Alternative titles; symbols
SNOMEDCT: 773230003; ICD10CM: G40.42; ORPHA: 1934, 3095, 3451, 505652; DO: 0080467;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.13 | Developmental and epileptic encephalopathy 2 | 300672 | X-linked dominant | 3 | CDKL5 | 300203 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-2 (DEE2) is caused by mutation in the CDKL5 gene (300203) on chromosome Xp22.
Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but DEE2 is considered to be a distinct entity (summary by Fehr et al., 2013).
For a discussion of genetic heterogeneity of DEE, see 308350.
Kalscheuer et al. (2003) reported 2 unrelated girls with early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation.
Weaving et al. (2004) reported a family with infantile spasms and severe mental retardation. After having seizures at age 9 weeks, the proband later developed hand-wringing and hand-mouthing stereotypies as well as breathing dysfunction with hyperventilation and breath-holding episodes, suggestive of an atypical form of Rett syndrome (312750). At 19 years of age, she had severe mental retardation and a mixed seizure disorder, small hands and feet, and was wheelchair-dependent. The proband's identical twin sister had mild mental retardation and autistic features, but no seizures. A brother of the girls was profoundly affected, with infantile seizures, a mixed seizure disorder, severe global developmental delay with no visual or social responses, spastic quadriparesis, cortical blindness, episodes of hyperventilation, and marked kyphoscoliosis. He died of respiratory failure at the age of 16 years. In a second family, an affected girl developed severe infantile spasms followed by intractable mixed seizures during childhood and adolescence. She had delayed psychomotor development no verbal communication skills, marked intellectual impairment, and scoliosis. Other features included hand stereotypies, hyperventilation when upset, and small feet. Weaving et al. (2004) considered a diagnosis of atypical Rett syndrome. The second family had been reported by Gill et al. (2003).
Tao et al. (2004) reported a female patient with early-onset infantile Blitz-Nick-Salaam-like seizures, hypotonia, and delayed development. A second family had monozygotic female twins with infantile spasms, delayed development, lack of speech, and inability to walk independently due to progressive thoracolumbar kyphoscoliosis. Aged 41 years at time of report, they both had stereotypic hand movements, mood swings, and episodes of hyperventilation, again suggestive of atypical Rett syndrome.
Scala et al. (2005) reported 2 unrelated girls who had seizures very early in life and otherwise fulfilled the criteria for Rett syndrome, with acquired microcephaly, hand apraxia, generalized hypotonia, and stereotypic hand motions. Both patients were found to have frameshift deletions in CDKL5 (see 300203.0005 and 300203.0006).
Rosas-Vargas et al. (2008) reported 3 unrelated girls with severe infantile encephalopathy associated with mutations in the CDKL5 gene (see, e.g., 300203.0009). The phenotype was characterized by early-onset seizures, delayed psychomotor development, hypotonia, scoliosis, microcephaly, lack of speech development, stereotypic hand movements, and repetitive behaviors. The features were consistent with an atypical form of Rett syndrome.
Pintaudi et al. (2008) reported 2 unrelated Italian girls with CDKL5 mutations and epileptic encephalopathy. Both had early-onset seizures, hand stereotypies, psychomotor delay, and hypotonia, although the severity differed between the 2 girls. One patient had predominantly myoclonic jerks. EEG studies of both showed some common features, including pseudoperiodicity and polyspike-wave discharges. One of the patients responded to treatment. Pintaudi et al. (2008) noted that the phenotype corresponded to the Hanefeld variant of atypical Rett syndrome.
Bahi-Buisson et al. (2008) retrospectively analyzed the electroclinical phenotypes of 12 girls, aged 2.5 to 19 years, with epilepsy associated with mutations in the CDKL5 gene. Three successive stages of the disorder were identified: early epilepsy, epileptic encephalopathy, and late multifocal and myoclonic epilepsy. Early epilepsy was characterized by onset between age 1 and 10 weeks of frequent, mostly tonic-clonic seizures with normal interictal EEG in 9 cases. Other features included gross motor hypotonia and poor eye contact. In the second stage, patients showed hypsarrhythmia, slow EEG activity with spike-wave anomalies, and mental retardation with no developmental progress. In the final stage, 7 patients no longer had epilepsy, but 5 had severe refractory seizures that were often myoclonic. Interictal EEG showed pseudoperiodic bursts of high-amplitude spikes and waves. Brain MRI showed delayed myelination in 4 patients and cerebellar atrophy in 1. Patients with mutations that truncated the catalytic domain tended to have a more severe phenotype compared to others, but this finding did not reach significance.
