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PRRT2 mutation in Japanese children with benign infantile epilepsy
Brain & Development xxx (2012) xxx–xxx www.elsevier.com/locate/braindev
Original article
PRRT2 mutation in Japanese children with benign infantile epilepsy Akihisa Okumura a,⇑, Keiko Shimojima b, Tetsuo Kubota c, Shinpei Abe a, Shintaro Yamashita d, Katsumi Imai e, Tohru Okanishi f, Hideo Enoki f, Tatsuya Fukasawa c, Takuya Tanabe g, Leanne M. Dibbens h, Toshiaki Shimizu a, Toshiyuki Yamamoto b a
Department of Pediatrics, Juntendo University Faculty of Medicine, Japan Tokyo Womens’ Medical University, Institute for Integrated Medical Sciences, Japan c Department of Pediatrics, Anjo Kosei Hospital, Japan d Department of Pediatrics, Juntendo Nerima Hospital, Japan e National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan f Department of Child Neurology, Seirei Hamamatsu General Hospital, Japan g Tanabe-Kadobayashi Children’s Clinic, Japan h Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Australia Received 27 March 2012; received in revised form 25 September 2012; accepted 28 September 2012 b
Abstract Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: PRRT2; Benign infantile epilepsy; Paroxysmal kinesigenic dyskinesia; Japanese children
1. Introduction Benign infantile epilepsy (BIE) have been established as a distinct epilepsy syndrome characterized by focal ⇑ Corresponding author. Address: Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan. Tel.: +81 3 3813 3111; fax: +81 3 5800 1580. E-mail address: [email protected] (A. Okumura).
seizures in clusters of infantile onset, with no clear etiological factors, normal interictal EEG and neuroimaging, and normal psychomotor development. Usual age of onset has been described from 3 to 10 months [1]. BIE is almost analogous to benign partial epilepsy in infancy proposed by Watanabe et al [2]. According to our previous study [1], about 40% of the children with BIE have a family history. An association of paroxysmal kinesigenic dyskinesia (PKD) was seen in some patients
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.09.015
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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A. Okumura et al. / Brain & Development xxx (2012) xxx–xxx
with BIE, indicating overlap between BIE and infantile convulsions with choreoathetosis syndrome (ICCA). We also showed that approximately 10% of children with BIE experienced convulsions with mild gastroenteritis [1]. Previous studies have revealed that mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2 cause benign familial neonatal-infantile seizures [3], suggesting overlap between BIE and benign neonatal seizures. Chen et al. recently identified mutations in prolinerich transmembrane protein 2 gene (PRRT2) in eight Chinese families affected by autosomal-dominant PKD by exome sequencing analysis [4]. In addition, Heron et al. identified five different mutations in PRRT2 in 14 of 17 families affected by BIE and in five of six families affected by ICCA [5] and Ono et al. found two mutations in PRRT2, c.649_650insC and c.748C>T, in all individuals with PKD and/or BIE [6]. Thereafter, several reports have shown that PRRT2 mutation will be one of the major genes relating to BIE, PKD, and ICCA [7–20]. However, we hypothesized that PRRT2 mutation may also be related to several phenotypes of infantile epilepsies other than BIE and/or PKD. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We also investigated the differences in phenotype of probands with BIE according to the presence or absence of PRRT2 mutation. 2. Patients and methods For the purpose of genetic analyses, we have recruited children with epilepsy of infantile or early childhood onset, who fulfilled the following conditions: normal development prior to the onset, no neurological abnormalities, no neuroimaging abnormalities, favorable response to antiepileptic drugs. All patients are Japanese. We collected blood samples from the recruited patients, when written informed consent was obtained. The probands included 16 children with BIE (including 1 child with ICCA), 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. This study is approved by the ethics committees in Tokyo Womens’ Medical University. We defined BIE as epilepsy meeting all of the following conditions: (1) clinical diagnosis of focal seizures and/or secondary generalized seizures; (2) normal psychomotor development and neurological findings prior to seizure onset; (3) normal interictal EEG; (4) normal neuroimaging findings; and (5) seizures onset at 3– 12 months of age. Sufficient information was difficult to obtain from some parents and most grandparents with unprovoked seizures during infancy. Such cases
