The aim of this study was to review and summarize the literature describing clinically observed or caregiver-reported and patient-reported KCNQ2 developmental and epileptic encephalopathy (DEE) outcomes. Three online databases and selected congress proceedings were searched (August 2023). Case reports and series, observational studies, non-randomized and single-arm trials, and registries and databases reporting seizure-related and non-seizure-related outcomes in patients aged 18 years or younger with KCNQ2 DEE were eligible for inclusion. Results were summarized according to outcome type (seizure-related and non-seizure-related) and patient age. Of 92 publications reporting KCNQ2 DEE outcomes, 70 reported patient-level data, of which the most common age was younger than 5 years old. Seizures were frequently reported (69 of 70 publications for 338 patients). Seizure onset was primarily within the first week of life (n = 334 of 356 seizure events; 93.8%), with frequency commonly reported as 'multiple daily'. Seizure resolution was reported for 56.2% of patients; most (87.0%) achieved resolution by age 5 years. Seventy publications reported non-seizure-related outcomes for 289 patients. Neurological (73.3%) and developmental (52.9%) manifestations were frequently reported, with muscle tone (71.7%), gross motor (67.3%), and communication (66.6%) impairments being most common. Similar findings were observed across 23 publications reporting pooled patient data. While seizures were typically resolved in early life, non-seizure-related outcomes gained more prominence as children aged, highlighting the evolving challenges for individuals living with KCNQ2 DEE.

Valid neurodevelopmental assessments for individuals with profound intellectual and multiple disabilities (PIMD) and/or developmental and epileptic encephalopathy (DEE) are critical for clinical trials and clinical care as families report functional abilities are a priority for improvement. However, most extant tools have limited ability to measure relevant skills and meaningful change for individuals with severe to profound impairment. We evaluated the psychometric properties of the Developmental Profile, Fourth Edition (DP-4), a measure of neurodevelopmental functioning, in individuals with DEE and/or PIMD (Mdn = 8.4 years, range 1-50, 54% female). Two hundred and nineteen caregivers completed the DP-4 during a larger online survey, DEE Parents Speak. In this etiologically diverse sample, neurodevelopmental functioning was very low, with norm-referenced scores at the floor for greater than 50% of individuals on all subscales (age equivalencies 6-10 months). Rasch analysis of DP-4 scores, comparison by known groups, and comparison with other measures of functional abilities suggest initial evidence of construct and convergent validity. During focus groups and interviews, caregivers reported DP-4 components that were relevant for their child and threats to content validity. The DP-4 may be a valid measure of neurodevelopment for individuals with PIMD and/or DEE in clinical care and trials, although additional study is necessary, especially to evaluate responsiveness to change.

OBJECTIVE:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs). METHODS:This cross-sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss-Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder. RESULTS:A total of 92 patients were enrolled (age range = 18-51 years, mean = 27.93 ± 8.59 years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty-three percent screened positive for social communication deficits. SIGNIFICANCE:This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.

AIM:To investigate how caregivers of children with developmental and epileptic encephalopathy and severe developmental impairments describe meaningful change for functional domains and why it is important. METHOD:This was a convergent mixed-methods design study. A survey was completed by 267 parents of children aged 12 months or older. For prioritized functional domains (communication, gross motor, fine motor, eating), parents reported the smallest improvement that would be important and explained why. Data were analyzed using directed content analysis and meaningful change codes were mapped to impairment levels. RESULTS:The median age of the children was 8 years 8 months (interquartile range 4 years 2 months-14 years 6 months) and 149 (55.8%) were female. Content analysis yielded 86 meaningful change codes. Common codes described capacity to communicate preferences and emotions, gain sitting and walking skills, grasp objects for play, eat foods without choking, or using utensils. Some codes were reported for each impairment level (e.g. communicating needs/wants/likes for expressive communication); others were specific to an impairment level (e.g. gaining head control if unable to walk). Meaningful change was anticipated to affect health, independence and safety, care regimens, and quality of life of affected individual and families. INTERPRETATION:The meaningful change codes indicate critical components within domains for evaluations in clinical trials.