Fehr et al. (2013) evaluated the phenotype of 77 girls and 9 boys with early-onset encephalopathy due to CDKL5 mutations. The disorder was characterized by seizure onset occurring usually before 3 months of age, severely impaired gross motor, language, and hand function skills, and subtle but shared dysmorphic features, such as prominent/broad forehead, deep-set and large-appearing eyes, well-defined eyebrows, full lips, and tapered fingers. Males were more severely affected than females and often had an anteverted nasal tip. Many patients had features observed in Rett syndrome, such as hand stereotypies (80% of females and 33% of males), gastrointestinal problems (79% of females and 8 males), spinal curvature (21% of females and 33% of males), and sleep problems (90% of females and 88% males). Compared to females with Rett syndrome, females with CDKL5 mutations were more likely to have seizures and sleep disturbances, but less likely to have breathing disturbances, spinal curvature, gastrointestinal problems, or hand stereotypies. Fehr et al. (2013) found that only 23.7% of females and no males fulfilled the criteria for the 'early-onset seizure variant of Rett syndrome' (ESV Rett), mostly because 67.5% of females and all males lacked a period of developmental regression, which is a necessary feature for the diagnosis of ESV Rett. The authors concluded that CDKL5 disorder is an independent entity from ESV Rett and should not be considered part of the Rett spectrum.
Affected Males
Elia et al. (2008) reported 3 unrelated Italian boys with profound mental retardation and early-onset intractable seizures. The 3 boys had mild facial dysmorphic features, including high-arched palate, depressed nasal bridge, high sloping forehead, and anteverted nares. One patient showed psychomotor regression after 1 year of normal development. Seizures included generalized tonic-clonic, myoclonic, loss of consciousness, and automatisms.
Masliah-Plachon et al. (2010) reported a 2-year-old boy with epileptic encephalopathy who was found to be somatic mosaic for a truncating mutation in the CDKL5 gene. He had onset of seizures and infantile spasms at age 2 months and was found to have EEG abnormalities, hypotonia, and delayed psychomotor development. At 14 months, he developed tonic and focal seizures associated with hypsarrhythmia. Brain MRI at age 2 years showed cerebral atrophy mainly affecting the white matter. At age 2 years 8 months, he had severe mental retardation, no language skills, and could sit alone, but not stand without support. Molecular studies of patient blood lymphocytes and fibroblasts revealed somatic mosaicism.
Saletti et al. (2009) reported a 4-year-old girl with a severe early-onset seizure disorder and mutation in the CDKL5 gene (I72T; 300203.0010). She had severe mental retardation, microcephaly, diffuse hypotonia, hyperreflexia, no language, numerous refractory seizures since 2 months of age, and stereotypic movement of the hands. At age 5 years, 3 months, she showed signs of precocious puberty, including rapid growth in height, increased sex hormones, and ultrasonic uterine and ovarian changes consistent with the onset of puberty. Saletti et al. (2009) noted that the onset of precocious puberty had not been reported in association with CDKL5 mutations.
In 2 unrelated girls with infantile spasms, Kalscheuer et al. (2003) identified de novo balanced X-autosome translocations that disrupted the STK9 gene on Xp22.3. Studies of normal female somatic cells showed that the STK9 gene is subject to X inactivation. The STK9 gene was functionally absent in the 2 patients because of preferential inactivation of the normal X chromosome.
Van Esch et al. (2007) reported a 10-month-old male infant with severe encephalopathy, congenital cataracts, and tetralogy of Fallot who had a hemizygous de novo 2.8-Mb microdeletion at chromosome Xp22.2-p22.13, including the CDKL5 and NHS (300457) genes. He had microphthalmia, refractory myoclonic seizures, and hypotonia. The clinical features were consistent with both DEE2 and the Nance-Horan syndrome (302350), which is caused by mutation in the NHS gene.
Nishimura et al. (2008) reported a Japanese girl with West syndrome associated with a t(X;18)(p22;p11.2) translocation. She presented with intractable infantile spasms and modified hypsarrhythmia at age of 4 months. FISH, Southern, and PCR analysis revealed that the breakpoints were in intron 17 of the CDKL5 gene and intron 7 of the PTPRM gene (176888). The translocation was not present in either parent. X inactivation was almost completely skewed in the patient. The pattern was consistent with X-linked dominant.