were referred as unconfirmed infantile seizures in our study. PKD was diagnosed when a patient experienced attacks with dystonia, chorea, and athetoid movements without loss or impairment of consciousness, precipitated by sudden movements, intention to move, startles, stress and anxiety. ICCA was diagnosed when a patient had both BIE and PKD. The patients with convulsions with mild gastroenteritis had had no unprovoked seizures. In siblings with benign early infantile epilepsy, the age at the onset of epilepsy ranged from 1 to 2 months, which are younger than that of BIE. Mutation analyses were performed based on the PCR-direct sequencing method described elsewhere [21]. Primer designs used in this study were same as those reported by Heron et al [5]. Clinical manifestation of each individual was collected by chart review and interview using a structured research form. Family history was collected within the third degree relatives. Statistical analyses were performed to identify differences in probands with BIE according to the presence or absence of PRRT2 mutation. The Kruskal-Wallis test was used to compare numerical variables. We compared categorical variables by using the Fisher’s exact probability test. A p value <0.05 was considered to be statistically significant. 3. Results PRRT2 mutation was found in 6 of 16 probands with BIE, including one with ICCA. The pedigrees of the 6 families with PRRT2 mutation is shown in Fig. 1A. BIE and/or PKD in one family were identified in 3 families (Families 2, 3, and 4). In Family 2, proband and her elder brother had BIE alone and their father had both BIE and PKD. In Family 3, proband and his younger sister had BIE alone, whereas their mother and maternal grandmother had PKD alone. In Family 4, all members with PRRT2 mutation had both BIE and PKD. In the other 3 families (Families 1, 5, and 6), PKD alone was observed. In these families, probands had BIE, whereas other members with PRRT2 mutation were asymptomatic, without BIE or PKD. All but one family showed a common insertion mutation, c.649_650insC (Fig. 1B), which has been previously reported [4–7,9–13,16–18]. In this study, only one family showed a novel missense mutation, c.981C>G (I327 M) (Fig. 1B). PolyPhen-2 (HumDiv model) and SIFT score of this mutation was 0.991 and 0.04, respectively, which indicated that the mutation will be damaging. This mutation was negative in the 100 normal Japanese volunteers. In addition, this mutation is located in a highly conserved amino acid site (Fig. 1C). Conversely, no PRRT2 mutation was observed in 10 probands with BIE, all 6 patients with convulsion with mild gastroenteritis, or siblings with benign early infantile epilepsy.
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
A. Okumura et al. / Brain & Development xxx (2012) xxx–xxx
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Fig. 1. PRRT2 analysis results. (A) Pedigrees of families with PRRT2 mutations. Individuals with a PRRT2 mutation are indicated by m/+, and those tested for mutations and found to be negative are indicated by +/+. Arrows indicated probands. BIE: benign partial epilepsy in infancy, PKD: paroxysmal kinesigenic diskinesia, ICCA: infantile convulsions with choreoathetosis syndrome. (B) Electrophoregram of the direct sequencing. A common insertion mutation of c.640_641insC and a novel missense mutation of c.981C>G (I327 M) identified in this study are shown. The locations of the one nucleotide insertion and the missense mutation are indicated by arrows. (C) Evolutionary conservation of PRRT2 amino acids. The amino acid sequences around the missense mutation of c.981C>G (I327 M) identified in this study, which is highlighted by UCSC genome browser (build19) (http://genome.ucsc.edu/). The amino-acid I327 is conserved among species.
