Molecular Neurobiology

, Volume 49, Issue 3, pp 1166–1180 | Cite as

Genetics, Molecular Biology, and Phenotypes of X-Linked Epilepsy

  • Hao DengEmail author
  • Wen Zheng
  • Zhi Song


Epilepsy is a common and diverse set of chronic neurological disorders characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Environmental factors and acquired disposition are proposed to play a role to the pathogenesis of epilepsy. Genetic factors are important contributors as well. Comparing to the phenotype of epilepsy caused by mutation of single gene on an autosome, the phenotype of X-linked epilepsy is more complex. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy, and the variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the type of genetic mutation, methylation, X chromosome random inactivation, and mosaic distribution. As a result, it is difficult to establish the genotype–phenotype correlation, diagnostic tests, and genetic counseling. In this review, we provide an overview of the X-linked epilepsy including responsible loci and genes, the molecular biology, the associated complex phenotypes, and the interference factors. This information may provide us a better understanding of the pathogenesis of X-linked epilepsy and may contribute to clinical diagnosis and therapy of epilepsy.


Genetics Molecular biology Phenotypes Seizure X-linked epilepsy 



The cyclin-dependent kinase-like 5 gene


The aristaless-related homeobox X-linked gene


The ATPase H+ transporting lysosomal accessory peotein 2 gene


The synapsin 1 gene


The Rho guanine nucleotide exchange factor 9 gene


The protocadherin 19 gene


The sushi-repeat protein X-linked 2 gene


The solute carrier family 9 member 6 gene


The methyl-CpG-binding protein 2 gene


The Ras-associated protein gene


The doublecortin gene


X-linked infantile spasm


Rett syndrome


X-linked lissencephaly with ambiguous genitalia


Hydranencephaly with abnormal genitalia


X-linked mental retardation


Partington syndrome


X-linked myoclonic epilepsy with spasticity and intellectual development


Early infantile epileptic encephalopathy


X-linked subcortical laminar heterotopia and lissencephaly syndrome



This work was funded by the National Natural Science Foundation of China [81271921, 81101339 and 30971534]; the Sheng Hua Scholars Program of Central South University, China (H.D.); the Research Fund for the Doctoral Program of Higher Education of China [20110162110026]; and the Natural Science Foundation of Hunan Province, China (10JJ5029).

