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Benign Familial Infantile Seizures and Paroxysmal CORRESPONDENCE als with isolated BFIS, 6 patients with pure PKD, 3 with RESEARCH LETTER both BFIS and PKD, and 1 nonmanifesting carrier (Figure). Genotyping of these pedigrees showed 4 in- dependent haplotypes, suggesting that this mutation arose from recurrent mutational events. Two Faces of the Same Coin: These results confirm that PRRT2 mutations cause PKD Benign Familial Infantile Seizures and ICPC in multi-ethnic populations including Ger- and Paroxysmal Kinesigenic Dyskinesia man, Turkish, and Russian. Most importantly, they pro- Caused by PRRT2 Mutations vide further evidence that the 2 apparently clinically dis- tinct syndromes of BFIS and PKD can be allelic conditions, huzo Kure, the first to describe paroxysmal ki- and they can both be caused by the same mutation in nesigenic dyskinesia (PKD) in a Japanese jour- PRRT2. nal in 1892,1 would have been pleased to learn There has been debate about whether paroxysmal dys- S 1,4 that the gene for this condition has now been identi- kinesias have an epileptic origin. It is notable that in fied.2,3 Paroxysmal kinesigenic dyskinesia is the most com- PKD, ictal and interictal changes are typically absent on mon paroxysmal movement disorder, presenting with electroencephalogram.1,4 However, the confirmation that brief episodes of dystonic, choreatic, or ballistic, and some- PKD and BFIS can have a shared genetic cause lends sup- times bizarre, involuntary movements triggered by sud- port to the concept that the pathophysiological mecha- den movement with onset in childhood or adoles- nism underlying PKD may be subcortical epileptogenic cence.4 Owing to its unusual semiology, PKD is often discharges, possibly originating from the basal ganglia. misdiagnosed as a psychogenic disorder. However, it is The molecular pathway may involve synaptic regula- easily treatable with low doses of anticonvulsants.4 No- tion via interactions with the SNAP25 protein, ulti- tably, PKD has been clinically and genetically linked to mately leading to neuronal hyperexcitability.6 a variety of heterogeneous and, at first sight, unrelated These findings are of interest to a broad range of cli- conditions. This includes benign familial infantile sei- nicians who may encounter patients presenting with in- zures (BFIS); the syndrome of rolandic epilepsy, parox- fantile convulsions or PKD. Paroxysmal kinesigenic dys- ysmal exercise–induced dyskinesia, and writer’s cramp; kinesia should be suspected in families with a child with and even the trait of wet ear wax (cerumen).1,4 Indeed, BFIS and vice versa. There is now evidence to suggest the co-occurrence of BFIS and PKD in families has re- that a simple genetic test (sequencing of the small PRRT2 sulted in the identification of another illness, infantile con- gene) may replace laborious and expensive diagnostic in- vulsions and paroxysmal choreo-athetosis (ICPC).1,4 vestigations in these patients. The finding of PRRT2 mu- Benign familial infantile seizures may be one of the most tations in families with isolated BFIS without co- common forms of epilepsy that develop in the first 2 years occurring PKD has been a recent development, further of life and is characterized by nonfebrile convulsions with expanding the phenotypic spectrum.7 onset at between 3 and 12 months of age.5 Seizures are fo- cal, with or without secondary generalization, occurring Alexander Schmidt, MD in clusters and often resulting in cyanosis. The disorder Kishore R. Kumar, MBBS, FRACP leads to considerable anxiety among parents and doctors Katharina Redyk, MD who are unfamiliar with it, but it also responds reliably to Anne Gru¨newald, PhD carbamazepine and has a benign prognosis.5 Matthias Leben, MD Mutations in the proline-rich transmembrane pro- Alexander Mu¨nchau, MD tein 2 (PRRT2) gene, which is located within the previ- Carolyn M. Sue, MBBS, FRACP, PhD ously linked region on chromosome 16, have been iden- Johann Hagenah, MD tified as the cause of PKD and ICPC.2,3,6 Hans Hartmann, MD We screened the entire PRRT2 gene