The clinical manifestations of 14 individuals with PRRT2 mutation is shown in Table 1. Two individuals (Family 1, II-2 and Family 5, II-3) are asymptomatic without seizures or movement disorders. BIE including unconfirmed infantile seizures was observed in 11 individuals. The age at the onset of BIE ranged from 3 to 10 months and the age at the last seizure from 3 to 15 months. A cluster of seizures was seen in 7. PKD was recognized in 6 individuals. Among them, one individual (Family 3, II-2) had not had BIE. Febrile seizures
were present in 2 individuals, whereas none had had convulsion with mild gastroenteritis or developmental delay. Table 2 shows comparison of probands with BIE according to the presence or absence of PRRT2 mutation. There were no significant differences in the manifestation of BIE, or the rate of PKD, febrile seizures or convulsion with mild gastroenteritis. Two probands were confirmed to have mild mental retardation with intelligence quotient 60–70 at 5–6 years of age. They
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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Table 1 Clinical features of individuals with PRRT2 mutation. Family Family II-2 III-1* Family II-2 III-1* III-2 Family II-2 III-1* III-2 Family II-1 III-1 III-2* Family II-3 III-1* Family III-1* *
PRRT2 mutation
Age at the Sz onset (m)
Age at the last Sz (m)
Sz Cluster
PKD
Febrile Szs
c.981C>G c.981C>G
None 10
None 11
N/A Yes
No No
No No
c.649_650insC c.649_650insC c.649_650insC
6 4 3
6 9 4
Yes Yes Yes
Yes Yes Yes
No No Yes
c.649_650insC c.649_650insC c.649_650insC
None 8 5
None 9 5
N/A No Yes
Yes No No
No No Yes
c.649_650insC c.649_650insC c.649_650insC
Unknown 7 4
Unknown 15 11
Unknown No No
Yes No No
No No No
c.649_650insC c.649_650insC
None 3
None 3
N/A Yes
No No
No No
c.649_650insC
5
11
Yes
No
No
1
2
3
4
5
6
Indicates a proband. Sz: seizure, N/A: not applicable. Table 2 Comparison of the probands according to the presence or absence of PRRT2 mutation.
Sex (M:F) Age at Sz onset (m) Age at the last Sz (m) Cluster of Szs PKD Febrile Sz CwG Developmental delay Family history Unprovoked infantile Sz PKD Febrile Sz CwG Developmental delay
Probands with PRRT2 mutation (n = 6)
Probands with no mutation (n = 10)
3:3 7.5 (3–11) 8 (3–21) 4 (67%) 1 (17%) 1 (17%) 0 0
3:7 4.5 (3–10) 10 (3–11) 9 (90%) 0 1 (10%) 2 (20%) 2 (20%)
NS NS NS NS NS NS NS NS
3 (50%) 3 (50%) 2 (33%) 0 0
4 (40%) 0 3 (30%) 0 0
NS p < 0.05 NS NS NS
Sz: seizure, PKD: paroxysmal kinesigenic dyskinesia, CwG: convulsion with mild gastroenteritis, NS: not significant.
have no motor impairment, autistic features, or attention deficit. The rate of developmental delay was not significantly different between the two groups. As to family history, PKD was significantly more common in probands with PRRT2 mutation than in those without mutation. 4. Discussion Our study revealed that PRRT2 mutations are not uncommon in our cohort of BIE/ICCA, especially in familial cases. The common mutation, c.649_650insC, is also common among our patients. These results are consistent with previous studies. [4–7,9–13,16–18]. On the other hand, PRRT2 mutation was not recognized in any patients with convulsion with mild gastroenteritis
or siblings with benign early infantile epilepsy. These clinical entities may have different genetic background from BIE and/or PKD, although some clinical features overlap among them. PRRT2 mutations are not present in 10 of 16 probands with BIE in our cohort. This contrasts with the results of the previous studies. Heron et al. reported that more than 80% of families with BIE/ICCA had mutations in PRRT2 [5]. Ono et al. identified mutations in PRRT2 in all patients with BIE and/or PKD [6]. Schubert et al. reported that 83% of the index cases with familial BIE [7]. In our study, there are no significant differences in phenotypes of probands suspected to having BIE according to the presence or absence of PRRT2 mutation, except for family history of PKD. It is interesting that several previous studies revealed that PRRT2
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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mutation is relatively less frequent in patients with nonfamilial BIE [8,9]. These results indicate that genes other than PRRT2 will contribute to the development of BIE. Some of them may be autosomal recessive trait, because more than half of patients with BIE do not have a family history of BIE [1]. There have been several reports on genetic mutations in patients with familial BIE or its related epilepsies including sodium channel, voltagegated, type I, alpha gene (SCN1A) mutations in benign familial neonatal-infantile seizures [22] and sodium/ potassium-transporting ATPase subunit alpha-2 gene (ATP1A2) mutations in benign familial infantile convulsions and