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Poduri A, Lowenstein D (2011) Epilepsy genetics—past, present, and future. Curr Opin Genet Dev 21:325–332PubMedGoogle Scholar
  2. 2.
    Zupanc ML (2009) Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood. J Child Neurol 24:6S–14SPubMedGoogle Scholar
  3. 3.
    Galanopoulou AS, Moshe SL (2009) The epileptic hypothesis: developmentally related arguments based on animal models. Epilepsia 50(Suppl 7):37–42PubMedCentralPubMedGoogle Scholar
  4. 4.
    Kalscheuer VM, Tao J, Donnelly A, Hollway G, Schwinger E, Kubart S, Menzel C, Hoeltzenbein M, Tommerup N, Eyre H, Harbord M, Haan E, Sutherland GR, Ropers HH, Gecz J (2003) Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet 72:1401–1411PubMedCentralPubMedGoogle Scholar
  5. 5.
    Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, Landsberger N (2012) What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural Plast 2012:728267PubMedCentralPubMedGoogle Scholar
  6. 6.
    Williamson SL, Giudici L, Kilstrup-Nielsen C, Gold W, Pelka GJ, Tam PP, Grimm A, Prodi D, Landsberger N, Christodoulou J (2012) A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Hum Genet 131:187–200PubMedGoogle Scholar
  7. 7.
    Castren M, Gaily E, Tengstrom C, Lahdetie J, Archer H, Ala-Mello S (2011) Epilepsy caused by CDKL5 mutations. Eur J Paediatr Neurol 15:65–69PubMedGoogle Scholar
  8. 8.
    Lin C, Franco B, Rosner MR (2005) CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. Hum Mol Genet 14:3775–3786PubMedGoogle Scholar
  9. 9.
    Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N (2008) CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. J Biol Chem 283:30101–30111PubMedCentralPubMedGoogle Scholar
  10. 10.
    Bertani I, Rusconi L, Bolognese F, Forlani G, Conca B, De Monte L, Badaracco G, Landsberger N, Kilstrup-Nielsen C (2006) Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. J Biol Chem 281:32048–32056PubMedGoogle Scholar
  11. 11.
    Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R, Scala E, Longo I, Grosso S, Pescucci C, Ariani F, Hayek G, Balestri P, Bergo A, Badaracco G, Zappella M, Broccoli V, Renieri A, Kilstrup-Nielsen C, Landsberger N (2005) CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet 14:1935–1946PubMedGoogle Scholar
  12. 12.
    Nectoux J, Fichou Y, Cagnard N, Bahi-Buisson N, Nusbaum P, Letourneur F, Chelly J, Bienvenu T (2011) Cell cloning-based transcriptome analysis in cyclin-dependent kinase-like 5 mutation patients with severe epileptic encephalopathy. J Mol Med (Berl) 89:193–202Google Scholar
  13. 13.
    Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183PubMedGoogle Scholar
  14. 14.
    Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V (2009) CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery. Hum Mol Genet 18:4590–4602PubMedGoogle Scholar
  15. 15.
    Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, Evans J, Clarke A, Pelka GJ, Tam PP, Watson C, Lahooti H, Ellaway CJ, Bennetts B, Leonard H, Gecz J (2004) Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 75:1079–1093PubMedCentralPubMedGoogle Scholar
  16. 16.
    Bartnik M, Derwinska K, Gos M, Obersztyn E, Kolodziejska KE, Erez A, Szpecht-Potocka A, Fang P, Terczynska I, Mierzewska H, Lohr NJ, Bellus GA, Reimschisel T, Bocian E, Mazurczak T, Cheung SW, Stankiewicz P (2011) Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females. Genet Med 13:447–452PubMedGoogle Scholar
  17. 17.
    Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, Delobel B, Layet V, N'Guyen MA, Saunier A, Verneau F, Jonveaux P, Philippe C (2009) Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature. Clin Genet 76:357–371PubMedGoogle Scholar
  18. 18.
    Stalpers XL, Spruijt L, Yntema HG, Verrips A (2012) Clinical phenotype of 5 females with a CDKL5 mutation. J Child Neurol 27:90–93PubMedGoogle Scholar
  19. 19.
    Liang JS, Shimojima K, Takayama R, Natsume J, Shichiji M, Hirasawa K, Imai K, Okanishi T, Mizuno S, Okumura A, Sugawara M, Ito T, Ikeda H, Takahashi Y, Oguni H, Imai K, Osawa M, Yamamoto T (2011) CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 52:1835–1842PubMedGoogle Scholar
  20. 20.
    Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gerard M, Giuliano F, Motte J, Heron D, Morel MA, Plouin P, Richelme C, des Portes V, Dulac O, Philippe C, Chiron C, Nabbout R, Bienvenu T (2008) The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 49:1027–1037PubMedGoogle Scholar
  21. 21.
    Evans JC, Archer HL, Colley JP, Ravn K, Nielsen JB, Kerr A, Williams E, Christodoulou J, Gecz J, Jardine PE, Wright MJ, Pilz DT, Lazarou L, Cooper DN, Sampson JR, Butler R, Whatley SD, Clarke AJ (2005) Early onset seizures and Rett-like features associated with mutations in CDKL5. Eur J Hum Genet 13:1113–1120PubMedGoogle Scholar
  22. 22.
    Bruyere H, Lewis S, Wood S, MacLeod PJ, Langlois S (1999) Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1. Clin Genet 55:173–181PubMedGoogle Scholar
  23. 23.
    Stromme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lutcherath V, Gedeon AK, Wallace RH, Scheffer IE, Turner G, Partington M, Frints SG, Fryns JP, Sutherland GR, Mulley JC, Gecz J (2002) Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 30:441–445PubMedGoogle Scholar
  24. 24.
