Alternative titles; symbols
ORPHA: 306; DO: 0081115;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p11.2 | Seizures, benign familial infantile, 2 | 605751 | Autosomal dominant | 3 | PRRT2 | 614386 |
A number sign (#) is used with this entry because benign familial infantile seizures-2 (BFIS2) is caused by heterozygous mutation in the PRRT2 gene (614386) on chromosome 16p11.
Benign familial infantile seizure is an autosomal dominant disorder characterized by afebrile partial complex or generalized tonic-clonic seizures occurring between 3 and 12 months of age with a good response to medication and no neurologic sequelae. Seizures usually remit by age 18 months (summary by Weber et al., 2004).
For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (601764).
Benign familial infantile seizures can also occur in 2 allelic disorders: infantile convulsions and choreoathetosis (ICCA; 602066) and paroxysmal kinesigenic choreoathetosis (EKD1; 128200).
Caraballo et al. (2001) identified and studied 7 families with autosomal dominant BFIS. In 1 family, Caraballo et al. (2001) observed a patient who was clearly homozygous for the BFIS2 gene. Infantile convulsions did not respond well to anticonvulsants, in contrast to all other affected members of his family and to classic BFIS. In addition, although the families had been selected on the basis of clinical evidence of BFIS only, this patient had atypical paroxysmal choreic/dystonic dyskinesia beginning at age 2 years. The age of onset was earlier than that of classic paroxysmal dyskinesias (which usually begins at age 5 to 16 years). Dyskinetic movements sometimes occurred a few seconds after starting exertion, which suggested a kinesigenic type. However, the patient did not respond to carbamazepine, a finding that is consistent with an exertional rather than a kinesigenic type.
Weber et al. (2004) reported 14 families with BFIS2 showing linkage to chromosome 16p12-q12. Onset of seizures occurred between 2 and 7 months of age and disappeared at the latest by age 18 months. Seizure types included complex partial seizures and generalized tonic-clonic seizures. Other features included loss of consciousness, paleness, cyanosis, hypotonia, gaze deviation, and focal clonicity. Medication was effective, and could be stopped by age 4 years without seizure relapse. Most interictal EEG did not show abnormalities, but some had focal seizure activity.
Schubert et al. (2012) reported 39 families with BFIS2. The phenotype was homogeneous, with an onset of seizures between 3 and 12 months of age and a benign outcome in almost all cases without long-term anticonvulsive treatment. Seizure types mainly included complex partial seizures and generalized tonic-clonic seizures. Some patients reported migraine, but none had febrile seizures, choreoathetosis, or dyskinesia. Some of the families had previously been reported by Striano et al. (2006) and Weber et al. (2004).
The transmission pattern of BFIS2 in the families reported by Schubert et al. (2012) was consistent with autosomal dominant inheritance with incomplete penetrance.
Caraballo et al. (2001) performed linkage analysis in 7 families with autosomal dominant BFIS. The results excluded linkage to chromosome 19q and established linkage to chromosome 16p12-q12 (maximum 2-point lod score of 3.32). The authors suggested that BFIS2, PKC, and ICCA syndrome may be allelic disorders. Alternatively, they suggested that homologous genes may have arisen through duplication in this region of chromosome 16 which may be responsible for nonallelic disorders.
In 14 families with BFIS, Weber et al. (2004) found linkage to a 22.5-Mb region on chromosome 16p12-q12 between D16S690 and D16S3136 (maximum cumulative 2-point lod score of 6.1 at D16S411). There was evidence for incomplete penetrance. Striano et al. (2006) found linkage to chromosome 16p12-q12 in 16 families with BFIS (maximum lod score of 10.18 at D16S401 under 1 model).
Callenbach et al. (2005) found linkage to 16p in 2 unrelated Dutch families with pure BFIS. By haplotype analysis and combination with data from earlier studies, Callenbach et al. (2005) narrowed the disease locus to a 2.7-Mb interval on 16p12-p11 between markers D16S690 and D16S685. Penetrance in both families was approximately 60%. Two additional Dutch families with BFIS did not map to any of the known BFIS loci, indicating further genetic heterogeneity.
In affected members of 14 (82%) of 17 families with benign familial infantile seizures-2, Heron et al. (2012) identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0001 and 614386.0006). The 649insC mutation (614386.0001) was the most common mutation, found in 12 families with BFIS2. Heterozygous mutations in the PRRT2 gene were also found in 5 (83%) of 6 families with familial infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066), a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (EKD1; 128200), cooccur. The 649insC mutation was found in 3 families with ICCA. 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.
Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). Three additional heterozygous PRRT2 mutations (see, e.g., 614386.0013; 614386.0014) were found in 3 other families with the disorder. The patients were of German, Italian, Japanese, and Turkish origin. Some of the families had previously been reported by Striano et al. (2006) and Weber et al. (2004). The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1 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. In 1 family, a Japanese mother and daughter both carried a heterozygous mutation (Q250X; 614386.0015). The mother had EKD1 and her daughter had BFIS2.