In 2 affected twin girls and an affected brother from a family with infantile spasms and mental retardation, Weaving et al. (2004) identified a mutation in the CDKL5 gene (183delT; 300203.0001). Affected girls of a second family had a different mutation in the CDKL5 gene (300203.0002).
In 2 unrelated girls with early-onset infantile spasms and neurodevelopmental deficits, Tao et al. (2004) identified 2 different mutations in the CDKL5 gene (C152F, 300203.0003; R175S, 300203.0004).
In 3 of 8 unrelated Italian boys with early-onset seizures and profound mental retardation, Elia et al. (2008) identified 3 different mutations in the CDKL5 gene (see, e.g., 300203.0011 and 300203.0012). The mutations were not present in 2 mothers; DNA from the third was not available. The authors noted the severe phenotype in boys with CDKL5 mutations.
Nemos et al. (2009) screened the CDKL5 gene in a cohort of 177 patients with onset of seizures before age 9 months, including 30 boys and 10 girls with Aicardi syndrome (AIC; 304050). Eleven girls had 9 different de novo mutations in the CDKL5 gene, including 1 large deletion found by multiplex ligation-dependent probe amplification (MLPA). Studies of genomic DNA extracted from patient peripheral blood lymphocytes showed that all mutations were associated with random X inactivation at the HUMARA locus. Nemos et al. (2009) generated cell lines that exclusively expressed mutant missense mutations (see, e.g., A40V; 300203.0009) and found that the mutant missense proteins properly localized to the nucleus. None of the girls with Aicardi syndrome had a CDKL5 mutation. Nemos et al. (2009) noted that this study brought the number of published CDKL5 mutations to 59, and indicated that CDKL5 mutations account for up to 28% of females with early-onset seizures and intractable epilepsy.
Bartnik et al. (2011) used comparative genomic hybridization (CGH) with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5, and identified mosaic exonic deletions of this gene in 1 male and 2 females with developmental delay and medically intractable seizures. These 3 mosaic changes represented 60% of all deletions detected in 12,000 patients analyzed by array CGH and involving the exonic portion of CDKL5.
Russo et al. (2009) identified 7 different mutations in the CDKL5 gene in 6 of 93 patients with classic or atypical Rett syndrome and 1 of 17 patients with an Angelman syndrome (105830)-like phenotype. Two of the patients were reported by Pintaudi et al. (2008) and 1 by Saletti et al. (2009). All were girls, and all except 1 showed progressive microcephaly during the first 2 years of life. All but 1 girl had severely impaired intellectual development, limited hand skills, hypotonia, lack of eye contact, and absence of speech and walking. Only 2 patients showed a clear regressive stage. Seizures appeared by the second week of life: 3 patients had drug-resistant seizures, 3 had some response, and 1 had spontaneous resolution of seizures at 6 months. The patient with features of Angelman syndrome, resulting from a 2-bp insertion (903insGA; 300203.0013), had absence of speech, severe developmental delay, ataxic gait, hypermotoric behavior, and easily excitable personality with uplifted hand-flapping. She was microcephalic, had intractable seizures, brachycephaly, wide mouth, widely dispersed teeth, and progressive prognathism. She was also autistic but had relatively better motor skills than the other girls. Overall, the CDKL5 mutations included 2 missense, 2 splicing, 1 in-frame deletion, 1 nonsense mutation, and 1 insertion. Four of the mutations affected the predicted N-terminal catalytic domain. Nonsense mutation carriers tended to have a milder phenotype than those with missense or splicing mutations.