familial hemiplegic migraine [23]. Linkage analyses of family with familial BIE demonstrated a linkage to chromosomal regions 19q12–13.1 [24] and 1p36.12-p35.1 [25]. The phenotypes of family members with BIE mapped to 19q [26] almost overlap with those of our patients without PRRT2 mutation in terms of age at onset, seizures in cluster, and seizure manifestations. In this region, sodium channel, voltage-gated, type I, beta gene (SCN1B) is included. Although we previously explored SCN1B mutations in 6 children with BIE and 6 children with convulsions with mild gastroenteritis, mutations were not recognized in any of them [27]. Clinical features of the family members with BIE mapped to 1q region [25] including age at the onset, seizure manifestations, and frequent occurrence of seizures in cluster, are also similar to those of our patients without PRRT2 mutation. These facts indicate that several other genes will be found to cause BIE in the near future. In this study, we identified a novel missense mutation, I327 M, in one family. PolyPhen-2 and SIFT score of this mutation indicated damaging, and this mutation is located in a highly conserved amino acid site and was not identified in 100 normal Japanese individuals. Thus, we consider that this mutation will be pathological one responsible for BIE. No obvious genotype-phenotype correlation has been observed in patients with PRRT2 mutation. The most common c.649_650insC mutation has been identified in a majority of families with BIE and/or PKD [4–7,9– 13,16–18]. Age at the onset and offset of epilepsy was variable among individuals even within a single family with c.649_650insC mutation [5]. The types of paroxysmal movements were also variable among the individuals with c.649_650insC mutation [10,11]. However, it is important that seizures and movement disorders are self-limiting and their adverse effects on quality of life will be limited in most patients with PRRT2 mutation. Because neurological symptoms are inherited in an autosomal dominant manner, information on favorable outcome will be reassuring for patients and their parents. It is remarkable that 2 of 14 individuals with PRRT2 mutation did not have BIE or PKD (Table 1). Such individuals are found in the families with common c.649_650insC mutation as well as a family with novel
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I327 M mutation. Several previous studies also showed that carriers with PRRT2 mutations without epilepsy or movement disorders are not uncommon in the families with BIE and/or PKD with PRRT2 mutation [5,9,12–16,18]. These facts suggest incomplete penetrance is likely to occur in PRRT2 mutation. The limitation of our study is that number of analyzed patients was rather small. The results of our study should be verified by further studies. Statistical analysis showed that PKD was significantly more common in probands with PRRT2 mutation than in those without mutation. However, the power of statistical analysis may be insufficient. A larger number of patients are necessary in order to elucidate the features of patients who are likely to have PRRT2 mutation. Nonetheless, it is interesting that the family history of PKD was exclusively seen in the families with PRRT2 mutation. An exploration of PRRT2 mutation will be worthwhile in patients with family history of PKD. On the other hand, PRRT2 mutation was not very common among our patients with sporadic BIE. Further studies are necessary in order to clarify whether or not testing PRRT2 mutation is valuable for patients with sporadic BIE. In conclusion, PRRT2 mutations were found in 6 of 16 probands with BIE. The common c.649_650insC mutation was observed in 5 of 6 families with PRRT2 mutation. The difference in phenotypes is unclear according to the presence or absence of PRRT2 mutations, although a family history of PKD was frequent in the patients with PRRT2 mutation. Further studies are necessary in order to understand the phenotypic spectrum of PRRT2 mutations. Acknowledgement This study is supported by Grant-in-aid from The Japan Epilepsy Research Foundation, A research grant Scientific Research (c) from The Japan Ministry of Education, Science, Sports and Culture, Grant-in-aid for Scientific Research on Innovative Areas from The Japan Ministry of Education, Science, and Grant-in-Aid for scientific research from Health Labor Sciences Research Grants. References [1] Okumura A, Watanabe K, Negoro T, Hayakawa F, Kakumurto T, Maruyama K, et al. Long-term follow-up of patients with benign partial epilepsy in infancy. Epilepsia 2006;47:181–5. [2] Watanabe K, Okumura A. Benign partial epilepsies in infancy. Brain Dev 2000;22:296–300. [3] Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010;133:1403–14. [4] Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252–5.