Background and Objectives SCN2A-related disorders (RDs) are genetic conditions characterized by severe to profound impairments in multiple domains including gross motor function, which could serve as a nonseizure outcome in precision medicine therapy trials. This study evaluated specific properties of the Vineland Adaptive Behavior Scales-3 (VABS3) and other motor assessments for their fitness for use in trials of SCN2A-RDs. Methods Sixty-five families recruited through the FamileSCN2A foundation enrolled their affected children ("participants," 28 female, median age 6.4 years, interquartile range [IQR] 4.1-10.5) in a 1-year, longitudinal study. Assessments were administered at 0 (study entry), 6, and 12 months. Assessments included the VABS3, Adaptive Behavior Assessment System 0-5 years (ABAS), a modified Functional Mobility Scale (FMS), and the Functional Activities Questionnaire-Walking Level (FAQ-WL). Results The VABS3 composite score (34 [IQR 26-46]) indicated overall adaptive function >4 SDs below the normative mean. Forty percent of participants aged 2 years or older required wheelchairs for home distances, and 28% could not take any steps. The median standardized scores (SSs) for the VABS3 motor domain (20 [IQR 20-32]) and gross motor subdomain (1 [IQR 1-2]) reflected performance at the floor of the measures. Standardized motor scores discriminated poorly among participants with different levels of mobility (FAQ-WL and FMS) and different markers of diseases severity (presence of epilepsy, history of epileptic spasms, number of seizure medications). Cross-sectionally, SSs declined with increasing age. By contrast, raw scores of the VABS3 and ABAS and growth scale values (GSVs) of the VABS3 had relatively little floor effects. They distinguished well between participants based on FAQ-WL and FMS scores and between those with different disease severity markers. Test-retest and inter-rater reliability for all scores were excellent. No motor score changed significantly over time in the longitudinal analyses. Discussion Gross motor function in people with SCN2A-RDs is so severely impaired that it cannot be adequately measured with norm-referenced (standardized) scores. GSVs and alternative scoring assessments used out of their intended age range have superior and promising psychometric features in this severely impaired group, and they should be considered in future precision medicine trials for SCN2A-RDs and other similarly severe, rare disorders.

OBJECTIVES:This study assessed impacts of non-seizure outcomes and caregiver priorities for improvement in individuals with severe neurodevelopmental encephalopathy with or without epilepsy (SNDE ± E). METHODS:In an online survey of parents recruited from several patient advocacy groups, parents rated the impacts of 17 non-seizure outcome domains on their children and identified their top three priority domains for improvement. Bivariate and stratified analyses compared impacts and priorities by burden of severe functional impairments, age, and diagnoses. RESULTS:Of 267 participants, 149 (56 %) were female (median [interquartile range] age: 8.7y [4.2y - 14.7y) and 169 (63 %) had epilepsy diagnoses. Profound impairments were reported for mobility (N = 142, 53 %), communication (N = 208, 78 %), eating (N = 100, 37 %), and hand use (N = 93, 35 %). Expressive communication had overwhelming or significantly negative impacts in 217 (83 %) followed by receptive communication (N = 185, 70 %). Parents identified expressive communication as a top (N = 211, 79 %) priority for improvement. The impact and prioritization of expressive communication were independent of other functional impairments, age, and other diagnoses. For those with epilepsy, relative to non-seizure outcomes, seizures were rated as more important by 35 % and of similar or less importance by 65 %; this strongly depended on recency of the last seizure (p < 0.0001). CONCLUSIONS:Improvement in expressive communication is a top priority in the SNDEs ± E and could be a valuable non-seizure outcome in future therapeutic trials for these rare diseases.