    Shoubridge C, Tan MH, Seiboth G, Gecz J (2012) ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Hum Mol Genet 21:1639–1647PubMedGoogle Scholar
  25. 25.
    Cho G, Nasrallah MP, Lim Y, Golden JA (2012) Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. Neurogenetics 13:23–29PubMedCentralPubMedGoogle Scholar
  26. 26.
    Gecz J, Cloosterman D, Partington M (2006) ARX: a gene for all seasons. Curr Opin Genet Dev 16:308–316PubMedGoogle Scholar
  27. 27.
    Depienne C, Gourfinkel-An I, Baulac S, LeGuern E (2012) Genes in infantile epileptic encephalopathies. In: Noebels JL, Avoli M, Rogawski MA, et al. (eds). Jasper's basic mechanisms of the epilepsies, 4th edition. National Center for Biotechnology Information: Bethesda, MDGoogle Scholar
  28. 28.
    Claes S, Devriendt K, Lagae L, Ceulemans B, Dom L, Casaer P, Raeymaekers P, Cassiman JJ, Fryns JP (1997) The X-linked infantile spasms syndrome (MIM 308350) maps to Xp11.4-Xpter in two pedigrees. Ann Neurol 42:360–364PubMedGoogle Scholar
  29. 29.
    Shoubridge C, Fullston T, Gecz J (2010) ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat 31:889–900PubMedGoogle Scholar
  30. 30.
    Pavone P, Spalice A, Polizzi A, Parisi P, Ruggieri M (2012) Ohtahara syndrome with emphasis on recent genetic discovery. Brain Dev 34:459–468PubMedGoogle Scholar
  31. 31.
    Marsh ED, Golden JA (2012) Developing models of Aristaless-related homeobox mutations. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds). Jasper's basic mechanisms of the epilepsies, 4th edition. National Center for Biotechnology Information: Bethesda, MDGoogle Scholar
  32. 32.
    Kato M, Das S, Petras K, Kitamura K, Morohashi K, Abuelo DN, Barr M, Bonneau D, Brady AF, Carpenter NJ, Cipero KL, Frisone F, Fukuda T, Guerrini R, Iida E, Itoh M, Lewanda AF, Nanba Y, Oka A, Proud VK, Saugier-Veber P, Schelley SL, Selicorni A, Shaner R, Silengo M, Stewart F, Sugiyama N, Toyama J, Toutain A, Vargas AL, Yanazawa M, Zackai EH, Dobyns WB (2004) Mutations of ARX are associated with striking pleiotropy and consistent genotype–phenotype correlation. Hum Mutat 23:147–159PubMedGoogle Scholar
  33. 33.
    Marsh E, Fulp C, Gomez E, Nasrallah I, Minarcik J, Sudi J, Christian SL, Mancini G, Labosky P, Dobyns W, Brooks-Kayal A, Golden JA (2009) Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. Brain 132:1563–1576PubMedCentralPubMedGoogle Scholar
  34. 34.
    Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, Omichi K, Suzuki R, Kato-Fukui Y, Kamiirisa K, Matsuo M, Kamijo S, Kasahara M, Yoshioka H, Ogata T, Fukuda T, Kondo I, Kato M, Dobyns WB, Yokoyama M, Morohashi K (2002) Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32:359–369PubMedGoogle Scholar
  35. 35.
    Albrecht A, Mundlos S (2005) The other trinucleotide repeat: polyalanine expansion disorders. Curr Opin Genet Dev 15:285–293PubMedGoogle Scholar
  36. 36.
    Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, Ben JL, Zemni R, Vinet MC, Francis F, Couvert P, Gomot M, Moraine C, van Bokhoven H, Kalscheuer V, Frints S, Gecz J, Ohzaki K, Chaabouni H, Fryns JP, Desportes V, Beldjord C, Chelly J (2002) ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 11:981–991PubMedGoogle Scholar
  37. 37.
    Colombo E, Galli R, Cossu G, Gecz J, Broccoli V (2004) Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons. Dev Dyn 231:631–639PubMedGoogle Scholar
  38. 38.
    Friocourt G, Kanatani S, Tabata H, Yozu M, Takahashi T, Antypa M, Raguenes O, Chelly J, Ferec C, Nakajima K, Parnavelas JG (2008) Cell-autonomous roles of ARX in cell proliferation and neuronal migration during corticogenesis. J Neurosci 28:5794–5805PubMedGoogle Scholar
  39. 39.
    Colombo E, Collombat P, Colasante G, Bianchi M, Long J, Mansouri A, Rubenstein JL, Broccoli V (2007) Inactivation of Arx, the murine ortholog of the X-linked lissencephaly with ambiguous genitalia gene, leads to severe disorganization of the ventral telencephalon with impaired neuronal migration and differentiation. J Neurosci 27:4786–4798PubMedGoogle Scholar
  40. 40.
    Colasante G, Collombat P, Raimondi V, Bonanomi D, Ferrai C, Maira M, Yoshikawa K, Mansouri A, Valtorta F, Rubenstein JL, Broccoli V (2008) Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons. J Neurosci 28:10674–10686PubMedCentralPubMedGoogle Scholar
  41. 41.
    McKenzie O, Ponte I, Mangelsdorf M, Finnis M, Colasante G, Shoubridge C, Stifani S, Gecz J, Broccoli V (2007) Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. Neuroscience 146:236–247PubMedGoogle Scholar
  42. 42.
    Fulp CT, Cho G, Marsh ED, Nasrallah IM, Labosky PA, Golden JA (2008) Identification of Arx transcriptional targets in the developing basal forebrain. Hum Mol Genet 17:3740–3760PubMedCentralPubMedGoogle Scholar
  43. 43.
    Seufert DW, Prescott NL, El-Hodiri HM (2005) Xenopus aristaless-related homeobox (xARX) gene product functions as both a transcriptional activator and repressor in forebrain development. Dev Dyn 232:313–324PubMedGoogle Scholar
  44. 44.
    Kato M, Saitoh S, Kamei A, Shiraishi H, Ueda Y, Akasaka M, Tohyama J, Akasaka N, Hayasaka K (2007) A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am J Hum Genet 81:361–366PubMedCentralPubMedGoogle Scholar
  45. 45.
