CDKL5 alterations lead to early epileptic encephalopathy in both genders
Jao-Shwann Liang
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorKeiko Shimojima
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorRumiko Takayama
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorJun Natsume
Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Japan
Search for more papers by this authorMinobu Shichiji
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKyoko Hirasawa
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKaoru Imai
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorTohru Okanishi
Department of Pediatrics, Seirei Hamamatsu Hospital, Hamamatsu, Japan
Search for more papers by this authorSeiji Mizuno
Department of Medical Genetics, Aichi Prefectural Colony Central Hospital, Kasugai, Japan
Search for more papers by this authorAkihisa Okumura
Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
Search for more papers by this authorMidori Sugawara
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorTomoshiro Ito
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorHiroko Ikeda
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorYukitoshi Takahashi
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorHirokazu Oguni
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKatsumi Imai
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorMakiko Osawa
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorToshiyuki Yamamoto
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorJao-Shwann Liang
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorKeiko Shimojima
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorRumiko Takayama
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorJun Natsume
Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Japan
Search for more papers by this authorMinobu Shichiji
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKyoko Hirasawa
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKaoru Imai
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorTohru Okanishi
Department of Pediatrics, Seirei Hamamatsu Hospital, Hamamatsu, Japan
Search for more papers by this authorSeiji Mizuno
Department of Medical Genetics, Aichi Prefectural Colony Central Hospital, Kasugai, Japan
Search for more papers by this authorAkihisa Okumura
Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
Search for more papers by this authorMidori Sugawara
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorTomoshiro Ito
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorHiroko Ikeda
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorYukitoshi Takahashi
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorHirokazu Oguni
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorKatsumi Imai
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
Search for more papers by this authorMakiko Osawa
Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Search for more papers by this authorToshiyuki Yamamoto
Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
Search for more papers by this authorSummary
Purpose: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders.
Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations.
Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features.
Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.
Supporting Information
Table S1. The physical positions of BAC clones.
Table S2. Primer sequences for CDKL5.
Table S3. The results of aCGH.
| Filename | Description |
|---|---|
| EPI_3174_sm_TableS1.doc26 KB | Supporting info item |
| EPI_3174_sm_TableS2.doc28 KB | Supporting info item |
| EPI_3174_sm_TableS3.doc26 KB | Supporting info item |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 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: 729–734.
- Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon M, Marozza A, Cilio MR, Specchio N, Vigevano F, Vecchi M, Boniver C, Bernardina BD, 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: 17–24.
- 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. (2008a) The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 49: 1027–1037.
- 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 Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T. (2008b) Key clinical features to identify girls with CDKL5 mutations. Brain 131: 2647–2661.
- Bahi-Buisson N, Girard B, Gautier A, Nectoux J, Fichou Y, Saillour Y, Poirier K, Chelly J, Bienvenu T. (2010) Epileptic encephalopathy in a girl with an interstitial deletion of Xp22 comprising promoter and exon 1 of the CDKL5 gene. Am J Med Genet B Neuropsychiatr Genet 153B: 202–207.
- Castren M, Gaily E, Tengstrom C, Lahdetie J, Archer H, Ala-Mello S. (2011) Epilepsy caused by CDKL5 mutations. Eur J Paediatr Neurol 15: 65–69.
- Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M. (2008) CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 71: 997–999.
- Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, Cheung SW, Lewis RA, Fang P, Davenport SL, Stankiewicz P, Lalani SR. (2009) Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder. Neurogenetics 10: 363–369.
- 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: 1113–1120.
- 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: 77–78; author reply 78.
- Fichou Y, Nectoux J, Bahi-Buisson N, Chelly J, Bienvenu T. (2010) An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain. J Hum Genet 56: 52–57.
- Gomot M, Gendrot C, Verloes A, Raynaud M, David A, Yntema HG, Dessay S, Kalscheuer V, Frints S, Couvert P, Briault S, Blesson S, Toutain A, Chelly J, Desportes V, Moraine C. (2003) MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. Am J Med Genet A 123A: 129–139.
- Huppke P, Ohlenbusch A, Brendel C, Laccone F, Gartner J. (2005) Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2. Am J Med Genet A 137: 136–138.
- 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: 1401–1411.
- Li MR, Pan H, Bao XH, Zhang YZ, Wu XR. (2007) MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. J Hum Genet 52: 38–47.
- 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: 1935–1946.
- Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, Parrini E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R. (2010) Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. Epilepsia 51: 647–654.
- Nabbout R, Dulac O. (2003) Epileptic encephalopathies: a brief overview. J Clin Neurophysiol 20: 393–397.
- Nabbout R, Dulac O. (2008) Epileptic syndromes in infancy and childhood. Curr Opin Neurol 21: 161–166.
- 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: 357–371.
- 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: 326–331.
- 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: 232–236.
- 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: 103–107.
- Shimojima K, Sugiura C, Takahashi H, Ikegami M, Takahashi Y, Ohno K, Matsuo M, Saito K, Yamamoto T. (2010) Genomic copy number variations at 17p13.3 and epileptogenesis. Epilepsy Res 89: 303–309.
- Van Esch H, Jansen A, Bauters M, Froyen G, Fryns JP. (2007) Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes. Am J Med Genet A 143: 364–369.
- Zupanc ML. (2009) Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood. J Child Neurol 24: 6S–14S.
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