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Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders

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Abstract

Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.

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References

  1. Juberg RC, Hellman CD (1971) A new familial form of convulsive disorder and mental retardation limited to females. J Pediatr 79:726–732

    Article  PubMed  CAS  Google Scholar 

  2. Fabisiak K, Erickson RP (1990) A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin Genet 38:353–358

    Article  PubMed  CAS  Google Scholar 

  3. Ryan SG, Chance PF, Zou CH, Spinner NB, Golden JA, Smietana S (1997) Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nat Genet 17:92–95

    Article  PubMed  CAS  Google Scholar 

  4. Scheffer IE, Turner SJ, Dibbens LM, Bayly MA, Friend K, Hodgson B, Burrows L, Shaw M, Wei C, Ullmann R, Ropers HH, Szepetowski P, Haan E, Mazarib A, Afawi Z, Neufeld MY, Andrews PI, Wallace G, Kivity S, Lev D, Lerman-Sagie T, Derry CP, Korczyn AD, Gecz J, Mulley JC, Berkovic SF (2008) Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain 131:918–927

    Article  PubMed  Google Scholar 

  5. Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens C, O’Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones D, Lee R, Madison M, Mironenko T, Varian J, West S, Widaa S, Wray P, Teague J, Dicks E, Butler A, Menzies A, Jenkinson A, Shepherd R, Gusella JF, Afawi Z, Mazarib A, Neufeld MY, Kivity S, Lev D, Lerman-Sagie T, Korczyn AD, Derry CP, Sutherland GR, Friend K, Shaw M, Corbett M, Kim HG, Geschwind DH, Thomas P, Haan E, Ryan S, McKee S, Berkovic SF, Futreal PA, Stratton MR, Mulley JC, Gécz J (2008) X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 40:776–781

    Article  PubMed  CAS  Google Scholar 

  6. Depienne C, Bouteiller D, Keren B, Cheuret E, Poirier K, Trouillard O, Benyahia B, Quelin C, Carpentier W, Julia S, Afenjar A, Gautier A, Rivier F, Meyer S, Berquin P, Hélias M, Py I, Rivera S, Bahi-Buisson N, Gourfinkel-An I, Cazeneuve C, Ruberg M, Brice A, Nabbout R, Leguern E (2009) Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet 2:e1000381

    Article  Google Scholar 

  7. Hynes K, Tarpey P, Dibbens LM, Bayly MA, Berkovic SF, Smith R, Raisi ZA, Turner SJ, Brown NJ, Desai TD, Haan E, Turner G, Christodoulou J, Leonard H, Gill D, Stratton MR, Gecz J, Scheffer IE (2010) Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet 47:211–216

    Article  PubMed  CAS  Google Scholar 

  8. Marini C, Mei D, Parmeggiani L, Norci V, Calado E, Ferrari A, Moreira A, Pisano T, Specchio N, Vigevano F, Battaglia D, Guerrini R (2010) Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology 75:646–653

    Article  PubMed  CAS  Google Scholar 

  9. Jamal SM, Basran RK, Newton S, Wang Z, Milunsky JM (2010) Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome. Am J Med Genet A 152A:2475–2481

    Article  PubMed  CAS  Google Scholar 

  10. Depienne C, Trouillard O, Bouteiller D, Gourfinkel-An I, Poirier K, Rivier F, Berquin P, Nabbout R, Chaigne D, Steschenko D, Gautier A, Hoffman-Zacharska D, Lannuzel A, Lackmy-Port-Lis M, Maurey H, Dusser A, Bru M, Gilbert-Dussardier B, Roubertie A, Kaminska A, Whalen S, Mignot C, Baulac S, Lesca G, Arzimanoglou A, LeGuern E (2011) Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum Mutat 32:E1959–E1975

    Article  PubMed  CAS  Google Scholar 

  11. Dibbens LM, Kneen R, Bayly MA, Heron SE, Arsov T, Damiano JA, Desai T, Gibbs J, McKenzie F, Mulley JC, Ronan A, Scheffer IE (2011) Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations. Neurology 76:1514–1519

