Convulsions, Familial Infantile, With Paroxysmal Choreoathetosis

A number sign (#) is used with this entry because familial infantile convulsions with paroxysmal choreoathetosis (ICCA) is caused by heterozygous mutation in the PRRT2 gene (614386) on chromosome 16p11.

Description

Benign familial infantile convulsions (BFIC; see 601764) is an autosomal dominant disorder characterized by afebrile seizures occurring between 3 and 12 months of age. Paroxysmal choreoathetosis is a disorder of involuntary movements characterized by attacks that occur spontaneously or are induced by a variety of stimuli.

The ICCA syndrome shares overlapping clinical features with benign familial infantile seizures-2 (BFIS2; 605751) and episodic kinesigenic dyskinesia-1 (EKD1; 128200), which are allelic disorders.

See also rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (608105), which maps to 16p.

Clinical Features

Szepetowski et al. (1997) studied 4 families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The authors suggested that the strong association of the 2 disorders in the same families defined a distinct neurologic syndrome. Partial seizures started with a psychomotor arrest and a deviation of the head and eyes to one side, often with secondary generalization. The seizures responded well to medication and remitted by age 12 months. Paroxysmal choreoathetotic movements were of the dystonic type and occurred at rest or in response to exertion or anxiety. Both seizures and movements occurred in clusters. Interictal EEGs were normal, and all patients showed normal psychomotor development.

Swoboda et al. (2000) reported 44 individuals from 11 families with infantile convulsions (62% of patients), PKC (86%), or both (50%). Infantile convulsions were common, occurring in 9 of 11 families, and were characterized by onset between 3 and 18 months of age, eye deviation, staring, altered consciousness, apnea, and tonic stiffening. Remission occurred within 3 years. Age at onset for PKC was 6 to 28 years. Episodes were provoked by anxiety or exertion. EEG studies were normal in all patients except one.

Mapping

Szepetowski et al. (1997) performed linkage analysis in families with this disorder and found strong evidence of linkage in the pericentromeric region of chromosome 16, with a maximum 2-point lod score for D16S3133 of 6.76 at a recombination fraction of 0.0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere, 16p12-q12.

In a Chinese family, Lee et al. (1998) confirmed that the autosomal dominant trait of benign infantile convulsions and paroxysmal choreoathetosis of the dystonic form, the ICCA syndrome, is linked to the 16p12-q12 region. Some patients in this family also exhibited recurrence of epileptic seizures at a much later age.

By analyzing 11 unrelated families with infantile convulsions, PKC, or both, Swoboda et al. (2000) defined a 26-cM candidate region between markers D16S3131 and D16S3396 on chromosome 16q (maximum lod score of 6.63 at D16S3131). In conjunction with previous data, the critical region was narrowed to a 3.2-cM region spanning the centromere.

Molecular Genetics

Using a combination of exome sequencing and linkage analysis in 2 large Han Chinese families with EKD1 (128200), Wang et al. (2011) identified 2 different heterozygous truncating mutations in the PRRT2 gene (649dupC; 614386.0001 and 614386.0009, respectively) that completely segregated with the phenotype in each family. Two patients in each family also had infantile convulsion and choreoathetosis syndrome, indicating intrafamilial variability.

In 5 (83%) of 6 families with ICCA, Heron et al. (2012) identified 1 of 3 different heterozygous mutations in the PRRT2 gene. Three families had the common 649insC mutation (614386.0001), and 2 additional families each had a private mutation (614386.0004 and 614386.0005). Heterozygous PRRT2 mutations were also found in 14 (82%) of 17 families with benign familial infantile seizures-2 (BFIS2; 605751). The 649insC mutation was the most common mutation, found in 12 families with BFIS2. The families with this mutation were of different ethnic origin, including Australasian of western European heritage, Swedish, and Israeli Sephardic-Jewish, and there was no evidence of a common haplotype among these families, indicating a mutation hotspot. These findings demonstrated that mutations in PRRT2 cause both epilepsy and a movement disorder, with obvious pleiotropy in age of expression. The mutations were identified by linkage analysis, confirming linkage to chromosome 16p, followed by sequence-capture array of coding and promoter sequences within the candidate region.

Lee et al. (2012) also identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0007 and 614386.0008) in affected members of families with ICCA. The mutations were identified by whole-genome sequencing of 6 well-characterized families. The findings were confirmed by the identification of PRRT2 mutations in 24 of 25 additional families with the disorder. The 649insC mutation was the most common mutation. Sanger sequencing of a third cohort of 78 probands with a less clear clinical diagnosis found that 10 patients with familial disease and 17 with sporadic disease had the common 649insC mutation; 1 additional patient had a different truncating PRRT2 mutation. None of the pathogenic alleles were found in over 2,500 control chromosomes. There was intrafamilial variability of the phenotype. In vitro functional expression assays showed that the mutant truncating proteins were not expressed and did not exert dominant-negative effect on the wildtype protein, suggesting haploinsufficiency as the pathologic mechanism.

Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism.