Interpretation of international consensus: recommendations for the assessment and management of individuals with CDKL5 defificiency disorder_Journal of Epilepsy

Authors：

ZHOU Fang , CUI Yuxia , WANG Xike , LIU Kaiyu ,  ZHOU Hao

Department of Pediatrics, Guizhou Provincial People's Hospital, Guiyang 550002, China;

Corresponding author：

ZHOU Hao, Email: haoye320@163.com

Keywords：

CDKL5 deficiency disorder; Assessment; Management; International consensus

DOI：

10.7507/2096-0247.202302006

Video：

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CDKL5 deficiency disorder (CDD), also known as developmental epileptic encephalopathy, is a rare X-linked dominant disease of the nervous system. Its main clinical manifestations include: uncontrollable seizures, cognitive impairment, motor retardation, visual impairment, sleep disorders, gastrointestinal impairment, autonomic nervous dysfunction, and autistic like manifestations. Its high disability rate and heavy disease burden bring heavy burden to society and family. However, the current domestic and foreign studies on this disease mainly focus on the clinical phenotype and pathogenesis, and there are few studies involving the standard clinical management of various systems. Therefore, a core committee composed of CDD experts from the United States, Europe, and the United Kingdom conducted a six-month investigation (August 2020—January 2021) and developed the international consensus: recommendations for the assessment and management of CDKL5 deficiency patients (hereafter referred to as the Consensus) based on the Durfel research methodology. This consensus invites multidisciplinary experts to put forward diagnosis and treatment suggestions for the diagnosis and treatment of CDD as well as the clinical management of various systemic systems, which will provide evidence-based basis for regulating the diagnosis and treatment behaviors of clinicians for CDD. In this paper, the consensus was interpreted to facilitate the long-term management of the disease.

Citation： ZHOU Fang, CUI Yuxia, WANG Xike, LIU Kaiyu, ZHOU Hao. Interpretation of international consensus: recommendations for the assessment and management of individuals with CDKL5 defificiency disorder. Journal of Epilepsy, 2023, 9(3): 248-254. doi: 10.7507/2096-0247.202302006 Copy