OBJECTIVE:This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). METHODS:Infants aged 2-24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high-dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal-to-hormonal, hormonal-to-nonstandard, vigabatrin-to-hormonal, and vigabatrin-to-nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3-month clinical remission using a binary logistic regression to estimate odds ratios (ORs). RESULTS:There were 153 infants with IESS who received second treatments. The highest rates of 3-month remission were among infants in the hormonal-to-vigabatrin (22/65, 34%) and vigabatrin-to-hormonal (9/26, 35%) groups, followed by vigabatrin-to-nonstandard (3/10, 30%), hormonal-to-hormonal (4/22, 18%), and hormonal-to-nonstandard (1/30, 3.3%). Compared to the hormonal-to-vigabatrin group (reference), fewer infants had remission in the hormonal-to-nonstandard group (OR = .07, 95% confidence interval [CI] = .01-.53), and there was a trend toward fewer infants in the hormonal-to-hormonal group (OR = .43, 95% CI = .13-1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. SIGNIFICANCE:This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Objectives: For individuals living with rare neurodevelopmental disorders, particularly those who are at the most severe end of the spectrum, standardized outcome measures may lack the sensitivity to capture small but meaningful changes. Personalized endpoints such as goal attainment scaling (GAS) allow the assessment of treatment response across variable baseline states and disease manifestations and, thus, provide a highly sensitive measure of efficacy. The current study tested the feasibility of using GAS in rare SCN2A-associated developmental and epileptic encephalopathy (SCN2A-DEE). Methods: The caregivers of 10 individuals with SCN2A-DEE (Mage = 8.2 years, SD = 5.62, range 3.420.4; Nmale = 8) took part in in-person goal setting and remote follow-up interviews facilitated by 4 clinical researchers. Implementation was standardized using clinician training, patient orientation, and an electronic data capture platform, GoalNav (R); surveys were used to evaluate implementation. Results: All 10 caregivers completed the goal-setting interviews and were able to set scale 3 goals, and assess attainment levels at follow-up interviews. The mean (SD) times to conduct the goal setting and follow-up interviews were 59.4 (14.5) and 18.4 (10.5) minutes, respectively. Participants set a variety of goals relating to communication (n = 10), feeding (n = 4), gross and fine motor abilities (n = 6), behavior (n = 5), gastrointestinal function (n = 3), sleep (n = 1), and seizures (n = 1). Data completeness, interview time, and the presence of high-quality goals (29/ 30) indicated the feasibility of using GAS in this population, whereas survey responses indicated its acceptability. Conclusions: This pilot project provided evidence supporting the feasibility of GAS as a method for assessing treatment outcomes for patients with rare neurodevelopmental disorders.

Purpose: The Vineland Adaptive Behavior Scales-3rd Edition (Vineland-3) is one of the most used measures of adaptive behavior among those with sodium channel protein type 2 subunit alpha related disorders (SCN2A-RDs). Several disease-modifying treatments are in early trials for SCN2A-RDs, and as such, clinical outcome assessments (COAs) are necessary. The Vineland-3 introduced growth scale values (GSVs), which are useful for measuring within-person change and thus may be useful in future clinical trials. The purpose of this study was to evaluate the psychometric properties of the Vineland-3 GSVs in SCN2A-RDs in preparation for future clinical trials. Methods: A sample of 65 individuals with SCN2A-RDs (mean = 108, SD = 76.0 months) was recruited for a clinical trial readiness study. The Vineland-3 Comprehensive Interview was administered by trained raters at regular intervals. Multiple psychometric properties were evaluated, including floor and ceiling effects, split-half internal consistency, test-retest reliability, and inter-rater reliability (on approximately 20% of all completions). Results: Floor effects were relatively infrequent on the GSV metric but occurred on all subdomains using the norm-referenced v-scale metric. Split-half and test-retest reliability were excellent for all subdomains (rxx >0.95 and inter-class correlation coefficient [ICC] >0.90, respectively), except for coping, which still maintained adequate reliability (rxx = 0.87, ICC = 0.65). Inter-rater reliability was also very strong, though it was more variable (αkripp range 0.78-1.00). Conclusion: The Vineland-3 holds great potential as a COA in SCN2A-RDs; it exhibited very strong psychometric properties in this sample. This is a prerequisite level of evidence needed to demonstrate that a measure is fit-for-purpose for future clinical trials. While some reliability was high, some domains (e.g., domestic) still exhibited problems related to floor effects, which may suggest that they are less relevant to this population. Future studies should expand on this with mixed-methods research for prioritizing concepts of interest on the Vineland-3.

