Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

STUDY OBJECTIVES: Sleep difficulties are common in CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy (DEE). This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Daytime Somnolence (DOES) and Sleep Breathing Disorders (SBD) domains of the Sleep Disturbance Scale for Children (SDSC) for CDD. METHODS: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a US Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. RESULTS: The median age was 10.3 years (range 3.2 - 40.7 years) and 105 (84%) were female. Two of the three SBD items related were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, two items in the DIMS domain and one item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (0.524-0.814) and internal consistency (DIMS: 0.78, DOES: 0.76) statistics were good. The square of the inter-domain correlation coefficient was 0.17, less than Average Variance Extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of >0.9 for establishing goodness of fit. CONCLUSIONS: The modified DIMS and DOES domains from the SDSC could be suitable clinical outcome assessments of insomnia and related impairments in CDD and potentially other DEE conditions.

Communication of individuals with CDKL5 deficiency disorder as observed by caregivers: A descriptive qualitative study.

CDKL5 deficiency disorder (CDD) is a genetically caused developmental epileptic encephalopathy that causes severe communication impairments. Communication of individuals with CDD is not well understood in the literature and currently available measures are not well validated in this population. Accurate and sensitive measurement of the communication of individuals with CDD is important for understanding this condition, clinical practice, and upcoming interventional trials. The aim of this descriptive qualitative study was to understand how individuals with CDD communicate, as observed by caregivers. Participants were identified through the International CDKL5 Disorder Database and invited to take part if their child had a pathogenic variant of the CDKL5 gene and they had previously completed the Communication and Symbolic Behavior Checklist (CSBS-DP ITC). The sample comprised caregivers of 23 individuals with CDD, whose ages ranged from 2 to 30 years (median 13 years), 15 were female, and most did not use words. Semistructured interviews were conducted via videoconference and analyzed using a conventional content analysis. Three overarching categories were identified: mode, purpose and meaning, and reciprocal exchanges. These categories described the purposes and mechanism of how some individuals with CDD communicate, including underpinning influential factors. Novel categories included expressing a range of emotions, and reciprocal exchanges (two-way interactions that varied in complexity). Caregivers observed many communication modes for multiple purposes. Understanding how individuals with CDD communicate improves understanding of the condition and will guide research to develop accurate measurement for clinical practice and upcoming medication trials.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

CDKL5 deficiency disorder and other infantile-onset genetic epilepsies.

AIM: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile-onset epilepsies. METHOD: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile-onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank-sum tests and χ2 or Fisher's exact tests were performed for between-cohort comparisons. RESULTS: We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow-up 3 year 11 months) and 313 individuals with infantile-onset epilepsies (156 females, 49.8%; median age at last follow-up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment-resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox-Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). INTERPRETATION: CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment-resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment.

The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder.

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity. METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended. RESULTS: The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects. CONCLUSIONS: This study modified the caregiver portion of the initial CCSA and provided evidence for its content and response process validity.

Validating the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder.

CDKL5 deficiency disorder (CDD) results in early-onset epilepsy and lifelong cognitive and motor impairments. With no validated measure for communication in CDD, this study evaluated the psychometric properties of the Communication and Symbolic Behavior Scales-Developmental Profile Infant Toddler Checklist (CSBS-DP ITC). Caregivers (n = 150; affected individuals aged 1-29 years) completed the CSBS-DP ITC. Distribution of scores indicated a floor effect. There was poor divergent validity for the three-factor model but goodness of fit and convergent validity data were satisfactory for the one-factor model. Individuals with poorer overall functional abilities scored lower on the CSBS-DP ITC. Test-retest reliability was excellent. The floor effect could explain the very high reliability, suggesting problems as a sensitive outcome measure in clinical trials for CDD.

Epilepsy panels in clinical practice: Yield, variants of uncertain significance, and treatment implications.

OBJECTIVE: There has been increasing utilization of genetic testing for pediatric epilepsy in recent years. Little systematic data is available examining how practice changes have impacted testing yields, diagnostic pace, incidence of variants of uncertain significance (VUSs), or therapeutic management. METHODS: A retrospective chart review was performed at Children's Hospital Colorado from February 2016 through February 2020. All patients under 18 years for whom an epilepsy gene panel was sent were included. RESULTS: A total of 761 epilepsy gene panels were sent over the study period. During the study period, there was a 292% increase in the average number of panels sent per month. The time from seizure onset to panel result decreased over the study period from a median of 2.9 years to 0.7 years. Despite the increase in testing, the percentage of panels yielding a disease-causing result remained stable at 11-13%. A total of 90 disease-causing results were identified, > 75% of which provided guidance in management. Children were more likely to have a disease-causing result if they were < 3 years old at seizure onset (OR 4.4, p < 0.001), had neurodevelopmental concerns (OR 2.2, p = 0.002), or had a developmentally abnormal MRI (OR 3.8, p < 0.001). A total of 1417 VUSs were identified, equating to 15.7 VUSs per disease-causing result. Non-Hispanic white patients had a lower average number of VUSs than patients of all other races/ethnicities (1.7 vs 2.1, p < 0.001). SIGNIFICANCE: Expansion in the volume of genetic testing corresponded to a decrease in the time from seizure onset to testing result. Diagnostic yield remained stable, resulting in an increase in the absolute number of disease-causing results annually-most of which have implications for management. However, there has also been an increase in total VUSs, which likely resulted in additional clinical time spent on VUS resolution.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

OBJECTIVE: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

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).