1.	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.
2.	Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3beta signaling. Neurobiol Dis, 2014, 70(100): 53-68.
3.	Gursoy S, Ercal D. Diagnostic approach to genetic causes of early-onset epileptic encephalopathy. J Child Neurol, 2016, 31(4): 523-532.
4.	Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain, 2019, 142(8): 2303-2318.
5.	Hagebeuk EE, van den Bossche RA, de Weerd AW. Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene. Dev Med Child Neurol, 2013, 55(5): 480-484.
6.	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.
7.	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.
8.	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.
9.	Artuso R, Mencarelli MA, Polli R, et al. Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria. Brain Dev, 2010, 32(1): 17-24.
10.	Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet, 2006, 43(9): 729-734.
11.	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.
12.	Liang JS, Huang H, Wang JS, et al. Phenotypic manifestations between male and female children with CDKL5 mutations. Brain Dev, 2019, 41(9): 783-789.
13.	Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res, 2016, 128: 43-47.
14.	Johannesen KM, Gardella E, Scheffer I, et al. Early mortality in SCN8A-related epilepsies. Epilepsy Res, 2018, 143: 79-81.
15.	Verducci C, Hussain F, Donner E, et al. SUDEP in the North American SUDEP Registry: the full spectrum of epilepsies. Neurology, 2019, 93(3): e227-e236.
16.	Bahi-Buisson N, Kaminska A, Boddaert N, et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia, 2008, 49(6): 1027-1037.
17.	胡春辉, 马洁卉, 邓小龙, 等. 基因突变相关早发性癫痫脑病4例的临床特征. 中华实用儿科临床杂志, 2017, 32(19): 1506-1509.
18.	Mei D, Marini C, Novara F, et al. Xp22. 3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. Epilepsia, 2010, 51(4): 647-654.
19.	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.
20.	Hirsch E, Velez A, Sellal F, et al. Electroclinical signs of benign neonatal familial convulsions. Ann Neurol, 1993, 34(6): 835-841.
21.	Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia, 2012, 53(12): 2067-2078.
22.	Muller 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.
23.	Boutry-Kryza N, Labalme A, Ville D, et al. Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. Eur J Med Genet, 2015, 58(2): 51-58.
24.	Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorde. Epilepsia, 2021, 62(7): e98-e102.
25.	Olson HE, Demarest ST, Pestana-Knight E M, et al. Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. Pediatr Neurol, 2019, 97: 18-25.
26.	Knight E, Amin S, Bahi-Buisson N, et al. 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.
27.	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.
28.	Chan AY, Rolston JD, Lee B, et al. Rates and predictors of seizure outcome after corpus callosotomy for drug-resistant epilepsy: a meta-analysis. J Neurosurg, 2018: 1-10.
29.	Hagebeuk EE, Duran M, Abeling NG, et al. S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation. J Inherit Metab Dis, 2013, 36(6): 967-972.
30.	Lo MV, Alvente S, Bastianini S, et al. CDKL5 deficiency entails sleep apneas in mice. J Sleep Res, 2017, 26(4): 495-497.
31.	Brod M, Tesler L E, Christensen T L. Qualitative research and content validity: developing best practices based on science and experience. Qual Life Res, 2009, 18(9): 1263-1278.
32.	Saldaris J, Weisenberg J, Pestana-Knight E, et al. Content validation of clinician-reported items for a severity measure for CDKL5 deficiency disorder. J Child Neurol, 2021, 36(11): 998-1006.
33.	MacKay CI, Wong K, Demarest ST, et al. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clin Genet, 2021, 99(1): 157-165.
34.	Russo S, Marchi M, Cogliati F, et al. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics, 2009, 10(3): 241-250.
35.	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.
36.	Benson-Goldberg S, Erickson K. Eye-trackers, digital-libraries, and print-referencing: a single case study in CDKL5. Res Dev Disabil, 2021, 112: 103913.
37.	Cutri-French C, Armstrong D, Saby J, et al. Comparison of core features in four developmental encephalopathies in the rett natural history study. Ann Neurol, 2020, 88(2): 396-406.
38.	Lin JL, Rigdon J, Van Haren K, et al. Gastrostomy tubes placed in children with neurologic impairment: associated morbidity and mortality. J Child Neurol, 2021, 36(9): 727-734.
39.	Howard C, Macken WL, Connolly A, et al. Percutaneous endoscopic gastrostomy for refractory epilepsy and medication refusal. Arch Dis Child, 2019, 104(7): 690-692.
40.	Hosain SA, La Vega-Talbott M, Solomon GE. Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding. Pediatr Neurol, 2005, 32(2): 81-83.
41.	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.
42.	Tangarorang J, Leonard H, Epstein A, et al. A framework for understanding quality of life domains in individuals with the CDKL5 deficiency disorder. Am J Med Genet A, 2019, 179(2): 249-256.
43.	Amin S, Majumdar A, Mallick AA, et al. Caregiver's perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients. Hippokratia, 2017, 21(3): 130-135.