SCN2A-related disorders (RDs) are genetic conditions characterized by severe to profound impairments in multiple domains including gross motor function, which could serve as a nonseizure outcome in precision medicine therapy trials. This study evaluated specific properties of the Vineland Adaptive Behavior Scales-3 (VABS3) and other motor assessments for their fitness for use in trials of SCN2A-RDs. Sixty-five families recruited through the FamileSCN2A foundation enrolled their affected children ("participants," 28 female, median age 6.4 years, interquartile range [IQR] 4.1-10.5) in a 1-year, longitudinal study. Assessments were administered at 0 (study entry), 6, and 12 months. Assessments included the VABS3, Adaptive Behavior Assessment System 0-5 years (ABAS), a modified Functional Mobility Scale (FMS), and the Functional Activities Questionnaire-Walking Level (FAQ-WL). The VABS3 composite score (34 [IQR 26-46]) indicated overall adaptive function >4 SDs below the normative mean. Forty percent of participants aged 2 years or older required wheelchairs for home distances, and 28% could not take any steps. The median standardized scores (SSs) for the VABS3 motor domain (20 [IQR 20-32]) and gross motor subdomain (1 [IQR 1-2]) reflected performance at the floor of the measures. Standardized motor scores discriminated poorly among participants with different levels of mobility (FAQ-WL and FMS) and different markers of diseases severity (presence of epilepsy, history of epileptic spasms, number of seizure medications). Cross-sectionally, SSs declined with increasing age. By contrast, raw scores of the VABS3 and ABAS and growth scale values (GSVs) of the VABS3 had relatively little floor effects. They distinguished well between participants based on FAQ-WL and FMS scores and between those with different disease severity markers. Test-retest and inter-rater reliability for all scores were excellent. No motor score changed significantly over time in the longitudinal analyses. Gross motor function in people with SCN2A-RDs is so severely impaired that it cannot be adequately measured with norm-referenced (standardized) scores. GSVs and alternative scoring assessments used out of their intended age range have superior and promising psychometric features in this severely impaired group, and they should be considered in future precision medicine trials for SCN2A-RDs and other similarly severe, rare disorders.

OBJECTIVE:Variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with developmental and epileptic encephalopathy (DEE) of varying severity. This study examined the relationship of KCNQ2 variant dysfunction with the neurodevelopmental phenotype of individuals with KCNQ2-DEE. METHODS:A parent-reported survey gathered clinical and genetic data for individuals with KCNQ2-DEE. Several clinical features were analyzed separately and as a composite non-seizure phenotype severity score (PSS) for six features (mobility, communication, hand use, eating, scoliosis, cerebral visual impairment). The effect of variants on KV7.2 channel function was determined by voltage-clamp recording in heterologous cells co-expressing KV7.3. Functional effects were classified as severe loss of function (SLOF), loss of function (LOF), wild-type-like (WTL), and gain of function (GOF). RESULTS:The study included 48 individuals each heterozygous for one of 38 unique variants. Median seizure-onset age was 1 day. Complete or significant seizure reduction was reported in 7/13 with carbamazepine, 13/17 with oxcarbazepine, 10/13 with phenytoin, and 3/4 with retigabine. The median PSS was 1 (interquartile range 1-3). On the participant level, 29 had SLOF variants, 13 had LOF variants, and the remaining participants had variants with GOF (3) or exhibited WTL (2) function. There were no significant associations of variant function with individual phenotypes in the PSS; however, the PSS itself was higher in those with SLOF versus LOF variants (p = 0.02). Among individuals with SLOF or LOF variants, there was an intriguing lower prevalence of epileptic spasms among individuals with dominant-negative variants. SIGNIFICANCE:Multiple and severe neurodevelopmental impairments are common in KCNQ2-DEE. There was a modest correlation between KV7.2 channel dysfunction and overall non-seizure phenotype severity in this cohort. These findings suggest that factors other than differences in channel dysfunction contribute to variable clinical severity in KCNQ2-DEE. PLAIN LANGUAGE SUMMARY:We examined how changes in the KCNQ2 gene, which affect the function of a brain potassium channel, relate to developmental and seizure features in children with KCNQ2-related epilepsy. Using parent surveys and lab studies of gene variants, we found that variants causing the channel to lose most of its function were linked to slightly worse overall development. Our results suggest that while channel dysfunction plays a role, other biological or environmental factors likely influence how severely children are affected.