OBJECTIVE: Chromosome 15q duplication (Dup15q) syndrome and cyclin­dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275). METHODS: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs). RESULTS: The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported. CONCLUSIONS: Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome.

Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder.

Introduction: SLC6A1-related disorder is a genetic neurodevelopmental disorder that is caused by loss of function variants in the SLC6A1 gene. Solute Carrier Family 6 Member 1 (SLC6A1) gene encodes for gamma-aminobutyric acid (GABA) transporter type 1 (GAT1), which is responsible for reuptake of GABA from the synaptic cleft. Tight regulation of GABA levels plays an important role in brain development by balancing inhibitory and excitatory neuronal signaling. Consequently, individuals with SLC6A1-related disorder can have manifestations such as developmental delay, epilepsy, autism spectrum disorder, and a subset have developmental regression. Methods: In this study, we identified patterns of developmental regression among a cohort of 24 patients with SLC6A1-related disorder and assessed for clinical characteristics associated with regression. We reviewed medical records of patients with SLC6A1-related disorder and divided subjects into two groups: 1) regression group and 2) control group. We described the patterns of developmental regression including whether there was a trigger prior to the regression, multiple episodes of regression, and whether or not skills were recovered. We assessed the relationship of clinical characteristics among the regression and control groups including demographic factors, seizures, developmental milestone acquisition, gastrointestinal problems, sleep problems, autism spectrum disorder, and behavioral problems. Results: Individuals with developmental regression had a loss of skills that were previously mastered in developmental domains including speech and language, motor, social, and adaptive skills. The mean age at regression was 2.7 years and most subjects had regression of language or motor skills triggered by seizures, infection, or spontaneously. Although there was no significant difference in clinical characteristics between the two groups, there was a higher prevalence of autism and severe language impairment in the regression group. Discussion: Future studies of a larger cohort of patients are required to make definitive conclusions. Developmental regression is often a sign of severe neurodevelopmental disability in genetic syndromes, but it is poorly understood in SLC6A1-related disorder. Understanding the patterns of developmental regression and the associated clinical characteristics in this rare disorder will be important to medical management, prognostication, and could impact the design of future clinical trials.

Psychometric properties of QI-Disability in CDKL5 Deficiency Disorder: Establishing readiness for clinical trials.

CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder with symptoms of epilepsy, developmental impairments, and other comorbidities. Currently, there are no outcome measures for CDD with comprehensive evidence of validation. This study aimed to evaluate the psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) in CDD. Quality of Life Inventory-Disability was administered to 152 parent caregivers registered with the International CDKL5 Disorder Database (ICDD). Confirmatory factor analysis was conducted and the goodness of fit of the factor structure was assessed. Fixed-effects linear regression models examined the responsiveness of QI-Disability to reported changes in child health. A subset of parent caregivers (n = 56) completed QI-Disability, as well as additional health-related questions, on two occasions separated by four weeks to evaluate test-retest reliability. Test-retest reliability was assessed using intra-class correlations (ICCs) calculated from QI-Disability scores. Based upon adjustments for changes in child health, ICCs were recalculated to estimate responsiveness to change. Confirmatory factor analysis, internal consistency, and divergent validity were mostly satisfactory, except divergent validity was not satisfactory for the Social Interactions and Independence domains. The Physical Health, Social Interactions, Leisure, and Total scores responded to changes in the child's Physical health, and the Negative Emotions and Leisure domains responded to changes in the child's behavior. Unadjusted and adjusted ICC values were above 0.8 for the Positive Emotions, Negative Emotions, Social Interactions, Leisure, Independence domains and Total score, and above 0.6 for the Physical Health domain. Findings suggest that QI-Disability is suitable to assess the quality of life of children and adults with CDD and could be of value for upcoming clinical trials.