    Article  PubMed  CAS  Google Scholar 

  12. Specchio N, Marini C, Terracciano A, Mei D, Trivisano M, Sicca F, Fusco L, Cusmai R, Darra F, Bernardina BD, Bertini E, Guerrini R, Vigevano F (2011) Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations. Epilepsia 52:1251–1257

    Article  PubMed  CAS  Google Scholar 

  13. Specchio N, Fusco L, Vigevano F (2011) Acute-onset epilepsy triggered by fever mimicking FIRES (febrile infection-related epilepsy syndrome): the role of protocadherin 19 (PCDH19) gene mutation. Epilepsia 52:e172–e175

    Article  PubMed  CAS  Google Scholar 

  14. Higurashi N, Shi X, Yasumoto S, Oguni H, Sakauchi M, Itomi K, Miyamoto A, Shiraishi H, Kato T, Makita Y, Hirose S (2012) PCDH19 mutation in Japanese females with epilepsy. Epilepsy Res 99:28–37

    Article  PubMed  CAS  Google Scholar 

  15. Vincent AK, Noor A, Janson A, Minassian BA, Ayub M, Vincent JB, Morel CF (2011) Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures. Clin Genet 82:540–545

    Google Scholar 

  16. Camacho A, Simón R, Sanz R, Viñuela A, Martínez-Salio A, Mateos F (2012) Cognitive and behavioral profile in females with epilepsy with PCDH19 mutation: two novel mutations and review of the literature. Epilepsy Behav 24:134–137

    Article  PubMed  Google Scholar 

  17. Depienne C, Leguern E (2012) PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat 33:627–634

    Article  PubMed  CAS  Google Scholar 

  18. Dimova PS, Kirov A, Todorova A, Todorov T, Mitev V (2012) A novel PCDH19 mutation inherited from an unaffected mother. Pediatr Neurol 46:397–400

    Article  PubMed  Google Scholar 

  19. Kwong AK, Fung CW, Chan SY, Wong VC (2012) Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome. PloS One 7:e41802. doi:10.1371/journal.pone.0041802

  20. Marini C, Darra F, Specchio N, Mei D, Terracciano A, Parmeggiani L, Ferrari A, Sicca F, Mastrangelo M, Spaccini L, Canopoli ML, Cesaroni E, Zamponi N, Caffi L, Ricciardelli P, Grosso S, Pisano T, Canevini MP, Granata T, Accorsi P, Battaglia D, Cusmai R, Vigevano F, Bernardina BD, Guerrini R (2012) Focal seizures with affective symptoms are a major feature of PCDH10 gene-related epilepsy. Epilepsia 53:2111–2119. doi:10.1111/j.1528-1167.2012.03649.x

  21. Terracciano A, Specchio N, Darra F, Sferra A, Bernardina BD, Vigevano F, Bertini E (2012) Somatic mosaicism of PCDH10 mutation in a family with low-penetrance EFMR. Neurogenetics 13:341–345

    Article  PubMed  CAS  Google Scholar 

  22. Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864

    Article  PubMed  CAS  Google Scholar 

  23. Claes L, Ceulemans B, Audenaert D, Smets K, Lofgren A, Del-Favero J, Ala-Mello S, Basel-Vanagaite L, Plecko B, Raskin S, Thiry P, Wolf NI, Van Broeckhoven C, De Jonghe P (2003) De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum Mutat 21:615–621

    Article  PubMed  CAS  Google Scholar 

  24. Wolff M, Casse-Perrot C, Dravet C (2006) Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Epilepsia 47(Suppl 2):45–48

    Article  PubMed  Google Scholar 

  25. Genton P, Velizarova R, Dravet C (2011) Dravet syndrome: the long-term outcome. Epilepsia 52(Suppl 2):44–49

    Article  PubMed  Google Scholar 

  26. Catarino CB, Liu JY, Liagkouras I, Gibbons VS, Labrum RW, Ellis R, Woodward C, Davis MB, Smith SJ, Cross JH, Appleton RE, Yendle SC, McMahon JM, Bellows ST, Jacques TS, Zuberi SM, Koepp MJ, Martinian L, Scheffer IE, Thom M, Sisodiya SM (2011) Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 134:2982–3010