    Price MG, Yoo JW, Burgess DL, Deng F, Hrachovy RA, Frost JJ, Noebels JL (2009) A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10 + 7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. J Neurosci 29:8752–8763PubMedCentralPubMedGoogle Scholar
  46. 46.
    Kitamura K, Itou Y, Yanazawa M, Ohsawa M, Suzuki-Migishima R, Umeki Y, Hohjoh H, Yanagawa Y, Shinba T, Itoh M, Nakamura K, Goto Y (2009) Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. Hum Mol Genet 18:3708–3724PubMedGoogle Scholar
  47. 47.
    Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, Gruss P (2003) Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 17:2591–2603PubMedCentralPubMedGoogle Scholar
  48. 48.
    Hedera P, Alvarado D, Beydoun A, Fink JK (2002) Novel mental retardation—epilepsy syndrome linked to Xp21.1-p11.4. Ann Neurol 51:45–50PubMedGoogle Scholar
  49. 49.
    Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G, Lubs HA, Engert S, Stevenson RE, Meindl A, Schwartz CE, Nguyen G (2005) A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet 14:1019–1027PubMedGoogle Scholar
  50. 50.
    Garcia CC, Blair HJ, Seager M, Coulthard A, Tennant S, Buddles M, Curtis A, Goodship JA (2004) Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J Med Genet 41:183–186PubMedCentralPubMedGoogle Scholar
  51. 51.
    Sudhof TC (1990) The structure of the human synapsin I gene and protein. J Biol Chem 265:7849–7852PubMedGoogle Scholar
  52. 52.
    Giovedi S, Darchen F, Valtorta F, Greengard P, Benfenati F (2004) Synapsin is a novel Rab3 effector protein on small synaptic vesicles. II. Functional effects of the Rab3A-synapsin I interaction. J Biol Chem 279:43769–43779PubMedGoogle Scholar
  53. 53.
    Chin LS, Li L, Ferreira A, Kosik KS, Greengard P (1995) Impairment of axonal development and of synaptogenesis in hippocampal neurons of synapsin I-deficient mice. Proc Natl Acad Sci U S A 92:9230–9234PubMedCentralPubMedGoogle Scholar
  54. 54.
    Li L, Chin LS, Shupliakov O, Brodin L, Sihra TS, Hvalby O, Jensen V, Zheng D, McNamara JO, Greengard P, Et A (1995) Impairment of synaptic vesicle clustering and of synaptic transmission, and increased seizure propensity, in synapsin I-deficient mice. Proc Natl Acad Sci U S A 92:9235–9239PubMedCentralPubMedGoogle Scholar
  55. 55.
    Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ, Smart TG, Luscher B, Rees MI, Harvey RJ (2004) The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci 24:5816–5826PubMedGoogle Scholar
  56. 56.
    Shimojima K, Sugawara M, Shichiji M, Mukaida S, Takayama R, Imai K, Yamamoto T (2011) Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J Hum Genet 56:561–565PubMedGoogle Scholar
  57. 57.
    Ropers HH (2006) X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev 16:260–269PubMedGoogle Scholar
  58. 58.
    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 17:92–95PubMedGoogle Scholar
  59. 59.
    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, Gecz J (2008) X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 40:776–781PubMedCentralPubMedGoogle Scholar
  60. 60.
    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, Helias 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 5:e1000381PubMedCentralPubMedGoogle Scholar
  61. 61.
    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 47:211–216PubMedGoogle Scholar
  62. 62.
    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 75:646–653PubMedGoogle Scholar
  63. 63.
    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 99:28–37PubMedGoogle Scholar
  64. 64.
    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 76:1514–1519PubMedGoogle Scholar
  65. 65.
    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–E1975PubMedCentralPubMedGoogle Scholar
  66. 66.
    Vanhalst K, Kools P, Staes K, van Roy F, Redies C (2005) delta-Protocadherins: a gene family expressed differentially in the mouse brain. Cell Mol Life Sci 62:1247–1259PubMedGoogle Scholar
  67. 67.
    Kim SY, Chung HS, Sun W, Kim H (2007) Spatiotemporal expression pattern of non-clustered protocadherin family members in the developing rat brain. Neuroscience 147:996–1021PubMedGoogle Scholar
  68. 68.
    Frank M, Kemler R (2002) Protocadherins. Curr Opin Cell Biol 14:557–562PubMedGoogle Scholar
  69. 69.
    Kamien BA, Cardamone M, Lawson JA, Sachdev R (2012) A genetic diagnostic approach to infantile epileptic encephalopathies. J Clin Neurosci 19:934–941PubMedGoogle Scholar
  70. 70.
    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 131:918–927PubMedGoogle Scholar
  71. 71.
    Roll P, Rudolf G, Pereira S, Royer B, Scheffer IE, Massacrier A, Valenti MP, Roeckel-Trevisiol N, Jamali S, Beclin C, Seegmuller C, Metz-Lutz MN, Lemainque A, Delepine M, Caloustian C, de Saint MA, Bruneau N, Depetris D, Mattei MG, Flori E, Robaglia-Schlupp A, Levy N, Neubauer BA, Ravid R, Marescaux C, Berkovic SF, Hirsch E, Lathrop M, Cau P, Szepetowski P (2006) SRPX2 mutations in disorders of language cortex and cognition. Hum Mol Genet 15:1195–1207PubMedGoogle Scholar
  72. 72.
    Kurosawa H, Goi K, Inukai T, Inaba T, Chang KS, Shinjyo T, Rakestraw KM, Naeve CW, Look AT (1999) Two candidate downstream target genes for E2A-HLF. Blood 93:321–332PubMedGoogle Scholar
  73. 73.
    Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Leveque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, Cau P, Szepetowski P (2008) Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum Mol Genet 17:3617–3630PubMedGoogle Scholar
