Abstract
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.
CDKL5 deficiency disorder, compared to other infantile-onset suspected or confirmed genetic epilepsies presenting in the first year of life is more often characterized by a combination of refractory seizures, seizures with multiple phases, diffuse hypotonia, CVI, and paroxysmal movement disorders. Defining core phenotypic characteristics of CDKL5 deficiency disorder will improve precision diagnosis and treatment.
Graphical Abstract
CDKL5 deficiency disorder, compared to other infantile-onset suspected or confirmed genetic epilepsies presenting in the first year of life is more often characterized by a combination of refractory seizures, seizures with multiple phases, diffuse hypotonia, CVI, and paroxysmal movement disorders. Defining core phenotypic characteristics of CDKL5 deficiency disorder will improve precision diagnosis and treatment.
CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe X-linked, infantile developmental and epileptic encephalopathy (DEE) syndrome.1–8 CDD occurs in 1 out of 40 000 to 1 out of 60 000 births, affecting females and males at a ratio of approximately 4:1.3 Pathogenic or likely pathogenic variants in the CDKL5 gene are among the most commonly identified positive findings on epilepsy panels.9
Phenotypic data on CDD, including epilepsy, developmental profile, and physical examination features, are largely collected from case studies without direct comparison with other infantile-onset genetic epilepsies.1–7 Typical features include treatment-resistant early infantile-onset epilepsy (90% with epilepsy onset within the first 3 months of life), global developmental delay, intellectual disability, hypotonia, and cerebral visual impairment (CVI).1–6 Although previously considered an early-onset seizure variant of Rett syndrome, CDD has since been distinguished from both Rett syndrome and FOXG1 as an independent disorder with severe developmental delays, increased likelihood of epilepsy, and a less common incidence of the developmental regression and core features that characterize Rett syndrome.4,8,10–12 There have not been studies directly comparing CDD with other genetic infantile-onset DEEs (e.g. KCNQ2, STXBP1, SCN2A).13
While broad genetic testing in early-life epilepsy is becoming a standard of care in the USA and Europe, interpretation of results and consideration of further testing or re-analysis of genetic data relies on a clear understanding of phenotype–genotype correlations.14 Our aim in this study was to identify phenotypic features that differentiate individuals with CDD from those of individuals with other infantile-onset epilepsies with suspected or confirmed genetic etiology.
METHOD
Ethics approval
Data for this study were collected by institutional review board-approved protocols at Boston Children’s Hospital, Cleveland Clinic, and Children’s Hospital Colorado, with informed consent or waiver of consent for retrospective data collection.
Cohorts
A retrospective cohort study was conducted. The CDD cohort contained 137 individuals meeting the proposed diagnostic criteria for CDD: a pathogenic or likely pathogenic variant in CDKL5, epilepsy onset in the first year of life, and motor and cognitive delays.3 All individuals were seen at one of the dedicated CDKL5 Centers of Excellence between 2010 and 2021 (Boston Children’s Hospital, n = 57; Cleveland Clinic, n = 29; University of Colorado/Children’s Hospital Colorado, n = 51).3,6
The comparison cohort, exclusively from Boston Children’s Hospital, consisted of individuals with epilepsy onset before 1 year of age with a suspected or confirmed genetic etiology. We identified patients as having a suspected genetic etiology if an epilepsy gene panel was done through the Boston Children’s Hospital as part of their workup at any time. From an initial sample of 640 individuals who underwent epilepsy gene panel testing sent to the contracted commercial laboratory GeneDx between 2012 and 2019, we reviewed medical records to confirm the diagnosis of epilepsy as defined by the International League Against Epilepsy and limited our cohort to those with seizure onset before 1 year of age (n = 313).15,16 For 110 of 313 individuals (35.1%), a genetic diagnosis was established through the epilepsy gene panel or additional genetic testing done at any point (chromosomal microarray, targeted genetic test, or exome sequencing). During the study period, most infants with clinical sequencing had panel sequencing. All gene panels sent between 2012 and 2019 included CDKL5, and seven individuals with CDKL5 variants were included in the CDD cohort rather than the comparison cohort. Brain malformations were not an exclusion because the cohort was defined by epilepsy gene panel testing.
A systematic evaluation of genetic and phenotypic characteristics was completed using data from retrospective medical records for both cohorts, and from a clinical research database consisting of data collected during clinic visits for the CDD cohort.
