Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1

Abstract

Paroxysmal kinesigenic choreoathetosis (PKC), the most frequently described type of paroxysmal dyskinesia, is characterized by recurrent, brief attacks of involuntary movements induced by sudden voluntary movements. Some patients with PKC have a history of infantile afebrile convulsions with a favorable outcome. To localize the PKC locus, we performed genomewide linkage analysis on eight Japanese families with autosomal dominant PKC. Two-point linkage analysis provided a maximum LOD score of 10.27 (recombination fraction [theta] =.00; penetrance [p] =.7) at marker D16S3081, and a maximum multipoint LOD score for a subset of markers was calculated to be 11.51 (p = 0.8) at D16S3080. Haplotype analysis defined the disease locus within a region of approximately 12.4 cM between D16S3093 and D16S416. P1-derived artificial chromosome clones containing loci D16S3093 and D16S416 were mapped, by use of FISH, to 16p11.2 and 16q12.1, respectively. Thus, in the eight families studied, the chromosomal localization of the PKC critical region (PKCR) is 16p11.2-q12.1. The PKCR overlaps with a region responsible for "infantile convulsions and paroxysmal choreoathetosis" (MIM 602066), a recently recognized clinical entity with benign infantile convulsions and nonkinesigenic paroxysmal dyskinesias.

Figure 1

Pedigrees of eight families with PKC. The blackened squares and circles and the letters “IC” denote individuals affected with PKC and those with infantile convulsion, respectively. The numbers in boxes and the numbers in parentheses represent putative disease haplotypes and haplotypes estimated (deduced from data in sibs and/or children), respectively, in family members. Thick short lines indicate definite recombination sites, and thick brackets indicate recombination sites that could have occurred on either side of the corresponding marker(s).

Figure 1

Pedigrees of eight families with PKC. The blackened squares and circles and the letters “IC” denote individuals affected with PKC and those with infantile convulsion, respectively. The numbers in boxes and the numbers in parentheses represent putative disease haplotypes and haplotypes estimated (deduced from data in sibs and/or children), respectively, in family members. Thick short lines indicate definite recombination sites, and thick brackets indicate recombination sites that could have occurred on either side of the corresponding marker(s).

Figure 2

Multipoint LOD scores with various values of penetrance (p), calculated with use of the VITTESE program (O'Connell and Weeks 1995). Intermarker distances and marker order are according to Dib et al. (1996). PKC denotes family members affected with PKC; PKC and/or IC denotes inclusion of those affected with PKC and/or IC.

Figure 3

Disease map of paroxysmal dyskinesias on chromosome 16. PKCR is deduced from data from the present study, ICCA is deduced from data from Szepetowski et al. (1997), and RE-PED-WC is deduced from data from Guerrini et al. (1999).