  74. 74.
    des Portes V, Pinard JM, Smadja D, Motte J, Boespflug-Tanguy O, Moutard ML, Desguerre I, Billuart P, Carrie A, Bienvenu T, Vinet MC, Bachner L, Beldjord C, Dulac O, Kahn A, Ponsot G, Chelly J (1997) Dominant X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/LIS): evidence for the occurrence of mutation in males and mapping of a potential locus in Xq22. J Med Genet 34:177–183PubMedCentralPubMedGoogle Scholar
  75. 75.
    Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA (1998) Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92:63–72PubMedGoogle Scholar
  76. 76.
    Aigner L, Uyanik G, Couillard-Despres S, Ploetz S, Wolff G, Morris-Rosendahl D, Martin P, Eckel U, Spranger S, Otte J, Woerle H, Holthausen H, Apheshiotis N, Fluegel D, Winkler J (2003) Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders. Neurology 60:329–332PubMedGoogle Scholar
  77. 77.
    Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N (2008) The location of DCX mutations predicts malformation severity in X-linked lissencephaly. Neurogenetics 9:277–285PubMedGoogle Scholar
  78. 78.
    des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrie A, Gelot A, Dupuis E, Motte J, Berwald-Netter Y, Catala M, Kahn A, Beldjord C, Chelly J (1998) A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92:51–61PubMedGoogle Scholar
  79. 79.
    Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA, Wolf SG, Francis F, Chelly J, Elbaum M, Pietrokovski S, Reiner O (2000) Doublecortin mutations cluster in evolutionarily conserved functional domains. Hum Mol Genet 9:703–712PubMedGoogle Scholar
  80. 80.
    Chou A, Boerkoel C, du Souich C, Rupps R (2009) Phenotypic and molecular characterization of a novel DCX deletion and a review of the literature. Clin Genet 76:214–218PubMedGoogle Scholar
  81. 81.
    Gleeson JG, Minnerath SR, Fox JW, Allen KM, Luo RF, Hong SE, Berg MJ, Kuzniecky R, Reitnauer PJ, Borgatti R, Mira AP, Guerrini R, Holmes GL, Rooney CM, Berkovic S, Scheffer I, Cooper EC, Ricci S, Cusmai R, Crawford TO, Leroy R, Andermann E, Wheless JW, Dobyns WB, Walsh CA, Et A (1999) Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol 45:146–153PubMedGoogle Scholar
  82. 82.
    Poolos NP, Das S, Clark GD, Lardizabal D, Noebels JL, Wyllie E, Dobyns WB (2002) Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX. Neurology 58:1559–1562PubMedGoogle Scholar
  83. 83.
    Sossey-Alaoui K, Hartung AJ, Guerrini R, Manchester DK, Posar A, Puche-Mira A, Andermann E, Dobyns WB, Srivastava AK (1998) Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2 + -dependent signaling protein which is mutated in human X-linked neuronal migration defects. Hum Mol Genet 7:1327–1332PubMedGoogle Scholar
  84. 84.
    Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23:257–271PubMedGoogle Scholar
  85. 85.
    Caspi M, Atlas R, Kantor A, Sapir T, Reiner O (2000) Interaction between LIS1 and doublecortin, two lissencephaly gene products. Hum Mol Genet 9:2205–2213PubMedGoogle Scholar
  86. 86.
    Schroer RJ, Holden KR, Tarpey PS, Matheus MG, Griesemer DA, Friez MJ, Fan JZ, Simensen RJ, Stromme P, Stevenson RE, Stratton MR, Schwartz CE (2010) Natural history of Christianson syndrome. Am J Med Genet A 152A:2775–2783PubMedGoogle Scholar
  87. 87.
    Christianson AL, Stevenson RE, van der Meyden CH, Pelser J, Theron FW, van Rensburg PL, Chandler M, Schwartz CE (1999) X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J Med Genet 36:759–766PubMedCentralPubMedGoogle Scholar
  88. 88.
    Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjoholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Stromme P (2008) SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet 82:1003–1010PubMedCentralPubMedGoogle Scholar
  89. 89.
    Garbern JY, Neumann M, Trojanowski JQ, Lee VM, Feldman G, Norris JW, Friez MJ, Schwartz CE, Stevenson R, Sima AA (2010) A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 133:1391–1402PubMedCentralPubMedGoogle Scholar
  90. 90.
    Numata M, Petrecca K, Lake N, Orlowski J (1998) Identification of a mitochondrial Na+/H + exchanger. J Biol Chem 273:6951–6959PubMedGoogle Scholar
  91. 91.
    Ohgaki R, Matsushita M, Kanazawa H, Ogihara S, Hoekstra D, van Ijzendoorn SC (2010) The Na+/H + exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells. Mol Biol Cell 21:1293–1304PubMedCentralPubMedGoogle Scholar
  92. 92.
    Ohgaki R, Fukura N, Matsushita M, Mitsui K, Kanazawa H (2008) Cell surface levels of organellar Na+/H + exchanger isoform 6 are regulated by interaction with RACK1. J Biol Chem 283:4417–4429PubMedGoogle Scholar
  93. 93.
    Zachariah RM, Rastegar M (2012) Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research. Neural Plast 2012:415825PubMedCentralPubMedGoogle Scholar
  94. 94.
    Webb T, Clarke A, Hanefeld F, Pereira JL, Rosenbloom L, Woods CG (1998) Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28. J Med Genet 35:997–1003PubMedCentralPubMedGoogle Scholar
  95. 95.
    Sirianni N, Naidu S, Pereira J, Pillotto RF, Hoffman EP (1998) Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet 63:1552–1558PubMedCentralPubMedGoogle Scholar
  96. 96.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedGoogle Scholar