1. 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.
2. Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3beta signaling. Neurobiol Dis, 2014, 70(100): 53-68.
3. Gursoy S, Ercal D. Diagnostic approach to genetic causes of early-onset epileptic encephalopathy. J Child Neurol, 2016, 31(4): 523-532.
4. Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain, 2019, 142(8): 2303-2318.
5. Hagebeuk EE, van den Bossche RA, de Weerd AW. Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene. Dev Med Child Neurol, 2013, 55(5): 480-484.
6. 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.
7. 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.
8. 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.
9. Artuso R, Mencarelli MA, Polli R, et al. Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria. Brain Dev, 2010, 32(1): 17-24.
10. Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet, 2006, 43(9): 729-734.
11. 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.
12. Liang JS, Huang H, Wang JS, et al. Phenotypic manifestations between male and female children with CDKL5 mutations. Brain Dev, 2019, 41(9): 783-789.
13. Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res, 2016, 128: 43-47.
14. Johannesen KM, Gardella E, Scheffer I, et al. Early mortality in SCN8A-related epilepsies. Epilepsy Res, 2018, 143: 79-81.
15. Verducci C, Hussain F, Donner E, et al. SUDEP in the North American SUDEP Registry: the full spectrum of epilepsies. Neurology, 2019, 93(3): e227-e236.
16. Bahi-Buisson N, Kaminska A, Boddaert N, et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia, 2008, 49(6): 1027-1037.
17. 胡春辉, 马洁卉, 邓小龙, 等. 基因突变相关早发性癫痫脑病4例的临床特征. 中华实用儿科临床杂志, 2017, 32(19): 1506-1509.
18. Mei D, Marini C, Novara F, et al. Xp22. 3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. Epilepsia, 2010, 51(4): 647-654.
19. 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.
20. Hirsch E, Velez A, Sellal F, et al. Electroclinical signs of benign neonatal familial convulsions. Ann Neurol, 1993, 34(6): 835-841.
21. Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia, 2012, 53(12): 2067-2078.
22. Muller 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.
23. Boutry-Kryza N, Labalme A, Ville D, et al. Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. Eur J Med Genet, 2015, 58(2): 51-58.
24. Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorde. Epilepsia, 2021, 62(7): e98-e102.
25. Olson HE, Demarest ST, Pestana-Knight E M, et al. Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. Pediatr Neurol, 2019, 97: 18-25.
26. Knight E, Amin S, Bahi-Buisson N, et al. 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.
27. 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.
28. Chan AY, Rolston JD, Lee B, et al. Rates and predictors of seizure outcome after corpus callosotomy for drug-resistant epilepsy: a meta-analysis. J Neurosurg, 2018: 1-10.
29. Hagebeuk EE, Duran M, Abeling NG, et al. S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation. J Inherit Metab Dis, 2013, 36(6): 967-972.
30. Lo MV, Alvente S, Bastianini S, et al. CDKL5 deficiency entails sleep apneas in mice. J Sleep Res, 2017, 26(4): 495-497.
31. Brod M, Tesler L E, Christensen T L. Qualitative research and content validity: developing best practices based on science and experience. Qual Life Res, 2009, 18(9): 1263-1278.
32. Saldaris J, Weisenberg J, Pestana-Knight E, et al. Content validation of clinician-reported items for a severity measure for CDKL5 deficiency disorder. J Child Neurol, 2021, 36(11): 998-1006.
33. MacKay CI, Wong K, Demarest ST, et al. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clin Genet, 2021, 99(1): 157-165.
34. Russo S, Marchi M, Cogliati F, et al. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics, 2009, 10(3): 241-250.
35. 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.
36. Benson-Goldberg S, Erickson K. Eye-trackers, digital-libraries, and print-referencing: a single case study in CDKL5. Res Dev Disabil, 2021, 112: 103913.
37. Cutri-French C, Armstrong D, Saby J, et al. Comparison of core features in four developmental encephalopathies in the rett natural history study. Ann Neurol, 2020, 88(2): 396-406.
38. Lin JL, Rigdon J, Van Haren K, et al. Gastrostomy tubes placed in children with neurologic impairment: associated morbidity and mortality. J Child Neurol, 2021, 36(9): 727-734.
39. Howard C, Macken WL, Connolly A, et al. Percutaneous endoscopic gastrostomy for refractory epilepsy and medication refusal. Arch Dis Child, 2019, 104(7): 690-692.
40. Hosain SA, La Vega-Talbott M, Solomon GE. Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding. Pediatr Neurol, 2005, 32(2): 81-83.
41. 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.
42. Tangarorang J, Leonard H, Epstein A, et al. A framework for understanding quality of life domains in individuals with the CDKL5 deficiency disorder. Am J Med Genet A, 2019, 179(2): 249-256.
43. Amin S, Majumdar A, Mallick AA, et al. Caregiver's perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients. Hippokratia, 2017, 21(3): 130-135.

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Interpretation of international consensus: recommendations for the assessment and management of individuals with CDKL5 defificiency disorder

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