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

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 kinesigenic 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. Paroxysmal dyskinesias. Mov Disord. 2011;26(6):1157-1165. Author Contributions: Study concept and design: Schmidt, 5. Caraballo R, Pavek S, Lemainque A, et al. Linkage of benign familial infantile Lohmann, Christen, and Klein. Acquisition of data: convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet. 2001;68(3):788- Schmidt, Kumar, Redyk, Leben, Mu¨ nchau, Hagenah, 794. Lohmann, Christen, and Klein. Analysis and interpreta- 6. Lee H-Y, Huang Y, Bruneau N, et al. Mutations in the gene PRRT2 cause par- tion of data: Schmidt, Kumar, Gru¨ newald, Leben, Mu¨ nchau, oxysmal kinesigenic dyskinesia with infantile convulsions. Cell. 2012;1(1): 2. doi:10.1016/j.celrep.2011.1011.1001. Sue, Hans, Lohmann, Christen, and Klein. Drafting of the 7. Heron SE, Grinton BE, Kivity S, et al. PRRT2 mutations cause benign familial manuscript: Schmidt, Kumar, Gru¨ newald, and Sue. Criti- infantile epilepsy and infantile convulsions with choreoathetosis syndrome. cal revision of the manuscript for important intellectual Am J Hum Genet. 2012;90(1):152-160. content: Schmidt, Kumar, Redyk, Gru¨ newald, Leben, Mu¨ nchau, Sue, Hagenah, Hans, Lohmann, Christen, and Klein. Obtained funding: Klein. Administrative, technical, COMMENTS AND OPINIONS and material support: Mu¨ nchau, Sue, Hans, and Klein. Study supervision: Schmidt, Gru¨ newald, Lohmann, and Klein. Financial Disclosure: Dr Schmidt receives research sup- Insulin and Alzheimer Disease port from the medical faculty of the University of Lu¨- beck. Dr Kumar’s work is supported by a National Health he article by Craft et al1 demonstrating that in- and Medical Research Council postgraduate scholar- tranasal insulin improves cognitive function and ship. Dr Gru¨ newald has received research support from T fludeoxyglucose F 18 uptake in specific regions the medical faculty of the University of Lu¨ beck, the of the brain in patients with mild cognitive impairment Deutsche Forschungsgemeinschaft, and the Dystonia and Alzheimer disease (AD) is a landmark study. For the Medical Research Foundation. She was also awarded travel first time, the previous data that AD is both a reflection grants from the GlaxoSmithKline Foundation, the Boeh- of a combination of diminished insulin bio-availability ringer Ingelheim Foundation, and the German Aca- and insulin action has been borne out. In addition, the demic Exchange Service. Dr Mu¨ nchau has received com- data are consistent with the fact that AD is a chronic in- mercial research support by Allergan, Ipsen, and Merz flammatory disease and that insulin exerts a potent anti- Pharmaceuticals, as well as honoraria for lectures from inflammatory effect.2 Allergan. He has also received research support from the More recently, it has also been shown that insulin sup- Dystonia Medical Research Foundation (USA), the To- presses the expression of genes related to AD: amyloid urette Society (Germany), and the Deutsche Forschun- precursor protein, presenilins 1 and 2, and glycogen syn- gsgemeinschaft (MU1692/2-2). Dr Sue has received re- thase kinase-3␤ in peripheral blood mononuclear cells.3 search support from the Australian Brain Foundation. Dr These actions could potentially limit the formation of Hagenah receives research support from the Bachmann- ␤-amyloid and the intracellular neurofibrillary tangles. Strauss Dystonia and Parkinson Disease Foundation and While these observations were not made in neurons, has received honoraria as an invited speaker from they were obtained in humans in vivo with doses and GlaxoSmithKline. Dr Lohmann receives research sup- concentrations of insulin that are therapeutically rel- port from the German Research Foundation and the Bach- evant. It is possible that intranasally administered insu- mann-Strauss Dystonia and Parkinson’s Disease Foun- lin achieves sufficiently high intracerebral concentra- dation. Dr Klein is a member of the editorial board of tions of insulin to suppress the expression of the genes Neurology and has served as faculty at the Annual Meet- just mentioned. ings of the American Academy of Neurology since 2004. In this context, it is also relevant that the amyloid pre- She has received consulting fees from Boehringer Ingel- cursor protein has recently been shown to be expressed heim and Centogene as well as honoraria for speaking in vascular tissue where it may, along with ␤-amyloid, engagements from Boehringer Ingelheim and Merz exert pro-inflammatory and potential pro-atherogenic ef- Pharma. Dr Klein is also the recipient of a career devel- fects. Thus, the effects of insulin are relevant both at the opment award from the Hermann and Lilly Schilling cerebral and vascular levels. Foundation. Her work is funded by the Deutsche Forsc- Clearly, larger long-term studies are required to es- hungsgemeinschaft, the Possehl Foundation, and the tablish the use of intranasal insulin in the treatment of Bachmann-Strauss Dystonia and Parkinson’s Disease AD. Additionally, specific biomarkers are readily obtain- Foundation, and she has received institutional support able samples and easy to measure, and those that are highly from the University of Lu¨ beck for genetics research. responsive to therapy are clearly needed. However, it is Conflicts of Interest: The authors report no conflicts of clear that a door has been opened for the rational treat- interest related to the research in this article. ment of this hitherto almost untreatable disease with a Additional Contributions: We thank the patients and fam- drug that has practically no adverse effects other than hy- ily members for their participation in the study. poglycemia. This effect can be avoided by its intranasal

ARCH NEUROL / VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM 670