  97. 97.
    Gadalla KK, Bailey ME, Cobb SR (2011) MeCP2 and Rett syndrome: reversibility and potential avenues for therapy. Biochem J 439:1–14PubMedGoogle Scholar
  98. 98.
    Hadzsiev K, Polgar N, Bene J, Komlosi K, Karteszi J, Hollody K, Kosztolanyi G, Renieri A, Melegh B (2011) Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations. J Hum Genet 56:183–187PubMedGoogle Scholar
  99. 99.
    Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon M, Marozza A, Cilio MR, Specchio N, Vigevano F, Vecchi M, Boniver C, Dalla BB, Parmeggiani A, Buoni S, Hayek G, Mari F, Renieri A, Murgia A (2010) Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria. Brain Dev 32:17–24PubMedGoogle Scholar
  100. 100.
    Girard M, Couvert P, Carrie A, Tardieu M, Chelly J, Beldjord C, Bienvenu T (2001) Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet 9:231–236PubMedGoogle Scholar
  101. 101.
    Trappe R, Laccone F, Cobilanschi J, Meins M, Huppke P, Hanefeld F, Engel W (2001) MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68:1093–1101PubMedCentralPubMedGoogle Scholar
  102. 102.
    Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, Jones JR, Scherer SW, Schanen NC, Friez MJ, Vincent JB, Minassian BA (2004) A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet 36:339–341PubMedGoogle Scholar
  103. 103.
    Fichou Y, Nectoux J, Bahi-Buisson N, Rosas-Vargas H, Girard B, Chelly J, Bienvenu T (2009) The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform. Neurogenetics 10:127–133PubMedGoogle Scholar
  104. 104.
    Smeets EE, Pelc K, Dan B (2012) Rett syndrome. Mol Syndromol 2:113–127PubMedCentralPubMedGoogle Scholar
  105. 105.
    Kishi N, Macklis JD (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 27:306–321PubMedGoogle Scholar
  106. 106.
    Klose RJ, Sarraf SA, Schmiedeberg L, McDermott SM, Stancheva I, Bird AP (2005) DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. Mol Cell 19:667–678PubMedGoogle Scholar
  107. 107.
    Galvao TC, Thomas JO (2005) Structure-specific binding of MeCP2 to four-way junction DNA through its methyl CpG-binding domain. Nucleic Acids Res 33:6603–6609PubMedCentralPubMedGoogle Scholar
  108. 108.
    Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389PubMedGoogle Scholar
  109. 109.
    Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S (2001) The Ski protein family is required for MeCP2-mediated transcriptional repression. J Biol Chem 276:34115–34121PubMedGoogle Scholar
  110. 110.
    Forlani G, Giarda E, Ala U, Di Cunto F, Salani M, Tupler R, Kilstrup-Nielsen C, Landsberger N (2010) The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis. Hum Mol Genet 19:3114–3123PubMedCentralPubMedGoogle Scholar
  111. 111.
    Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY (2005) Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A 102:17551–17558PubMedCentralPubMedGoogle Scholar
  112. 112.
    Chandler SP, Guschin D, Landsberger N, Wolffe AP (1999) The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA. Biochemistry Us 38:7008–7018Google Scholar
  113. 113.
    Huppke P, Laccone F, Kramer N, Engel W, Hanefeld F (2000) Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 9:1369–1375PubMedGoogle Scholar
  114. 114.
    Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243–254PubMedGoogle Scholar
  115. 115.
    Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229PubMedCentralPubMedGoogle Scholar
  116. 116.
    Ellaway C, Christodoulou J (2001) Rett syndrome: clinical characteristics and recent genetic advances. Disabil Rehabil 23:98–106PubMedGoogle Scholar
  117. 117.
    Ballas N, Lioy DT, Grunseich C, Mandel G (2009) Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 12:311–317PubMedCentralPubMedGoogle Scholar
  118. 118.
    Maezawa I, Swanberg S, Harvey D, LaSalle JM, Jin LW (2009) Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci 29:5051–5061PubMedCentralPubMedGoogle Scholar
  119. 119.
    Maezawa I, Jin LW (2010) Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci 30:5346–5356PubMedGoogle Scholar
  120. 120.
    Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G (2011) A role for glia in the progression of Rett's syndrome. Nature 475:497–500PubMedCentralPubMedGoogle Scholar
  121. 121.
    Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331PubMedGoogle Scholar
  122. 122.
    Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639PubMedGoogle Scholar
  123. 123.
    Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Clayton-Smith J (2001) Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet 38:224–228PubMedCentralPubMedGoogle Scholar
  124. 124.
    Miltenberger-Miltenyi G, Laccone F (2003) Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. Hum Mutat 22:107–115PubMedGoogle Scholar
  125. 125.
    Zoghbi HY (2005) MeCP2 dysfunction in humans and mice. J Child Neurol 20:736–740PubMedGoogle Scholar
  126. 126.
    Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G (2005) Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 77:442–453PubMedCentralPubMedGoogle Scholar
  127. 127.
    Van Esch H (2012) MECP2 duplication syndrome. Mol Syndromol 2:128–136PubMedCentralPubMedGoogle Scholar
  128. 128.
    Tate P, Skarnes W, Bird A (1996) The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nat Genet 12:205–208PubMedGoogle Scholar