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Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
Original article
PRRT2 mutation in Japanese children with benign infantile epilepsy Akihisa Okumura a,⇑, Keiko Shimojima b, Tetsuo Kubota c, Shinpei Abe a, Shintaro Yamashita d, Katsumi Imai e, Tohru Okanishi f, Hideo Enoki f, Tatsuya Fukasawa c, Takuya Tanabe g, Leanne M. Dibbens h, Toshiaki Shimizu a, Toshiyuki Yamamoto b a
Department of Pediatrics, Juntendo University Faculty of Medicine, Japan Tokyo Womens’ Medical University, Institute for Integrated Medical Sciences, Japan c Department of Pediatrics, Anjo Kosei Hospital, Japan d Department of Pediatrics, Juntendo Nerima Hospital, Japan e National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan f Department of Child Neurology, Seirei Hamamatsu General Hospital, Japan g Tanabe-Kadobayashi Children’s Clinic, Japan h Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Australia Received 27 March 2012; received in revised form 25 September 2012; accepted 28 September 2012 b
Abstract Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: PRRT2; Benign infantile epilepsy; Paroxysmal kinesigenic dyskinesia; Japanese children
1. Introduction Benign infantile epilepsy (BIE) have been established as a distinct epilepsy syndrome characterized by focal ⇑ Corresponding author. Address: Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan. Tel.: +81 3 3813 3111; fax: +81 3 5800 1580. E-mail address: [email protected] (A. Okumura).
seizures in clusters of infantile onset, with no clear etiological factors, normal interictal EEG and neuroimaging, and normal psychomotor development. Usual age of onset has been described from 3 to 10 months [1]. BIE is almost analogous to benign partial epilepsy in infancy proposed by Watanabe et al [2]. According to our previous study [1], about 40% of the children with BIE have a family history. An association of paroxysmal kinesigenic dyskinesia (PKD) was seen in some patients
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.09.015
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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with BIE, indicating overlap between BIE and infantile convulsions with choreoathetosis syndrome (ICCA). We also showed that approximately 10% of children with BIE experienced convulsions with mild gastroenteritis [1]. Previous studies have revealed that mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2 cause benign familial neonatal-infantile seizures [3], suggesting overlap between BIE and benign neonatal seizures. Chen et al. recently identified mutations in prolinerich transmembrane protein 2 gene (PRRT2) in eight Chinese families affected by autosomal-dominant PKD by exome sequencing analysis [4]. In addition, Heron et al. identified five different mutations in PRRT2 in 14 of 17 families affected by BIE and in five of six families affected by ICCA [5] and Ono et al. found two mutations in PRRT2, c.649_650insC and c.748C>T, in all individuals with PKD and/or BIE [6]. Thereafter, several reports have shown that PRRT2 mutation will be one of the major genes relating to BIE, PKD, and ICCA [7–20]. However, we hypothesized that PRRT2 mutation may also be related to several phenotypes of infantile epilepsies other than BIE and/or PKD. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We also investigated the differences in phenotype of probands with BIE according to the presence or absence of PRRT2 mutation. 2. Patients and methods For the purpose of genetic analyses, we have recruited children with epilepsy of infantile or early childhood onset, who fulfilled the following conditions: normal development prior to the onset, no neurological abnormalities, no neuroimaging abnormalities, favorable response to antiepileptic drugs. All patients are Japanese. We collected blood samples from the recruited patients, when written informed consent was obtained. The probands included 16 children with BIE (including 1 child with ICCA), 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. This study is approved by the ethics committees in Tokyo Womens’ Medical University. We defined BIE as epilepsy meeting all of the following conditions: (1) clinical diagnosis of focal seizures and/or secondary generalized seizures; (2) normal psychomotor development and neurological findings prior to seizure onset; (3) normal interictal EEG; (4) normal neuroimaging findings; and (5) seizures onset at 3– 12 months of age. Sufficient information was difficult to obtain from some parents and most grandparents with unprovoked seizures during infancy. Such cases
