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CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development with mutations causing deficiencies in the protein level. It regulates neuronal morphology through cytoplasmic signaling and controlling gene expression. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.
CDKL5 Deficiency had been thought of as a variant of Rett’s Syndrome due to some similarities in the clinical presentation, but it is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate to Rett Syndrome rather than a variant of it. While CDKL5 is primarily associated with girls, it has been seen in boys as well. This disorder includes many of the features of classic Rett syndrome (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements), but also causes recurrent seizures beginning in infancy. Some CDKL5 mutations change a single protein building block (amino acid) in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctional version of the protein.
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by this study, published in April 2016, which concluded 'There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics'. At one time, mutations in the CDKL5 gene were said to cause a disorder called X-linked infantile spasm syndrome (ISSX) or West syndrome. but this research established CDKL5 disorder as a distinct clinical entity.
There are currently no approved drugs to treat CDKL5 Deficiency, save for Anti-Epileptic Drugs (AEDs) to treat the epileptic seizures. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients.
A clinical trial of Ataluren for nonsense mutations in CDKL5 and Dravet Syndrome has been announced. This same drug was approved by the UK's National Institute for Health and Care Excellence (NICE) for use in treating nonsense mutations in Duchenne muscular dystrophy. Finally a CDKL5 protein replacement therapy is in development.
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
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- CDKL5 on Genetics Home Reference
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- Infantile spasm syndrome, X-linked
- Kalscheuer VM, Tao J, Donnelly A, Hollway G, Schwinger E, Kübart S, Menzel C, Hoeltzenbein M, Tommerup N, Eyre H, Harbord M, Haan E, Sutherland GR, Ropers HH, Gécz J (June 2003). "Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation". (primary). American Journal of Human Genetics. 72 (6): 1401–11. doi:10.1086/375538. PMC 1180301. PMID 12736870.
- West Syndrome
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- Clinical trial number NCT02758626 for "Ataluren for Nonsense Mutation in CDKL5 and Dravet Syndrome" at ClinicalTrials.gov
- "NICE recommends ataluren for treating Duchenne muscular dystrophy caused by a nonsense mutation". National Institute for Health and Care Excellence. 15 April 2016.
- "Preclinical Program for Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency". Amicus Therapeutics Press Release. 6 July 2016.
- Montini E, Andolfi G, Caruso A, Buchner G, Walpole SM, Mariani M, Consalez G, Trump D, Ballabio A, Franco B (August 1998). "Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region". (primary). Genomics. 51 (3): 427–33. doi:10.1006/geno.1998.5391. PMID 9721213.
- Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V (December 2009). "CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery". Human Molecular Genetics. 18 (23): 4590–602. doi:10.1093/hmg/ddp426. PMID 19740913.
- Grosso S, Brogna A, Bazzotti S, Renieri A, Morgese G, Balestri P (May 2007). "Seizures and electroencephalographic findings in CDKL5 mutations: case report and review". Brain & Development. 29 (4): 239–42. doi:10.1016/j.braindev.2006.09.001. PMID 17049193.
- Rosas-Vargas H, Bahi-Buisson N, Philippe C, Nectoux J, Girard B, N'Guyen Morel MA, Gitiaux C, Lazaro L, Odent S, Jonveaux P, Chelly J, Bienvenu T (March 2008). "Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy". Journal of Medical Genetics. 45 (3): 172–8. doi:10.1136/jmg.2007.053504. PMID 17993579.
- Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gérard M, Giuliano F, Motte J, Héron D, Morel MA, Plouin P, Richelme C, des Portes V, Dulac O, Philippe C, Chiron C, Nabbout R, Bienvenu T (June 2008). "The three stages of epilepsy in patients with CDKL5 mutations". Epilepsia. 49 (6): 1027–37. doi:10.1111/j.1528-1167.2007.01520.x. PMID 18266744.
- Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, Parrini E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R (April 2010). "Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy". Epilepsia. 51 (4): 647–54. doi:10.1111/j.1528-1167.2009.02308.x. PMID 19780792.
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- Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N (October 2008). "CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail". The Journal of Biological Chemistry. 283 (44): 30101–11. doi:10.1074/jbc.M804613200. PMC 2662074. PMID 18701457.
- 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 (October 2009). "Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature". Clinical Genetics. 76 (4): 357–71. doi:10.1111/j.1399-0004.2009.01194.x. PMID 19793311.
- Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M (September 2008). "CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology. 71 (13): 997–9. doi:10.1212/01.wnl.0000326592.37105.88. PMID 18809835.
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- Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, Saletti V, Balestrini M, Ben-Zeev B, Larizza L (July 2009). "Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes". Neurogenetics. 10 (3): 241–50. doi:10.1007/s10048-009-0177-1. PMID 19241098.
- Li MR, Pan H, Bao XH, Zhu XW, Cao GN, Zhang YZ, Wu XR (February 2009). "[Methyl-CpG-binding protein 2 gene and CDKL5 gene mutation in patients with Rett syndrome: analysis of 177 Chinese pediatric patients]". Zhonghua Yi Xue Za Zhi. 89 (4): 224–9. PMID 19552836.
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- Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, Cheung SW, Lewis RA, Fang P, Davenport SL, Stankiewicz P, Lalani SR (October 2009). "Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder". Neurogenetics. 10 (4): 363–9. doi:10.1007/s10048-009-0195-z. PMID 19471977.
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- CDKL5 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Cure CDKL5 Disorder resources for Families and Professionals - based in the UK
- International Foundation for CDKL5 Research - based in the US
- CDKL5 Forum - a professional forum to share current research on CDKL5 and to stimulate peer-group discussion