Bahi-Buisson, N., Kaminska, A., Boddaert, N., Rio, M., Afenjar, A., Gerard, M., Giuliano, F., Motte, J., Heron, D., N'Guyen Morel, M. A., Plouin, P., Richelme, C., des Portes, V., Dulac, O., Philippe, C., Chiron, C., Nabbout, R., Bienvenu, T. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 49: 1027-1037, 2008. [PubMed: 18266744] [Full Text: https://doi.org/10.1111/j.1528-1167.2007.01520.x]
Bartnik, M., Derwinska, K., Gos, M., Obersztyn, E., Kolodziejska, K. E., Erez, A., Szpecht-Potocka, A., Fang, P., Terczynska, I., Mierzewska, H., Lohr, N. J., Bellus, G. A., Reimschiesel, T., Bocian, E., Mazurczak, T., Cheung, S. W., Stankiewicz, P. Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females. Genet. Med. 13: 447-452, 2011. [PubMed: 21293276] [Full Text: https://doi.org/10.1097/GIM.0b013e31820605f5]
Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology 71: 997-999, 2008. [PubMed: 18809835] [Full Text: https://doi.org/10.1212/01.wnl.0000326592.37105.88]
Fehr, S., Wilson, M., Downs, J., Williams, S., Murgia, A., Sartori, S., Vecchi, M., Ho, G., Polli, R., Psoni, S., Bao, X., de Klerk, N., Leonard, H., Christodoulou, J. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Europ. J. Hum. Genet. 21: 266-273, 2013. [PubMed: 22872100] [Full Text: https://doi.org/10.1038/ejhg.2012.156]
Gill, H., Cheadle, J. P., Maynard, J., Fleming, N., Whatley, S., Cranston, T., Thompson, E. M., Leonard, H., Davis, M., Christodoulou, J., Skjeldal, O., Hanefeld, F., Kerr, A., Tandy, A., Ravine, D., Clarke, A. Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome. J. Med. Genet. 40: 380-384, 2003. [PubMed: 12746405] [Full Text: https://doi.org/10.1136/jmg.40.5.380]
Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am. J. Hum. Genet. 72: 1401-1411, 2003. [PubMed: 12736870] [Full Text: https://doi.org/10.1086/375538]
Masliah-Plachon, J., Auvin, S., Nectoux, J., Fichou, Y., Chelly, J., Bienvenu, T. Somatic mosaicism for a CDKL5 mutation as an epileptic encephalopathy in males. (Letter) Am. J. Med. Genet. 152A: 2110-2111, 2010. [PubMed: 20602487] [Full Text: https://doi.org/10.1002/ajmg.a.33037]
Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. 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, 2009. [PubMed: 19793311] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01194.x]
Nishimura, A., Takano, T., Mizuguchi, T., Saitsu, H., Takeuchi, Y., Matsumoto, N. CDKL5 disruption by t(X;18) in a girl with West syndrome. (Letter) Clin. Genet. 74: 288-290, 2008. [PubMed: 18564362] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01048.x]
Pintaudi, M., Baglietto, M. G., Gaggero, R., Parodi, E., Pessagno, A., Marchi, M., Russo, S., Veneselli, E. Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. Epilepsy Behav. 12: 326-331, 2008. [PubMed: 18063413] [Full Text: https://doi.org/10.1016/j.yebeh.2007.10.010]
Rosas-Vargas, H., Bahi-Buisson, N., Philippe, C., Nectoux, J., Girard, B., N'Guyen Morel, M. A., Gitiaux, C., Lazaro, L., Odent, S., Jonveaux, P., Chelly, J., Bienvenu, T. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. (Letter) J. Med. Genet. 45: 172-178, 2008. [PubMed: 17993579] [Full Text: https://doi.org/10.1136/jmg.2007.053504]
Russo, S., Marchi, M., Cogliati, F., Bontai, M. T., Pintaudi, M., Veneselli, E., Saletti, V., Balestrini, M., Ben-Zeev, B., Larizza, L. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 10: 241-250, 2009. [PubMed: 19241098] [Full Text: https://doi.org/10.1007/s10048-009-0177-1]
Saletti, V., Canafoglia, L., Cambiaso, P., Russo, S., Marchi, M., Riva, D. A CDKL5 mutated child with precocious puberty. Am. J. Med. Genet. 149A: 1046-1051, 2009. [PubMed: 19396824] [Full Text: https://doi.org/10.1002/ajmg.a.32806]
Scala, E., Ariani, F., Mari, F., Caselli, R., Pescucci, C., Longo, I., Meloni, I., Giachino, D., Bruttini, M., Hayek, G., Zappella, M., Renieri, A. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J. Med. Genet. 42: 103-107, 2005. [PubMed: 15689447] [Full Text: https://doi.org/10.1136/jmg.2004.026237]
Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am. J. Hum. Genet. 75: 1149-1154, 2004. [PubMed: 15499549] [Full Text: https://doi.org/10.1086/426460]
Van Esch, H., Jansen, A., Bauters, M., Froyen, G., Fryns, J.-P. Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes. Am. J. Med. Genet. 143A: 364-369, 2007. [PubMed: 17256798] [Full Text: https://doi.org/10.1002/ajmg.a.31572]
Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am. J. Hum. Genet. 75: 1079-1093, 2004. [PubMed: 15492925] [Full Text: https://doi.org/10.1086/426462]