Vol 33, No 61 (2023): Continuous Publishing
Review paper
Published online: 2024-03-28
Unraveling the complexities of CDKL5 deficiency disorder: Is an emerging treatment on the horizon?
DOI: 10.5603/cne.98938
Neurol Dziec 2023;33(61):35-40.
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy in which epilepsy and impaired development are prominent features. Previously, CDD was considered a variant of Rett syndrome (Hanefeld variant). However, it is now recognized as an independent clinical entity. It is characterized by early-onset epilepsy, typically occurring within 3 months of age in majority of cases and presenting with polymorphic seizures. Severely impaired development leads to only a small percentage of affected patients achieving independent walking. Other notable clinical features include cortical visual impairment, sleep disturbances, stereotypical hand movements, hypotonia, gastrointestinal problems, scoliosis and respiratory tract infections. The management of epilepsy in CDD is highly demanding due to its refractory nature. The results of conventional antiseizure management have been disappointing, exhibiting minimal or transient clinical effects. Alternative treatments like the ketogenic diet and vagus nerve stimulation have shown limited efficacy. However, new treatment options, such as ganaxolone are emerging and the results seem promising. Further research is needed to explore the potential of other treatments such as soticlestat, fenfluramine and cannabidiol, particularly in larger cohorts. CDD is a multifaceted disorder and its underlying mechanisms remain incompletely elucidated. Further research is needed to better understand the pathological processes of the disorder and to develop more effective treatments for individuals with CDD. Healthcare professionals should be aware of the clinical symptoms and challenges associated with CDD to provide appropriate care and support to individuals affected by this complex disorder.
Keywords: Cyclin-depedent kinase-like 5CDKL5 deficiencyepilepsyganaxolone
References
- Rusconi L, Salvatoni L, Giudici L, et al. CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. J Biol Chem. 2008; 283(44): 30101–30111.
- Chen Q, Zhu YC, Yu J, et al. CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. J Neurosci. 2010; 30(38): 12777–12786.
- Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiol Dis. 2014; 70(100): 53–68.
- Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004; 75(6): 1079–1093.
- Hanefeld F. The clinical pattern of the Rett syndrome. Brain Dev. 1985; 7(3): 320–325.
- Mari F, Azimonti S, Bertani I, et al. 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. 2005; 14(14): 1935–1946.
- Carouge D, Host L, Aunis D, et al. CDKL5 is a brain MeCP2 target gene regulated by DNA methylation. Neurobiol Dis. 2010; 38(3): 414–424.
- Olson HE, Daniels CI, Haviland I, et al. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. J Neurodev Disord. 2021; 13(1): 40.
- Olson HE, Demarest ST, Pestana-Knight EM, et al. Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. Pediatr Neurol. 2019; 97: 18–25.
- Fehr S, Leonard H, Ho G, et al. There is variability in the attainment of developmental milestones in the CDKL5 disorder. J Neurodev Disord. 2015; 7(1): 2.
- Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis. 2016; 11: 39.
- Demarest ST, Olson HE, Moss A, et al. CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia. 2019; 60(8): 1733–1742.
- Knight EM, Amin S, Bahi-Buisson N, et al. Marigold Trial Group. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2022; 21(5): 417–427.
- Klein KM, Yendle SC, Harvey AS, et al. A distinctive seizure type in patients with CDKL5 mutations: Hypermotor-tonic-spasms sequence. Neurology. 2011; 76(16): 1436–1438.
- Fehr S, Wilson M, Downs J, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013; 21(3): 266–273.
- Fehr S, Wong K, Chin R, et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology. 2016; 87(21): 2206–2213.
- Melani F, Mei D, Pisano T, et al. CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life. Dev Med Child Neurol. 2011; 53(4): 354–360.
- Olson HE, Demarest S, Pestana‐Knight E, et al. Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first‐line therapies. Epilepsia. 2023; 64(7): 1821–1832.
- Leonard H, Downs J, Benke TA, et al. CDKL5 deficiency disorder: clinical features, diagnosis, and management. Lancet Neurol. 2022; 21(6): 563–576.
- Fehr S, Downs J, Ho G, et al. Functional abilities in children and adults with the CDKL5 disorder. Am J Med Genet A. 2016; 170(11): 2860–2869.
- Olson HE, Costantini JG, Swanson LC, et al. Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure. Dev Med Child Neurol. 2021; 63(11): 1308–1315.
- Bahi-Buisson N, Nectoux J, Rosas-Vargas H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008; 131(Pt 10): 2647–2661.
- Amin S, Monaghan M, Aledo-Serrano A, et al. International consensus recommendations for the assessment and management of individuals with CDKL5 deficiency disorder. Front Neurol. 2022; 13: 874695.
- Müller A, Helbig I, Jansen C, et al. Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy. Eur J Paediatr Neurol. 2016; 20(1): 147–151.
- Aledo-Serrano Á, Gómez-Iglesias P, Toledano R, et al. Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort. Epilepsy Behav. 2021; 118: 107946.
- Devinsky O, Verducci C, Thiele EA, et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018; 86: 131–137.
- Demarest S, Jeste S, Agarwal N, et al. Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE). Epilepsy Behav. 2023; 142: 109173.
- Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia. 2021; 62(7): e98–e9e102.
- Lamb YN. Ganaxolone: first approval. Drugs. 2022; 82(8): 933–940.
- Lim Z, Wong K, Olson HE, et al. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia. 2017; 58(8): 1415–1422.
- Lim Z, Wong K, Downs J, et al. Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder. Epilepsy Res. 2018; 146: 36–40.
- Spagnoli C, Fusco C, Pisani F. Rett syndrome spectrum in monogenic developmental-epileptic encephalopathies and epilepsies: a review. Genes (Basel). 2021; 12(8).
- Vignoli A, Savini MN, Nowbut MS, et al. Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome. Epilepsy Behav. 2017; 66: 27–33.
- Nissenkorn A, Levy-Drummer RS, Bondi O, et al. Epilepsy in Rett syndrome - lessons from the Rett networked database. Epilepsia. 2015; 56(4): 569–576.