    Article  PubMed  Google Scholar 

  27. Petrelli C, Passamonti C, Cesaroni E, Mei D, Guerrini R, Zamponi N, Provinciali L (2012) Early clinical features in Dravet syndrome patients with and without SCN1A mutations. Epilepsy Res 99:21–27

    Article  PubMed  CAS  Google Scholar 

  28. Wakai S, Ito N, Sueoka H, Kawamoto Y, Hayasaka H, Chiba S (1996) Severe myoclonic epilepsy in infancy and carbamazepine. Eur J Pediatr 155:724

    Article  PubMed  CAS  Google Scholar 

  29. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O (1998) Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39:508–512

    Article  PubMed  CAS  Google Scholar 

  30. Lindhout D (2008) Somatic mosaicism as a basic epileptogenic mechanism? Brain 131:900–901

    Article  PubMed  Google Scholar 

  31. Piton A, Gauthier J, Hamdan FF, Lafrenière RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Côté M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Rivière JB, Tarabeux J, Cossette P, Krebs MO, Rapoport JL, Addington A, Delisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA (2011) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16:867–880

    Article  PubMed  CAS  Google Scholar 

  32. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O’Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41:535–543

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the patients and their family members for their cooperation and participation in this study. We also thank the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) for the genetic analyses. The research is supported by the Fund for Scientific Research Flanders (FWO), Methusalem excellence grant of the Flemish Government, University of Antwerp, the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office, the Eurocores program EuroEPINOMICS of the European Science Foundation. A.S. is a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB, Utrecht, the Netherlands

    J. J. T. van Harssel, M. J. A. van Kempen, N. E. Verbeek, C. G. F. de Kovel, D. Lindhout, B. P. C. Koeleman & E. H. Brilstra

  2. Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium

    S. Weckhuysen, K. Hardies, P. De Jonghe & A. Suls

  3. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    S. Weckhuysen, K. Hardies, P. De Jonghe & A. Suls

  4. Epilepsy Center Kempenhaeghe, Oosterhout, the Netherlands

    S. Weckhuysen

  5. The Epilepsy Institutes of the Netherlands Foundation (SEIN), Zwolle, the Netherlands

    W. B. Gunning

  6. Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands

    E. van Daalen & M. V. de Jonge

  7. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium

    A. C. Jansen

  8. Department of Public Health, Vrije Universiteit Brussel, Brussels, Belgium

    A. C. Jansen

  9. Department of Pediatric Neurology, VU University Medical Center, Amsterdam, the Netherlands

    R. J. Vermeulen

  10. Department of Neurology, Erasmus Medical Center—Sophia Children’s Hospital, Rotterdam, the Netherlands

    W. F. M. Arts

  11. Division of Pediatric Neurology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium

    H. Verhelst

  12. Epilepsy Center, Bethesda Children’s Hospital, Budapest, Hungary

    A. Fogarasi

  13. Department of Neurology, Amphia Hospital, Breda, the Netherlands

    J. F. de Rijk-van Andel

  14. Epilepsy Center, National Institute of Neurosciences, Budapest, Hungary

    A. Kelemen

  15. SEIN—Epilepsy Institutes in the Netherlands Foundation, Hoofddorp, the Netherlands

    D. Lindhout

  16. Division of Neurology, Antwerp University Hospital, Antwerp, Belgium

    P. De Jonghe

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  1. J. J. T. van Harssel
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  2. S. Weckhuysen
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  6. C. G. F. de Kovel
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  8. E. van Daalen
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  15. J. F. de Rijk-van Andel
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  17. D. Lindhout
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  18. P. De Jonghe
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  19. B. P. C. Koeleman
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  20. A. Suls
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  21. E. H. Brilstra
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Correspondence to E. H. Brilstra.

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van Harssel, J.J.T., Weckhuysen, S., van Kempen, M.J.A. et al. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. Neurogenetics 14, 23–34 (2013). https://doi.org/10.1007/s10048-013-0353-1

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  • DOI: https://doi.org/10.1007/s10048-013-0353-1

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