for mutations in Katja Lohmann, PhD 3 families with ICPC and 1 family with PKD—3 of Ger- Hans-Ju¨rgen Christen, MD man and 1 of Turkish-Russian descent. Neuropediatri- Christine Klein, MD cians reviewed the patients, and the diagnoses of PKD and BFIS were based on established criteria.4,5 All af- Accepted for Publication: February 1, 2012. fected members had typical features of PKD and/or BFIS Author Affiliations: Section of Clinical and Molecular and were identified with the previously reported hetero- Neurogenetics, Department of Neurology, University of zygous truncating c.649dupC (p.R217PX8) muta- Lu¨ beck, Lu¨ beck, (Drs Schmidt, Kumar, Redyk, tion.2,3,6 Notably, this mutation was found in 3 individu- Gru¨ newald, Hagenah, Lohmann, and Klein), Children’s ARCH NEUROL / VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM 668 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A B Control C C C C G A G T L-5826 C C C C S R R K c.649duplC L-5826 L-6120 L-6191 na/10/52 L-5827 na/8/61 L-6119 na/9/46 D16S403 8 3 3 4 8 2 2 6 8 6 D16S769 2 3 3 3 1 3 4 2 1 2 D16S3093 6 6 6 5 1 1 6 6 1 2 D16S3022 2 2 2 2 1 2 3 2 1 6 PRRT2 m w w w m w w w m w D16S3396 4 4 1 5 1 5 8 2 1 5 D16S2623 5 3 4 3 5 5 5 5 5 5 D16S419 9 5 12 8 10 3 3 4 10 3 D16S3253 4 5 6 4 5 5 3 5 5 5 D16S2624 3 3 2 3 3 3 2 4 3 4 L-5828 L-5825 L-5829 L-6121 8/9/20 8/na/7 8/6/7 5/9/27 3 3 8 4 8 4 8 2 2 3 2 3 2 3 1 4 6 5 6 5 6 5 1 6 2 2 2 2 2 2 1 3 m w m w m w m w 4 1 4 5 4 1 1 8 5 4 5 3 5 4 5 5 9 12 9 8 9 12 10 4 4 6 4 4 4 6 5 5 3 2 3 3 3 2 3 4 C D L-1906 na/9/76 3 8 2 1 L-5929 L-5932 2 4 1 2 m w 1 3 L-1864 3 6 7 7 5 6 na/12/50 3 4 2 1 4 10 5 2 6 2 4 5 2 1 2 4 2 3 w w m w 3 6 1 1 4 5 2 3 2 3 5 4 2 1 4 11 9 14 1 1 5 3 5 5 m w 2 4 3 3 1 4 5 5 4 9 4 6 L-5930 L-5931 L-5928 2 2 4/na/7 4/na/6 na/11/13 Control C C C C G A G T 7 3 7 3 7 4 L-5930 2 3 2 3 2 3 C C C C S R R K 6 5 6 5 6 6 2 2 2 2 2 2 BFIS m w m w m w PKD c.649duplC 4 1 4 1 4 5 5 2 5 2 5 5 9 4 9 4 9 8 5 5 5 5 5 6 3 2 3 2 3 3 Figure. Pedigrees of families with benign familial infantile seizures (BFIS) and paroxysmal kinesigenic dyskinesia (PKD) in families of German origin (A, B, and D) and Turkish-Russian descent (C). Examples of electropherograms illustrating the heterozygous c.649duplC mutation (m) in 1 patient with isolated BFIS and 1 with PKD are given in the inserts. As comparison, a wild-type sequence (w) of a control individual is shown. Circles indicate females; squares, males; and dot mark, an unaffected carrier. The mutant allele is indicated by a line adjacent to the haplotype. Patients with an L-code have been genetically tested and neurologically examined. In patients with an L-code, diagnosis was based on history by family members. The following items are listed directly beneath each L-code: age at onset for BFIS (months)/age at onset for PKD (years)/current age (years). Hospital, Salzgitter (Drs Redyk and Leben), Depart- ric Kidney, Liver, and Metabolic Diseases, Hanover ment of Neurology, University Medical Center Hamburg- Medical School, (Dr Hartmann) and Children’s Hospi- Eppendorf, Hamburg (Dr Mu¨ nchau); Clinic for Pediat- tal Auf der Bult, Hanover (Dr Christen), Germany; and ARCH NEUROL / VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM 669 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Department of Neurogenetics, Kolling Institute of Medi- 1. Kato N, Sadamatsu M, Kikuchi T, Niikawa N, Fukuyama Y. Paroxysmal ki- nesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with cal Research, Royal North Shore Hospital and Univer- benign familial infantile convulsions. Epilepsy Res. 2006;70(suppl 1):S174- sity of Sydney, Sydney, Australia (Drs Kumar and Sue). S184. Correspondence: Dr Klein, Department of Neurology, 2. Wang JL, Cao L, Li XH, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain. 2011;134(pt 12):3493-3501. University of Lu¨ beck, Ratzeburger Allee 160, Lu¨ beck, 3. Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mu- 23538, Germany ([email protected] tations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011;43(12):1252-1255. .de). 4. Bhatia KP.
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