were referred as unconfirmed infantile seizures in our study. PKD was diagnosed when a patient experienced attacks with dystonia, chorea, and athetoid movements without loss or impairment of consciousness, precipitated by sudden movements, intention to move, startles, stress and anxiety. ICCA was diagnosed when a patient had both BIE and PKD. The patients with convulsions with mild gastroenteritis had had no unprovoked seizures. In siblings with benign early infantile epilepsy, the age at the onset of epilepsy ranged from 1 to 2 months, which are younger than that of BIE. Mutation analyses were performed based on the PCR-direct sequencing method described elsewhere [21]. Primer designs used in this study were same as those reported by Heron et al [5]. Clinical manifestation of each individual was collected by chart review and interview using a structured research form. Family history was collected within the third degree relatives. Statistical analyses were performed to identify differences in probands with BIE according to the presence or absence of PRRT2 mutation. The Kruskal-Wallis test was used to compare numerical variables. We compared categorical variables by using the Fisher’s exact probability test. A p value <0.05 was considered to be statistically significant. 3. Results PRRT2 mutation was found in 6 of 16 probands with BIE, including one with ICCA. The pedigrees of the 6 families with PRRT2 mutation is shown in Fig. 1A. BIE and/or PKD in one family were identified in 3 families (Families 2, 3, and 4). In Family 2, proband and her elder brother had BIE alone and their father had both BIE and PKD. In Family 3, proband and his younger sister had BIE alone, whereas their mother and maternal grandmother had PKD alone. In Family 4, all members with PRRT2 mutation had both BIE and PKD. In the other 3 families (Families 1, 5, and 6), PKD alone was observed. In these families, probands had BIE, whereas other members with PRRT2 mutation were asymptomatic, without BIE or PKD. All but one family showed a common insertion mutation, c.649_650insC (Fig. 1B), which has been previously reported [4–7,9–13,16–18]. In this study, only one family showed a novel missense mutation, c.981C>G (I327 M) (Fig. 1B). PolyPhen-2 (HumDiv model) and SIFT score of this mutation was 0.991 and 0.04, respectively, which indicated that the mutation will be damaging. This mutation was negative in the 100 normal Japanese volunteers. In addition, this mutation is located in a highly conserved amino acid site (Fig. 1C). Conversely, no PRRT2 mutation was observed in 10 probands with BIE, all 6 patients with convulsion with mild gastroenteritis, or siblings with benign early infantile epilepsy.
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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Fig. 1. PRRT2 analysis results. (A) Pedigrees of families with PRRT2 mutations. Individuals with a PRRT2 mutation are indicated by m/+, and those tested for mutations and found to be negative are indicated by +/+. Arrows indicated probands. BIE: benign partial epilepsy in infancy, PKD: paroxysmal kinesigenic diskinesia, ICCA: infantile convulsions with choreoathetosis syndrome. (B) Electrophoregram of the direct sequencing. A common insertion mutation of c.640_641insC and a novel missense mutation of c.981C>G (I327 M) identified in this study are shown. The locations of the one nucleotide insertion and the missense mutation are indicated by arrows. (C) Evolutionary conservation of PRRT2 amino acids. The amino acid sequences around the missense mutation of c.981C>G (I327 M) identified in this study, which is highlighted by UCSC genome browser (build19) (http://genome.ucsc.edu/). The amino-acid I327 is conserved among species.
