Original article| Volume 35, ISSUE 6, P524-530, June 2013

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


      Purpose: PRRT2 mutations were recently identified in benign familial infantile epilepsy (BFIE) and infantile convulsions with paroxysmal choreoathetosis (ICCA) but no abnormalities have so far been identified in their phenotypically similar seizure disorder of benign convulsions with mild gastroenteritis (CwG), while mutations in KCNQ2 and KCNQ3 have been recognized in benign familial neonatal epilepsy (BFNE). The aim of this study was to identify PRRT2 mutations in infantile convulsions in Asian families with BFIE and ICCA, CwG and BFNE. Methods: We recruited 26 unrelated Japanese affected with either BFIE or non-familial benign infantile seizures and their families, including three families with ICCA. A total of 17 Japanese and Taiwanese with CwG, 50 Japanese with BFNE and 96 healthy volunteers were also recruited. Mutations of PRRT2 were sought using direct sequencing. Results: Heterozygous truncation mutation (c.649dupC) was identified in 15 of 26 individuals with benign infantile epilepsy (52.1%). All three families of ICCA harbored the same mutation (100%). Another novel mutation (c.1012+2dupT) was found in the proband of a family with BFIE. However, no PRRT2 mutation was found in either CwG or BFNE. Conclusions: The results confirm that c.649dupC, a truncating mutation of PRRT2, is a hotspot mutation resulting in BFIE or ICCA regardless of the ethnic background. In contrast, PRRT2 mutations do not seem to be associated with CwG or BFNE. Screening for PRRT2 mutation might be useful in early-stage differentiation of BFIE from CwG.