Analysis of electrocardiograms in individuals with CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an epileptic encephalopathy associated with medically refractory epilepsy. We sought to determine whether prolonged corrected QT interval (QTc) or other cardiac conduction abnormalities were seen in CDD in a clinical cohort. A cohort of individuals with CDD was evaluated in the Children's Hospital Colorado's International Foundation for CDKL5 Research designated Center of Excellence clinic with routine electrocardiograms obtained as part of routine clinical care. Retrospective review of electrocardiograms was completed. ECGs from 44 individuals (7 male, 37 female, age range 0-34.5 years) with pathogenic mutations and findings consistent with CDD were evaluated. Multiple ECGs were available from the 44 individuals obtained from 1996 to 2020. Prolonged QTc was found in two individuals (4.5%) and either resolved or was not confirmed on Holter monitor; no additional interventions were performed. A total of 11 individuals had echocardiograms for a variety of indications including unexplained tachycardia and ECG abnormalities; all were normal. Two individuals in the cohort died during the study with no abnormal findings on ECG. The incidence of prolonged QTc or other significant actionable cardiac abnormalities was rare in a cohort of individuals with CDD though was higher than the prevalence seen within the general population. Further studies in a larger, confirmatory cohort over a longer period are needed.

Factors influencing the attainment of major motor milestones in CDKL5 deficiency disorder.

This study investigated the influence of factors at birth and in infancy on the likelihood of achieving major motor milestones in CDKL5 Deficiency Disorder (CDD). Data on 350 individuals with a pathogenic CDKL5 variant was sourced from the International CDKL5 Disorder Database. A first model included factors available at birth (e.g., sex, variant group and mosaicism) and the second additionally included factors available during infancy (e.g., age at seizure onset, number of anti-seizure medications used, experience of a honeymoon period and formal therapy). Cox regression was used to model the time to achieve the milestones. The probability of attaining the outcomes at specific ages was estimated by evaluating the time-to-event function at specific covariate values. Independent sitting and walking were achieved by 177/350 and 57/325 children respectively. By seven years of age, 67.1% of females but only 37.3% of males could sit independently. About a quarter each of females and males achieved independent walking by eight and six years, respectively. When observed from birth, female gender, a late truncating variant and mosaicism impacted most positively on the likelihood of independent sitting. When observed from one year, later seizure onset and experiencing a honeymoon period also improved the likelihood of independent sitting. Factors that favoured sitting (except gender) also improved walking. Having a truncating variant between aa178 and aa781 reduced the likelihood of achieving independent sitting and walking. It is possible to utilise factors occurring early in life to inform the likelihood of future motor development in CDD.

Quality of life beyond diagnosis in intellectual disability - Latent profiling.

OBJECTIVE: To compare quality of life (QOL) across diagnoses associated with intellectual disability, construct QOL profiles and evaluate membership by diagnostic group, function and comorbidities. METHOD: Primary caregivers of 526 children with intellectual disability (age 5-18 years) and a diagnosis of cerebral palsy, autism spectrum disorder, Down syndrome, CDKL5 deficiency disorder or Rett syndrome completed the Quality of Life Inventory-Disability (QI-Disability) questionnaire. Latent profile analysis of the QI-Disability domain scores was conducted. RESULTS: The mean (SD) total QOL score was 67.8 (13.4), ranging from 60.3 (14.6) for CDD to 77.5 (11.7) for Down syndrome. Three classes describing domain scores were identified: Class 1 was characterised by higher domain scores overall but poorer negative emotions scores; Class 2 by average to high scores for most domains but low independence scores; and Class 3 was characterised by low positive emotions, social interaction, and leisure and the outdoors scores, and extremely low independence scores. The majority of individuals with autism spectrum disorder and Down syndrome belonged to Class 1 and the majority with CDKL5 deficiency disorder belonged to Class 3. Those with better functional abilities (verbal communication and independent walking were predominately members of Class 1 and those with frequent seizures were more often members of Class 2 and 3. CONCLUSION: The profiles illustrated variation in QOL across a diverse group of children. QOL evaluations illustrate areas where interventions could improve QOL and provide advice to families as to where efforts may be best directed.

International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.

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.

Whole-exome sequencing and adrenocorticotropic hormone therapy in individuals with infantile spasms.

AIM: To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms. METHOD: Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease. RESULTS: Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology. INTERPRETATION: This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High-priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.

Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress.

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.

CDKL5 deficiency disorder: clinical features, diagnosis, and management.

CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures that are usually refractory to polypharmacy. Development is severely impaired in patients with CDD, with only a quarter of girls and a smaller proportion of boys achieving independent walking; however, there is clinical variability, which is probably genetically determined. Gastrointestinal, sleep, and musculoskeletal problems are common in CDD, as in other developmental epileptic encephalopathies, but the prevalence of cerebral visual impairment appears higher in CDD. Clinicians diagnosing infants with CDD need to be familiar with the complexities of this disorder to provide appropriate counselling to the patients' families. Despite some benefit from ketogenic diets and vagal nerve stimulation, there has been little evidence that conventional antiseizure medications or their combinations are helpful in CDD, but further treatment trials are finally underway.