  129. 129.
    Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David SJ, Zoghbi HY (2004) Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 13:2679–2689PubMedGoogle Scholar
  130. 130.
    McGraw CM, Samaco RC, Zoghbi HY (2011) Adult neural function requires MeCP2. Science 333:186PubMedCentralPubMedGoogle Scholar
  131. 131.
    Russo S, Cogliati F, Cavalleri F, Cassitto MG, Giglioli R, Toniolo D, Casari G, Larizza L (2000) Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family. Am J Med Genet 94:376–382PubMedGoogle Scholar
  132. 132.
    Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, Ropers HH, Tzschach A, Kalscheuer V, Oehl-Jaschkowitz B, Skinner C, Schwartz CE, Gecz J, Van Esch H, Raynaud M, Chelly J, de Brouwer AP, Toniolo D, D'Adamo P (2010) Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet 86:185–195PubMedCentralPubMedGoogle Scholar
  133. 133.
    Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, Saletti V, Balestrini M, Ben-Zeev B, Larizza L (2009) Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 10:241–250PubMedGoogle Scholar
  134. 134.
    Scala E, Ariani F, Mari F, Caselli R, Pescucci C, Longo I, Meloni I, Giachino D, Bruttini M, Hayek G, Zappella M, Renieri A (2005) CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J Med Genet 42:103–107PubMedCentralPubMedGoogle Scholar
  135. 135.
    Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O'Callaghan F, Huyton M, O'Regan M, Tolmie J, Sampson J, Clarke A, Osborne J (2006) CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet 43:729–734PubMedCentralPubMedGoogle Scholar
  136. 136.
    Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, Afenjar A, Rio M, Heron D, N'Guyen MM, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T (2008) Key clinical features to identify girls with CDKL5 mutations. Brain 131:2647–2661PubMedGoogle Scholar
  137. 137.
    Fichou Y, Bieth E, Bahi-Buisson N, Nectoux J, Girard B, Chelly J, Chaix Y, Bienvenu T (2009) Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 73:77–78PubMedGoogle Scholar
  138. 138.
    Nectoux J, Heron D, Tallot M, Chelly J, Bienvenu T (2006) Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome. Clin Genet 70:29–33PubMedGoogle Scholar
  139. 139.
    Tao J, Van Esch H, Hagedorn-Greiwe M, Hoffmann K, Moser B, Raynaud M, Sperner J, Fryns JP, Schwinger E, Gecz J, Ropers HH, Kalscheuer VM (2004) Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet 75:1149–1154PubMedCentralPubMedGoogle Scholar
  140. 140.
    Pintaudi M, Baglietto MG, Gaggero R, Parodi E, Pessagno A, Marchi M, Russo S, Veneselli E (2008) Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. Epilepsy Behav 12:326–331PubMedGoogle Scholar
  141. 141.
    Sprovieri T, Conforti FL, Fiumara A, Mazzei R, Ungaro C, Citrigno L, Muglia M, Arena A, Quattrone A (2009) A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype. Am J Med Genet A 149A:722–725PubMedGoogle Scholar
  142. 142.
    Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo GM, Fichera M (2008) CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 71:997–999PubMedGoogle Scholar
  143. 143.
    Sartori S, Di Rosa G, Polli R, Bettella E, Tricomi G, Tortorella G, Murgia A (2009) A novel CDKL5 mutation in a 47, XXY boy with the early-onset seizure variant of Rett syndrome. Am J Med Genet A 149A:232–236PubMedGoogle Scholar
  144. 144.
    Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, Sofokleous C, Makrythanassis P, Kitsiou-Tzeli S (2010) A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder. Eur J Paediatr Neurol 14:188–191PubMedGoogle Scholar
  145. 145.
    Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schafer H, Hehr U, Winkler J (2003) ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 61:232–235PubMedGoogle Scholar
  146. 146.
    Bhat SS, Rogers RC, Holden KR, Srivastava AK (2005) A novel in-frame deletion in ARX is associated with lissencephaly with absent corpus callosum and hypoplastic genitalia. Am J Med Genet A 138:70–72PubMedGoogle Scholar
  147. 147.
    Hahn A, Gross C, Uyanik G, Hehr U, Hugens-Penzel M, Alzen G, Neubauer BA (2004) X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting. Neuropediatrics 35:202–205PubMedGoogle Scholar
  148. 148.
    Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB (2003) Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology 61:267–276PubMedGoogle Scholar
  149. 149.
    Wohlrab G, Uyanik G, Gross C, Hehr U, Winkler J, Schmitt B, Boltshauser E (2005) Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation. Eur J Pediatr 164:326–328PubMedGoogle Scholar
  150. 150.
    Poirier K, Lacombe D, Gilbert-Dussardier B, Raynaud M, Desportes V, de Brouwer AP, Moraine C, Fryns JP, Ropers HH, Beldjord C, Chelly J, Bienvenu T (2006) Screening of ARX in mental retardation families: consequences for the strategy of molecular diagnosis. Neurogenetics 7:39–46PubMedGoogle Scholar
  151. 151.
    Partington MW, Turner G, Boyle J, Gecz J (2004) Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clin Genet 66:39–45PubMedGoogle Scholar
  152. 152.
    Gronskov K, Hjalgrim H, Nielsen IM, Brondum-Nielsen K (2004) Screening of the ARX gene in 682 retarded males. Eur J Hum Genet 12:701–705PubMedGoogle Scholar
  153. 153.