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        • Caraballo R.
        • Pavek S.
        • Lemainque A.
        • Gastaldi M.
        • Echenne B.
        • Motte J.
        • et al.
        Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome.
        Am J Hum Genet (in eng). 2001; 68: 788-794
        • Szepetowski P.
        • Rochette J.
        • Berquin P.
        • Piussan C.
        • Lathrop G.M.
        • Monaco A.P.
        Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16.
        Am J Hum Genet (in Eng). 1997; 61: 889-898
        • Chen W.J.
        • Lin Y.
        • Xiong Z.Q.
        • Wei W.
        • Ni W.
        • Tan G.H.
        • et al.
        Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia.
        Nat Genet (in Eng). 2011; 43: 1252-1255
        • Heron S.E.
        • Grinton B.E.
        • Kivity S.
        • Afawi Z.
        • Zuberi S.M.
        • Hughes J.N.
        • et al.
        PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.
        Am J Hum Genet (in Eng). 2012; 90: 152-160
        • Contino M.F.
        • Lebby T.
        • Arcinue E.L.
        Rotaviral gastrointestinal infection causing afebrile seizures in infancy and childhood.
        Am J Emerg Med (in Eng). 1994; 12: 94-95
        • Kawano G.
        • Oshige K.
        • Syutou S.
        • Koteda Y.
        • Yokoyama T.
        • Kim B.G.
        • et al.
        Benign infantile convulsions associated with mild gastroenteritis: a retrospective study of 39 cases including virological tests and efficacy of anticonvulsants.
        Brain Dev (in Eng). 2007; 29: 617-622
        • Lin S.C.
        • Hsu H.Y.
        • Wang P.J.
        • Lee C.N.
        • Chang M.H.
        • Shen Y.Z.
        • et al.
        Rotavirus gastroenteritis associated with afebrile seizure in childhood.
        Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi (in Eng). 1996; 37: 204-207
        • Biervert C.
        • Schroeder B.C.
        • Kubisch C.
        • Berkovic S.F.
        • Propping P.
        • Jentsch T.J.
        • et al.
        A potassium channel mutation in neonatal human epilepsy.
        Science (in Eng). 1998; 279: 403-406
        • Charlier C.
        • Singh N.A.
        • Ryan S.G.
        • Lewis T.B.
        • Reus B.E.
        • Leach R.J.
        • et al.
        A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.
        Nat Genet (in Eng). 1998; 18: 53-55
        • Claes L.R.
        • Ceulemans B.
        • Audenaert D.
        • Deprez L.
        • Jansen A.
        • Hasaerts D.
        • et al.
        De novo KCNQ2 mutations in patients with benign neonatal seizures.
        Neurology (in Eng). 2004; 63: 2155-2158
        • de Haan G.J.
        • Pinto D.
        • Carton D.
        • Bader A.
        • Witte J.
        • Peters E.
        • et al.
        A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years.
        Epilepsia (in Eng). 2006; 47: 851-859
        • Hirose S.
        • Okada M.
        • Kaneko S.
        • Mitsudome A.
        Are some idiopathic epilepsies disorders of ion channels?: a working hypothesis.
        Epilepsy Res (in Eng). 2000; 41: 191-204
        • Hirose S.
        • Zenri F.
        • Akiyoshi H.
        • Fukuma G.
        • Iwata H.
        • Inoue T.
        • et al.
        A novel mutation of KCNQ3 (c.925T -->C) in a Japanese family with benign familial neonatal convulsions.
        Ann Neurol (in Eng). 2000; 47: 822-826
        • Ishii A.
        • Fukuma G.
        • Uehara A.
        • Miyajima T.
        • Makita Y.
        • Hamachi A.
        • et al.
        A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions.
        Brain Dev (in Eng). 2009; 31: 27-33
        • Singh N.A.
        • Charlier C.
        • Stauffer D.
        • DuPont B.R.
        • Leach R.J.
        • Melis R.
        • et al.
        A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.
        Nat Genet (in Eng). 1998; 18: 25-29
        • Fukuma G.
        • Oguni H.
        • Shirasaka Y.
        • Watanabe K.
        • Miyajima T.
        • Yasumoto S.
        • et al.
        Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB).
        Epilepsia (in Eng). 2004; 45: 140-148
        • Hirose S.
        • Iwata H.
        • Akiyoshi H.
        • Kobayashi K.
        • Ito M.
        • Wada K.
        • et al.
        A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.
        Neurology (in Eng). 1999; 53: 1749-1753
        • Ishii A.
        • Zhang B.
        • Kaneko S.
        • Hirose S.
        Positive association between benign familial infantile convulsions and LGI4.
        Brain Dev (in Eng). 2010; 32: 538-543
        • Cao L.
        • Huang X.J.
        • Zheng L.
        • Xiao Q.
        • Wang X.J.
        • Chen S.D.
        Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot.
        Parkinsonism Relat Disord (in Eng). 2012;
        • Li J.
        • Zhu X.
        • Wang X.
        • Sun W.
        • Feng B.
        • Du T.
        • et al.
        Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis.
        J Med Genet (in Eng). 2012; 49: 76-78
        • Liu Q.
        • Qi Z.
        • Wan X.H.
        • Li J.Y.
        • Shi L.
        • Lu Q.
        • et al.
        Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.
        J Med Genet (in Eng). 2012; 49: 79-82
        • Wang J.L.
        • Cao L.
        • Li X.H.
        • Hu Z.M.
        • Li J.D.
        • Zhang J.G.
        • et al.
        Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.
        Brain (in Eng). 2011; 134: 3493-3501
        • Ono S.
        • Yoshiura K.
        • Kinoshita A.
        • Kikuchi T.
        • Nakane Y.
        • Kato N.
        • et al.
        Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions.
        J Hum Genet (in Eng). 2012; 57: 338-341
        • Lee H.-Y.
        • Huang Y.
        • Bruneau N.
        • Roll P.
        • Roberson Elisha D.O.
        • Hermann M.
        • et al.
        Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.
        Cell Rep. 2012; 1: 2-12
        • Zhao N.
        • Hashida H.
        • Takahashi N.
        • Sakaki Y.
        Cloning and sequence analysis of the human SNAP25 cDNA.
        Gene (in Eng). 1994; 145: 313-314
        • Seagar M.
        • Takahashi M.
        Interactions between presynaptic calcium channels and proteins implicated in synaptic vesicle trafficking and exocytosis.
        J Bioenerg Biomembr (in Eng). 1998; 30: 347-356
        • Sheng Z.H.
        • Rettig J.
        • Cook T.
        • Catterall W.A.
        Calcium-dependent interaction of N-type calcium channels with the synaptic core complex.
        Nature (in Eng). 1996; 379: 451-454
        • Verderio C.
        • Pozzi D.
        • Pravettoni E.
        • Inverardi F.
        • Schenk U.
        • Coco S.
        • et al.
        SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization.
        Neuron (in Eng). 2004; 41: 599-610