BACKGROUND:KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) is a rare pediatric disorder characterized by seizures and neurodevelopmental impairments. Parent- and healthcare professional (HCP)-reported outcomes regarding the impacts of seizures and neurodevelopmental impairments may guide the design of clinically meaningful KCNQ2-DEE outcome measures. METHODS:Parents of children with KCNQ2-DEE (N = 53) and HCPs with KCNQ2-DEE expertise (N = 2) participated in qualitative interviews exploring signs, symptoms, and impacts of KCNQ2-DEE, and how varying KCNQ2-DEE phenotypes affect child development. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.Ti v23 software. RESULTS:The most common KCNQ2-DEE concepts parents reported were difficulties with communication (88.9 %), and gross (81.5 %) and fine (63.0 %) motor problems. Difficulty with communication (74.1 %), behavioral disorders (37.0 %), and gross motor problems (24.1 %) were the most impactful and bothersome issues for parents. When asked to rate how impacted they were by each concept (0 = "not impacted" to 10 = "extremely impacted"), the most bothersome symptoms were difficulty with communication (mean score [SD] = 8.6 [1.7]; 87.0 % of parents), cognitive delays (8.1 [2.0]; 37.0 % parents), and personal care and hygiene issues (7.4 [2.2]; 29.6 % parents). Seizures were the least bothersome symptom post-infancy (mean score [SD] = 5.3 [3.6]; 87.0 % parents). Children's developmental abilities varied substantially within and between KCNQ2-DEE phenotypes and across age groups. Overall, HCPs reported largely similar concepts to parents of children with KCNQ2-DEE. CONCLUSIONS:These findings identify outcome domains important to those with KCNQ2-DEE and may inform the development of measurement tools and endpoint selection for therapeutic trials.

PURPOSE:This subgroup analysis of the BECOME (BEhavior, COgnition, and More with Epidiolex®) survey analyzed caregiver-reported seizure and non-seizure outcomes, including changes in caregiver burden, following cannabidiol (CBD) treatment in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) aged ≥2 years taking concomitant clobazam, aligned with the European Medicines Agency indication. METHODS:US-based caregivers of patients with LGS/DS receiving CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months rated patient outcome changes, comparing the previous month with pre-CBD initiation. Multiple-choice and rank-order questions with symmetrical 3-, 5-, or 7-point scales ranging from worsening to improvement were used. RESULTS:Patients (N = 243; 76 % LGS, 24 % DS; 52 % male; mean [range] age 15 [2-53] years) took a median of 14 mg/kg/day CBD and a median of four other antiseizure medications, including clobazam. Caregivers reported improvements in seizure frequency (87 %), severity (81 %), and weekly seizure-free days (net improvement across seizure types 68 %). Caregivers noted improvements in ≥1 question for non-seizure domains (net data across questions within each domain): alertness, cognition, and executive function (84 %); language and communication in non-verbal (81 %) and verbal (76 %) patients; emotional and social functioning (79 %); daily activities (56 %); physical functioning (44 %); and sleep (56 %). Additionally, 4-26 % of caregivers (net) reported worsening in ≥1 question in any domain. Overall, 94 % of caregivers planned to continue CBD treatment. CONCLUSIONS:Consistent with the overall BECOME survey, most caregivers of patients with LGS/DS aged ≥2 years taking concomitant clobazam reported improvements in seizure and non-seizure outcomes since initiating CBD treatment.

