation of chromosome 16, showing the overlapping loci …