Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis

Ishii, Atsushi; Yasumoto, Sawa; Ihara, Yukiko; Inoue, Takahito; Fujita, Takako; Nakamura, Noriko; Ohfu, Masaharu; Yamashita, Yushiro; Takatsuka, Hideo; Taga, Toshiaki; Miyata, Rie; Ito, Masahiro; Matsuoka, Taro; Kitao, Toshio; Murakami, Kiyotaka; Lee, Wang-Tso; Kaneko, Sunao; Hirose, Shinichi

doi:10.1016/j.braindev.2012.09.006

Cited by 28 publications

(27 citation statements)

References 27 publications

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“…The positive rate of PRRT2 mutations in our ICCA families was 93.3%. This result was consistent with the rate that had been reported by other research groups [19,[21][22][23][24]. The identification of SCN2A mutations in 5 BFIE families in our cohort further proved that this gene is also involved in families with a delayed age of onset [25].…”

Section: Discussionsupporting

confidence: 81%

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Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

et al. 2017

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Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75.9%). A total of 42 families had PRRT2 mutations, 9 had KCNQ2 mutations, 8 had SCN2A mutations, and 1 had a GABRA6 mutation. In total three of four BFNE families were detected with KCNQ2 mutations. Mutations were detected in all BFNIE families, including 3 KCNQ2 mutations, 3 SCN2A mutations, and 1 PRRT2 mutation. Gene mutations were identified in 50 out of 68 BFIE families (73.5%), including 41 PRRT2 mutations (41 out of 68, 60.3%), 5 SCN2A mutations, 3 KCNQ2 mutations, and 1 GABRA6 mutation. Our results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE.

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Section: Discussionsupporting

confidence: 81%

“…PRRT2 mutations were clustered in families with BFIE (41 out of 68, 60.3%). It may be due to regional and racial differences, however, our rate was lower than those rates found by other research groups [11,12,14,21]. In our study, most PRRT2 mutations were frameshift mutations.…”

Section: Discussioncontrasting

confidence: 54%

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

et al. 2017

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“…PRRT2 is the major causative gene of PKD, BFIE, and ICCA [5-8,12-19], and is also responsible for several familial or sporadic cases with paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exercised-induced dyskinesia (PED), sporadic BIE, and hemiplegic migraine (HM) [20-24]. In this study, we observed that PRRT2 mutations are also common in Chinese families with BFIE and ICCA.…”

Section: Discussionmentioning

confidence: 84%

“…This was also present in our BFIE families, accounting for 69.2% (9/13) of PRRT2 mutation-positive families. In previous studies, the percentage of c.649_650insC in BFIE families with a PRRT2 mutation ranged from 85.7% to 92.9% [6,12,24]. This mutation was observed mainly with a BFIE, PKD and ICCA phenotype [6,8,12,13,28,29], and but also in a few familial or sporadic cases of PNKD, PED, HM and episodic ataxia [20-22].…”

Section: Discussionmentioning

confidence: 99%

Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

Yang

Zhang

et al. 2013

BMC Neurol

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BackgroundMutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA.MethodsClinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing.ResultsNinety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A > T (X341C). c.1023A > T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues.ConclusionsOur data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A > T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in PKD, ICCA and hemiplegic migraine families, but we further detected it in BFIE-only families. c.904_905insG was reported in an ICCA family, but we identified it in a BFIE family. c.514_517delTCTG was previously reported in a PKD family, but we identified it in an ICCA family. Migraine and febrile seizures plus could co-exist in ICCA families.

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“…PRRT2 mutations have not been associated with other phenotypes that include infantile seizures. In particular, no mutations have been identified in patients with convulsions with gastroenteritis (CwG) or benign familial neonatal epilepsy (BFNE) 43 48 50. BFNE is most commonly caused by mutations in the potassium channel subunit genes KCNQ2 and KCNQ3 61.…”

Section: Identification Of Mutations In Prrt2mentioning

confidence: 99%

Role ofPRRT2in common paroxysmal neurological disorders: a gene with remarkable pleiotropy

Heron

Dibbens

2013

J Med Genet

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Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain individuals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined.

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Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis

Cited by 28 publications

References 27 publications

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

Role ofPRRT2in common paroxysmal neurological disorders: a gene with remarkable pleiotropy

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