What is this summary about? Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare forms of epilepsy that start in childhood and cause life-long disability. People with LGS and DS experience many seizure types and nonseizure-related problems with cognition (ability to think and understand), learning, behaviour and communication. People with LGS and DS depend on caregivers to assist with daily activities. Although many medications are available to treat seizures associated with LGS and DS, the effect on nonseizure outcomes is unclear. A highly purified (defined as a substance that has undergone a special process to remove impurities) oral (by mouth) solution of cannabidiol (CBD; Epidiolex®) from plants is approved by the United States (US) Food and Drug Administration (FDA) for the treatment of seizures associated with LGS, DS and tuberous sclerosis complex in people who are at least 1 year old. In clinical studies, treatment with CBD reduced the number of seizures. Common side effects (secondary, typically unintended effects of the medication) were increased liver enzyme levels, sleepiness, decreased appetite, diarrhea, fever, vomiting, tiredness, rash, problems with sleep and infections. CBD may also improve nonseizure outcomes, such as cognition, behavior and quality of life. The BEhavior, COgnition and More with Epidiolex® (BECOME) survey was designed to find out whether caregivers of people with LGS or DS taking CBD noticed changes in nonseizure and seizure outcomes. What are the key takeaways? Caregivers of people with LGS or DS taking CBD noticed improvements in cognition, language and communication, emotional and social functioning, physical functioning, sleep and ability to do daily activities, as well as a reduction in the number and severity of seizures. People with reduction in seizures were more likely to experience nonseizure benefits, but some people without seizure reduction also experienced improvements in nonseizure outcomes. Caregivers reported that both seizure and nonseizure effects were important when thinking about treatment options. What were the main conclusions reported by the researchers? The BECOME survey provides a unique caregiver perspective on nonseizure outcomes that may be affected by CBD. These results support further study of CBD for nonseizure outcomes in people with LGS or DS.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relationship to channel function, 81 patients (36 female, 44%, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their Nav1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal onset, n = 27; infant onset, n = 18; and later onset n = 24; and autism without seizures, n = 12) was strongly correlated with a non-seizure severity index (P = 0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (P = 0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score of 49.5 (>3 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was also strongly correlated with variant function (P < 0.0001); gain-of-function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy and to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) and severe/complete loss-of-function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relationship between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on Nav1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance towards clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Background and Objectives SCN2A-related disorders (SCN2A-RDs) entail severe impairments in multiple domains that could serve as nonseizure outcomes in clinical trials. This study evaluated the fitness for purpose of several clinical instruments with both standardized and alternative scoring and with some measures used out of their intended age range for assessing communication in SCN2A-affected participants. Methods Parents of SCN2A-affected children were recruited through FamilieSCN2A Foundation outreach for a combined cross-sectional and longitudinal study. They completed assessments of their children at study entry and 6 and 12 months later. Assessments included the Vineland Adaptive Behavior Scale (VABS-3), Adaptive Behavior Assessment System (ABAS), Communication Matrix, and Communication and Symbolic Behavior Scale (CSBS). Analyses examined floor and ceiling effects, inter-rater and test-retest reliability, discrimination among different levels of functional impairment, and sensitivity to clinical aspects of SCN2A-RDs. Results Of 65 participants (28 females, median age 6.4 years, IQR 4.1-10.5), 56 (86%) had epilepsy. Eleven (17%) used speech as their primary communication mode; 84% were considered ineffective communicators. The mean Vineland composite standardized score (SS) was 34 (IQR 26-46). Cross-sectionally, standardized scores decreased with increasing age. There were substantial floor effects for receptive (75%) and expressive (83%) communication. SSs discriminated poorly between verbal vs nonverbal and communicative vs noncommunicative participants and were not sensitive to features reflecting epilepsy severity (e.g., epileptic spasms and number of current medications). By contrast, Vineland growth scale value (GSV) and ABAS, Matrix, and CSBS raw scores had minimal floor effects; most increased with age. These alternative scores distinguished clearly between participants with different levels of communication and were sensitive to aspects of epilepsy severity. Longitudinally, SSs decreased, but other scores remained relatively stable over a year. Discussion SCN2A-RD is characterized by severe-to-profound impairment with a SS <4 SDs of the norm-referenced mean. Owing to severe floor effects and their insensitivity to markers of communication function, age-standardized scores (e.g., Vineland SS) are not fit for purpose in clinical trials or other settings for evaluating nonseizure outcomes such as communication. GSVs and alternative scoring and assessments have much better measurement profiles in all these regards and should be considered in future precision medicine trials for SCN2A-RDs and other similar rare diseases.