Pelzer et al. (2014) reexamined a large multigenerational Dutch family segregating both BFIS and familial hemiplegic migraine. The family had previously been reported by Terwindt et al. (1997) and Vanmolkot et al. (2003) as having BFIS and familial hemiplegic migraine-2 (FHM2; 602481) associated with a heterozygous mutation in the ATP1A2 gene (R689Q; 182340.0004). Pelzer et al. (2014) identified a heterozygous truncating mutation in the PRRT2 gene (614386.0016) in 4 members of this family who had BFIS. The mutation was also found in 4 family members without a history of febrile seizures. Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance.
Callenbach, P. M. C., van den Boogerd, E. H., de Coo, R. F. M., ten Houten, R., Oosterwijk, J. C., Hageman, G., Frants, R. R., Brouwer, O. F., van den Maagdenberg, A. M. J. M. Refinement of the chromosome 16 locus for benign familial infantile convulsions. Clin. Genet. 67: 517-525, 2005. [PubMed: 15857419] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00445.x]
Caraballo, R., Pavek, S., Lemainque, A., Gastaldi, M., Echenne, B., Motte, J., Genton, P., Cersosimo, R., Humbertclaude, V., Fejerman, N., Monaco, A. P., Lathrop, M. G., Rochette, J., Szepetowski, P. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am. J. Hum. Genet. 68: 788-794, 2001. [PubMed: 11179027] [Full Text: https://doi.org/10.1086/318805]
Heron, S. E., Grinton, B. E., Kivity, S., Afawi, Z., Zuberi, S. M., Hughes, J. N., Pridmore, C., Hodgson, B. L., Iona, X., Sadleir, L. G., Pelekanos, J., Herlenius, E., and 12 others. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am. J. Hum. Genet. 90: 152-160, 2012. [PubMed: 22243967] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.003]
Ono, S., Yoshiura, K., Kinoshita, A., Kikuchi, T., Nakane, Y., Kato, N., Sadamatsu, M., Konishi, T., Nagamitsu, S., Matsuura, M., Yasuda, A., Komine, M., and 10 others. Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions. J. Hum. Genet. 57: 338-341, 2012. Note: Erratum: J. Hum. Genet. 57: 399 only, 2012. [PubMed: 22399141] [Full Text: https://doi.org/10.1038/jhg.2012.23]
Pelzer, N., de Vries, B., Kamphorst, J. T., Vijfhuizen, L. S., Ferrari, M. D., Haan, J., van den Maagdenberg, A. M. J. M., Terwindt, G. M. PRRT2 and hemiplegic migraine: a complex association. Neurology 83: 288-290, 2014. [PubMed: 24928127] [Full Text: https://doi.org/10.1212/WNL.0000000000000590]
Schubert, J., Paravidino, R., Becker, F., Berger, A., Bebek, N., Bianchi, A., Brockmann, K., Capovilla, G., Dalla Bernardina, B., Fukuyama, Y., Hoffmann, G. F., Jurkat-Rott, K., and 25 others. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum. Mutat. 33: 1439-1443, 2012. [PubMed: 22623405] [Full Text: https://doi.org/10.1002/humu.22126]
Striano, P., Lispi, M. L., Gennaro, E., Madia, F., Traverso, M., Bordo, L., Aridon, P., Boneschi, F. M., Barone, B., dalla Bernardina, B., Bianchi, A., and 15 others. Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families. Epilepsia 47: 1029-1034, 2006. [PubMed: 16822249] [Full Text: https://doi.org/10.1111/j.1528-1167.2006.00521.x]
Terwindt, G. M., Ophoff, R. A., Lindhout, D., Haan, J., Halley, D. J., Sandkuijl, L. A., Brouwer, O. F., Frants, R. R., Ferrari, M. D. Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome. Epilepsia 38: 915-921, 1997. [PubMed: 9579893] [Full Text: https://doi.org/10.1111/j.1528-1157.1997.tb01257.x]
Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. Novel mutations in the Na(+),K(+)-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann. Neurol. 54: 360-366, 2003. [PubMed: 12953268] [Full Text: https://doi.org/10.1002/ana.10674]
Weber, Y. G., Berger, A., Bebek, N., Maier, S., Karafyllakes, S., Meyer, N., Fukuyama, Y., Halbach, A., Hikel, C., Kurlemann, G., Neubauer, B., Osawa, M., Pust, B., Rating, D., Saito, K., Stephani, U., Tauer, U., Lehmann-Horn, F., Jurkat-Rott, K., Lerche, H. Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families. Epilepsia 45: 601-609, 2004. [PubMed: 15144424] [Full Text: https://doi.org/10.1111/j.0013-9580.2004.48203.x]