The clinical manifestations of 14 individuals with PRRT2 mutation is shown in Table 1. Two individuals (Family 1, II-2 and Family 5, II-3) are asymptomatic without seizures or movement disorders. BIE including unconfirmed infantile seizures was observed in 11 individuals. The age at the onset of BIE ranged from 3 to 10 months and the age at the last seizure from 3 to 15 months. A cluster of seizures was seen in 7. PKD was recognized in 6 individuals. Among them, one individual (Family 3, II-2) had not had BIE. Febrile seizures
were present in 2 individuals, whereas none had had convulsion with mild gastroenteritis or developmental delay. Table 2 shows comparison of probands with BIE according to the presence or absence of PRRT2 mutation. There were no significant differences in the manifestation of BIE, or the rate of PKD, febrile seizures or convulsion with mild gastroenteritis. Two probands were confirmed to have mild mental retardation with intelligence quotient 60–70 at 5–6 years of age. They
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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Table 1 Clinical features of individuals with PRRT2 mutation. Family Family II-2 III-1* Family II-2 III-1* III-2 Family II-2 III-1* III-2 Family II-1 III-1 III-2* Family II-3 III-1* Family III-1* *
PRRT2 mutation
Age at the Sz onset (m)
Age at the last Sz (m)
Sz Cluster
PKD
Febrile Szs
c.981C>G c.981C>G
None 10
None 11
N/A Yes
No No
No No
c.649_650insC c.649_650insC c.649_650insC
6 4 3
6 9 4
Yes Yes Yes
Yes Yes Yes
No No Yes
c.649_650insC c.649_650insC c.649_650insC
None 8 5
None 9 5
N/A No Yes
Yes No No
No No Yes
c.649_650insC c.649_650insC c.649_650insC
Unknown 7 4
Unknown 15 11
Unknown No No
Yes No No
No No No
c.649_650insC c.649_650insC
None 3
None 3
N/A Yes
No No
No No
c.649_650insC
5
11
Yes
No
No
1
2
3
4
5
6
Indicates a proband. Sz: seizure, N/A: not applicable. Table 2 Comparison of the probands according to the presence or absence of PRRT2 mutation.
Sex (M:F) Age at Sz onset (m) Age at the last Sz (m) Cluster of Szs PKD Febrile Sz CwG Developmental delay Family history Unprovoked infantile Sz PKD Febrile Sz CwG Developmental delay
Probands with PRRT2 mutation (n = 6)
Probands with no mutation (n = 10)
3:3 7.5 (3–11) 8 (3–21) 4 (67%) 1 (17%) 1 (17%) 0 0
3:7 4.5 (3–10) 10 (3–11) 9 (90%) 0 1 (10%) 2 (20%) 2 (20%)
NS NS NS NS NS NS NS NS
3 (50%) 3 (50%) 2 (33%) 0 0
4 (40%) 0 3 (30%) 0 0
NS p < 0.05 NS NS NS
Sz: seizure, PKD: paroxysmal kinesigenic dyskinesia, CwG: convulsion with mild gastroenteritis, NS: not significant.
have no motor impairment, autistic features, or attention deficit. The rate of developmental delay was not significantly different between the two groups. As to family history, PKD was significantly more common in probands with PRRT2 mutation than in those without mutation. 4. Discussion Our study revealed that PRRT2 mutations are not uncommon in our cohort of BIE/ICCA, especially in familial cases. The common mutation, c.649_650insC, is also common among our patients. These results are consistent with previous studies. [4–7,9–13,16–18]. On the other hand, PRRT2 mutation was not recognized in any patients with convulsion with mild gastroenteritis
or siblings with benign early infantile epilepsy. These clinical entities may have different genetic background from BIE and/or PKD, although some clinical features overlap among them. PRRT2 mutations are not present in 10 of 16 probands with BIE in our cohort. This contrasts with the results of the previous studies. Heron et al. reported that more than 80% of families with BIE/ICCA had mutations in PRRT2 [5]. Ono et al. identified mutations in PRRT2 in all patients with BIE and/or PKD [6]. Schubert et al. reported that 83% of the index cases with familial BIE [7]. In our study, there are no significant differences in phenotypes of probands suspected to having BIE according to the presence or absence of PRRT2 mutation, except for family history of PKD. It is interesting that several previous studies revealed that PRRT2
Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015
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mutation is relatively less frequent in patients with nonfamilial BIE [8,9]. These results indicate that genes other than PRRT2 will contribute to the development of BIE. Some of them may be autosomal recessive trait, because more than half of patients with BIE do not have a family history of BIE [1]. There have been several reports on genetic mutations in patients with familial BIE or its related epilepsies including sodium channel, voltagegated, type I, alpha gene (SCN1A) mutations in benign familial neonatal-infantile seizures [22] and sodium/ potassium-transporting ATPase subunit alpha-2 gene (ATP1A2) mutations in benign familial infantile convulsions and familial hemiplegic migraine [23]. Linkage analyses of family with familial BIE demonstrated a linkage to chromosomal