    Stepp ML, Cason AL, Finnis M, Mangelsdorf M, Holinski-Feder E, Macgregor D, MacMillan A, Holden JJ, Gecz J, Stevenson RE, Schwartz CE (2005) XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. BMC Med Genet 6:16PubMedCentralPubMedGoogle Scholar
  154. 154.
    Van Esch H, Poirier K, de Zegher F, Holvoet M, Bienvenu T, Chelly J, Devriendt K, Fryns JP (2004) ARX mutation in a boy with transsphenoidal encephalocele and hypopituitarism. Clin Genet 65:503–505PubMedGoogle Scholar
  155. 155.
    Lesca G, Till M, Labalme A, Vallee D, Hugonenq C, Philip N, Edery P, Sanlaville D (2011) De novo Xq11.11 microdeletion including ARHGEF9 in a boy with mental retardation, epilepsy, macrosomia, and dysmorphic features. Am J Med Genet A 155A:1706–1711PubMedGoogle Scholar
  156. 156.
    Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, Sherr EH (2008) ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. J Med Genet 45:100–105PubMedGoogle Scholar
  157. 157.
    Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R, Tommerup N, Dalpra L, Tzschach A, Selicorni A, Luscher B, Ropers HH, Harvey K, Harvey RJ (2009) A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat 30:61–68PubMedCentralPubMedGoogle Scholar
  158. 158.
    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:2475–2481PubMedGoogle Scholar
  159. 159.
    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 52:1251–1257PubMedGoogle Scholar
  160. 160.
    Camacho A, Simon R, Sanz R, Vinuela A, Martinez-Salio A, Mateos F (2012) Cognitive and behavioral profile in females with epilepsy with PDCH19 mutation: two novel mutations and review of the literature. Epilepsy Behav 24:134–137PubMedGoogle Scholar
  161. 161.
    Dimova PS, Kirov A, Todorova A, Todorov T, Mitev V (2012) A novel PCDH19 mutation inherited from an unaffected mother. Pediatr Neurol 46:397–400PubMedGoogle Scholar
  162. 162.
    Friez MJ, Jones JR, Clarkson K, Lubs H, Abuelo D, Bier JA, Pai S, Simensen R, Williams C, Giampietro PF, Schwartz CE, Stevenson RE (2006) Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 118:e1687–e1695PubMedGoogle Scholar
  163. 163.
    Meins M, Lehmann J, Gerresheim F, Herchenbach J, Hagedorn M, Hameister K, Epplen JT (2005) Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J Med Genet 42:e12PubMedCentralPubMedGoogle Scholar
  164. 164.
    Clayton-Smith J, Walters S, Hobson E, Burkitt-Wright E, Smith R, Toutain A, Amiel J, Lyonnet S, Mansour S, Fitzpatrick D, Ciccone R, Ricca I, Zuffardi O, Donnai D (2009) Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur J Hum Genet 17:434–443PubMedCentralPubMedGoogle Scholar
  165. 165.
    Lugtenberg D, Kleefstra T, Oudakker AR, Nillesen WM, Yntema HG, Tzschach A, Raynaud M, Rating D, Journel H, Chelly J, Goizet C, Lacombe D, Pedespan JM, Echenne B, Tariverdian G, O'Rourke D, King MD, Green A, van Kogelenberg M, Van Esch H, Gecz J, Hamel BC, van Bokhoven H, de Brouwer AP (2009) Structural variation in Xq28: MECP2 duplications in 1 % of patients with unexplained XLMR and in 2 % of male patients with severe encephalopathy. Eur J Hum Genet 17:444–453PubMedCentralPubMedGoogle Scholar
  166. 166.
    Shimada S, Okamoto N, Ito M, Arai Y, Momosaki K, Togawa M, Maegaki Y, Sugawara M, Shimojima K, Osawa M, Yamamoto T (2013) MECP2 duplication syndrome in both genders. Brain Dev 35:411–419PubMedGoogle Scholar
  167. 167.
    Del GD, Fang P, Scaglia F, Ward PA, Craigen WJ, Glaze DG, Neul JL, Patel A, Lee JA, Irons M, Berry SA, Pursley AA, Grebe TA, Freedenberg D, Martin RA, Hsich GE, Khera JR, Friedman NR, Zoghbi HY, Eng CM, Lupski JR, Beaudet AL, Cheung SW, Roa BB (2006) Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med 8:784–792Google Scholar
  168. 168.
    Smyk M, Obersztyn E, Nowakowska B, Nawara M, Cheung SW, Mazurczak T, Stankiewicz P, Bocian E (2008) Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections. Am J Med Genet B Neuropsychiatr Genet 147B:799–806PubMedGoogle Scholar
  169. 169.
    Velinov M, Novelli A, Gu H, Fenko M, Dolzhanskaya N, Bernardini L, Capalbo A, Dallapiccola B, Jenkins EC, Brown WT (2009) De-novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation. Clin Dysmorphol 18:9–12PubMedGoogle Scholar
  170. 170.
    Kirk EP, Malaty-Brevaud V, Martini N, Lacoste C, Levy N, Maclean K, Davies L, Philip N, Badens C (2009) The clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA. Clin Genet 75:301–303PubMedGoogle Scholar
  171. 171.
    Ravn K, Roende G, Duno M, Fuglsang K, Eiklid KL, Tumer Z, Nielsen JB, Skjeldal OH (2011) Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations. Orphanet J Rare Dis 6:58PubMedCentralPubMedGoogle Scholar
  172. 172.
    Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D'Adamo P, Denvriendt K, Fryns JP, Toniolo D, Renieri A (2000) A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet 67:982–985PubMedCentralPubMedGoogle Scholar
  173. 173.
    Orrico A, Lam C, Galli L, Dotti MT, Hayek G, Tong SF, Poon PM, Zappella M, Federico A, Sorrentino V (2000) MECP2 mutation in male patients with non-specific X-linked mental retardation. Febs Lett 481:285–288PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Experimental Medicine, The Third Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Department of Neurology, the Third Xiangya HospitalCentral South UniversityChangshaChina

Personalised recommendations