Abstract
CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.
From the article:
There were many areas of consensus recommendations identified. The majority of these are for completion at baseline. There is an emphasis upon holistic care, such as the monitoring of systemic functions and educational needs, with certain areas recommended to be reviewed, not only at baseline, but also annually and if clinically indicated. These included the monitoring of growth, the need for a regular review of feeding and swallowing, and non-specialist screening for respiratory difficulties.
A comprehensive neurological assessment is encouraged at baseline. The consensus recommendations are for the individual with CDD to be reviewed by a pediatric neurologist with experience in managing epilepsy, clinician discussion to inform families about the risk of SUDEP, completion of a baseline MRI and EEG, consideration for epilepsy surgery, screening for the presence of a movement disorder, registration with the CDKL5 international registry and a review of the individual's sleep. Despite limited published evidence on the use of novel antiseizure drugs for CDD in the literature, Ganaxolone and Epidiolex are encouraged to be offered for epilepsy associated with CDD, if clinically indicated, dependent on FDA and EMA approvals and legal and regulatory requirements, respectively.
Discussion
CDD is a debilitating condition where there is an urgent need for further development of management options. To achieve these necessary advances will require large scale and international, collaborative efforts to evaluate potentially effective interventions in sufficiently powered clinical trials. Progress will rely heavily on cooperation between international medical and scientific professionals, affected families, industry and funding organizations. The extensive experience of the author group includes those with direct experience in CDD management including authors of a clinically relevant CDD severity assessment tool. We hope that this survey adds to the current knowledge base concerning clinical aspects of care and provides a useful proposed standard of care elucidated by the agreed areas of consensus. These recommendations can support clinicians with less experience of CDD and act as a catalyst for further research that would aim to increase capacity for evidence-based management in CDD.
Dell'Isola GB, Antonella F, Francesco P, Mario M, Cordelli DM, Piero P, Pasquale P, Alessandro F, Operto FF, Maurizio E, Marco C, Dario P, Sara M, Elisabetta S, Alberto S, Giovanna S, Savasta S, Paolo P, Di Cara G, Fruttini D, Vincenzo S, Pasquale S, Alberto V. CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy. J Neurol. 2024 Jun 14. doi: 10.1007/s00415-024-12421-1. Epub ahead of print. PMID: 38874638.
Abstract
CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder.
Benke TA, Demarest S, Angione K, Downs J, Leonard H, Saldaris J, Marsh ED, Olson H, Haviland I. CDKL5 Deficiency Disorder. 2024 Apr 11. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 38603524.
Excerpt
Clinical characteristics: CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset intractable epilepsy and motor, cognitive, visual, and autonomic disturbances. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements.
Although females are more commonly affected than males (female-to-male ratio is approximately 4:1), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism in males or females, who can have mild manifestations.
Diagnosis/testing: The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous CDKL5 pathogenic variant identified by molecular genetic testing.
The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDKL5 pathogenic variant identified by molecular genetic testing.
Management: Treatment of manifestations: International consensus recommendations for the assessment and management of individuals with CDD have been published. The management of individuals with CDD is complex and requires multiple specialty evaluations; referral to a CDKL5 Center of Excellence may allow families to coordinate care more easily for affected individuals.
Targeted therapy: Ztalmy® (ganaxolone) is a targeted therapy for the treatment of epilepsy associated with CDD in individuals aged two years and older. This is the first approved treatment for seizures associated with CDD and the first treatment specifically for CDD.
Supportive care: Multidisciplinary care by specialists in the fields of pediatric neurology including pediatric epilepsy, feeding and nutrition, sleep disorders, behavioral disorders, orthopedics, physical therapy, occupational therapy, speech-language disorders, and genetic counseling.
Surveillance: Annual assessments by a medical home / primary care physician and specialists.
Genetic counseling: CDD is inherited in an X-linked manner. Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a de novo germline or (rarely) postzygotic CDKL5 pathogenic variant. Rarely, an individual with CDD has the disorder as the result of a CDKL5 pathogenic variant inherited from a heterozygous or mosaic mother. If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype. Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected. Once the CDKL5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
See: https://childnervoussystem.blogspot.com/2019/10/cdkl5-genetic-disorder.html
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