regions 19q12–13.1 [24] and 1p36.12-p35.1 [25]. The phenotypes of family members with BIE mapped to 19q [26] almost overlap with those of our patients without PRRT2 mutation in terms of age at onset, seizures in cluster, and seizure manifestations. In this region, sodium channel, voltage-gated, type I, beta gene (SCN1B) is included. Although we previously explored SCN1B mutations in 6 children with BIE and 6 children with convulsions with mild gastroenteritis, mutations were not recognized in any of them [27]. Clinical features of the family members with BIE mapped to 1q region [25] including age at the onset, seizure manifestations, and frequent occurrence of seizures in cluster, are also similar to those of our patients without PRRT2 mutation. These facts indicate that several other genes will be found to cause BIE in the near future. In this study, we identified a novel missense mutation, I327 M, in one family. PolyPhen-2 and SIFT score of this mutation indicated damaging, and this mutation is located in a highly conserved amino acid site and was not identified in 100 normal Japanese individuals. Thus, we consider that this mutation will be pathological one responsible for BIE. No obvious genotype-phenotype correlation has been observed in patients with PRRT2 mutation. The most common c.649_650insC mutation has been identified in a majority of families with BIE and/or PKD [4–7,9– 13,16–18]. Age at the onset and offset of epilepsy was variable among individuals even within a single family with c.649_650insC mutation [5]. The types of paroxysmal movements were also variable among the individuals with c.649_650insC mutation [10,11]. However, it is important that seizures and movement disorders are self-limiting and their adverse effects on quality of life will be limited in most patients with PRRT2 mutation. Because neurological symptoms are inherited in an autosomal dominant manner, information on favorable outcome will be reassuring for patients and their parents. It is remarkable that 2 of 14 individuals with PRRT2 mutation did not have BIE or PKD (Table 1). Such individuals are found in the families with common c.649_650insC mutation as well as a family with novel
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I327 M mutation. Several previous studies also showed that carriers with PRRT2 mutations without epilepsy or movement disorders are not uncommon in the families with BIE and/or PKD with PRRT2 mutation [5,9,12–16,18]. These facts suggest incomplete penetrance is likely to occur in PRRT2 mutation. The limitation of our study is that number of analyzed patients was rather small. The results of our study should be verified by further studies. Statistical analysis showed that PKD was significantly more common in probands with PRRT2 mutation than in those without mutation. However, the power of statistical analysis may be insufficient. A larger number of patients are necessary in order to elucidate the features of patients who are likely to have PRRT2 mutation. Nonetheless, it is interesting that the family history of PKD was exclusively seen in the families with PRRT2 mutation. An exploration of PRRT2 mutation will be worthwhile in patients with family history of PKD. On the other hand, PRRT2 mutation was not very common among our patients with sporadic BIE. Further studies are necessary in order to clarify whether or not testing PRRT2 mutation is valuable for patients with sporadic BIE. In conclusion, PRRT2 mutations were found in 6 of 16 probands with BIE. The common c.649_650insC mutation was observed in 5 of 6 families with PRRT2 mutation. The difference in phenotypes is unclear according to the presence or absence of PRRT2 mutations, although a family history of PKD was frequent in the patients with PRRT2 mutation. Further studies are necessary in order to understand the phenotypic spectrum of PRRT2 mutations. Acknowledgement This study is supported by Grant-in-aid from The Japan Epilepsy Research Foundation, A research grant Scientific Research (c) from The Japan Ministry of Education, Science, Sports and Culture, Grant-in-aid for Scientific Research on Innovative Areas from The Japan Ministry of Education, Science, and Grant-in-Aid for scientific research from Health Labor Sciences Research Grants. References [1] Okumura A, Watanabe K, Negoro T, Hayakawa F, Kakumurto T, Maruyama K, et al. Long-term follow-up of patients with benign partial epilepsy in infancy. Epilepsia 2006;47:181–5. [2] Watanabe K, Okumura A. Benign partial epilepsies in infancy. Brain Dev 2000;22:296–300. [3] Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010;133:1403–14. [4] Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252–5.
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Please cite this article in press as: Okumura A et al. PRRT2 mutation in Japanese children with benign infantile epilepsy.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.015