Genetic variants
We extracted details of individuals’ genetic test results from laboratory reports and clinical notes in the medical records. Results of genetic testing were considered diagnostic if the identified variants were classified as pathogenic or probably pathogenic on the basis of most updated clinical and genetic information. Variant classification was documented according to laboratory report and updated as relevant on the basis of the American College of Medical Genetics and Genomics guidelines and gene- or copy-number variant-specific literature.17,18 Genetic testing was considered non-diagnostic for variants of uncertain significance and variants in genes with phenotypic associations inconsistent with the patient’s phenotype or mode of inheritance, or if no variant was reported.
Demographic and clinical features
To differentiate CDD from other early-onset epilepsy syndromes, we systematically collected data from four broad categories: demographics, epilepsy and seizure types, developmental features, and examination/imaging findings (Tables 1–6). We provide detailed definitions for a subset of the variables (Table 1).19–21 Certain variables required a minimum age at last follow-up (Table 1).
TABLE 1.
Definitions and age requirements for variables in the study
| Datapoint | Definitions | Age cut-offs if relevant, for confidence of diagnosis |
|---|---|---|
| Racial and ethnic categories Seizure types |
According to United States National Institute of Health categories According to International League Against Epilepsy definitions16 |
N/A N/A |
| Epilepsy type | According to International League Against Epilepsy definitions of seizure types above including generalized types, focal types, both, or unknown | N/A |
| EEG encephalopathy patterns (burst suppression, hypsarrhythmia, generalized slowing with multifocal sharp waves, slow spike and wave with or without fast activity, electrical status epilepticus in sleep, othera) | On the basis of clinical EEG reports, with overall consistency with American Clinical Neurophysiology Society and International League Against Epilepsy guidelines. Electrical status epilepticus in sleep defined as spike wave index > 50% | N/A |
| Status epilepticus | Continuous seizure or back-to-back seizures without recovery lasting 30 minutes or longer19 | N/A |
| Developmental and epileptic encephalopathy | A combination of infantile/childhood onset epilepsy (onset < 18 years), an encephalopathy pattern on EEG (as defined above), and developmental delay or intellectual disability15 | ≥1 year of age at last follow-up |
| Treatment-resistant epilepsy | Not responsive to two or more appropriately chosen antiseizure medications at therapeutic doses20 | N/A |
| Sequential seizures (seizures with multiple phases) | A sequence of ictal patterns, motor or non-motor, not following an expected pattern of evolution based on spread (e.g. hypermotor–tonic–spasms sequence)26 | N/A |
| Cerebral visual impairment | Visual dysfunction in the absence of ocular or anterior visual pathway abnormalities21 | ≥2 years of age at last follow-up |
| Microcephaly Macrocephaly |
Head size > 2 standard deviations below the mean Head size > 2 standard deviations above the mean |
N/A |
| Intellectual disability | DSM-5 criteria, as documented in clinical notes (not requiring neuropsychological evaluation) | ≥5 years of age at last follow-up |
| Autism spectrum disorder | DSM-5 criteria, as documented in clinical notes (not requiring neuropsychological evaluation) | ≥3 years of age at last follow-up |
Other encephalopathy patterns on EEG included discontinuous patterns, abundant epileptiform activity (focal or generalized) not meeting criteria for electrical status epilepticus in sleep, and generalized slowing with poorly organized wake and/or sleep features.
Abbreviations: EEG, electroencephalogram; N/A, not applicable.
TABLE 6.
Physical examination features and metabolic testing data for individuals with CDD compared with those with other infantile-onset epilepsies with a suspected or defined genetic etiology
| Clinical feature | CDD | Other infantile-onset epilepsies | p | Other infantile-onset, no genetic diagnosis | p | Other infantile-onset, genetic diagnosis | p |
|---|---|---|---|---|---|---|---|
|
| |||||||
| n (%) | n (%) | n (%) | n (%) | ||||
| Total cohort | 137 | 313 | 203 | 110 | |||
| Head size | 0.342 | 0.271 | 0.571 | ||||
| Normal | 99 (81.1) | 234 (75.7) | 149 (74.5) | 85 (78.0) | |||
| Microcephaly | 22 (18.0) | 66 (21.4) | 45 (22.5) | 21 (19.3) | |||
| Macrocephaly | 1 (0.8) | 9 (2.9) | 6 (3.0) | 3 (2.8) | |||
| Dysmorphic features | 40 (31.8) | 51 (16.3) | <0.001 | 31 (15.3) | <0.001 | 20 (18.2) | 0.023 |
| Short stature | 16 (18.2) c | 34 (10.9) | 0.068 | 20 (9.9) | 0.048 | 14 (12.8) | 0.300 |
| Failure to thrive | 37 (38.1) c | 70 (22.4) | 0.002 | 39 (19.2) | <0.001 | 31 (28.4) | 0.154 |
| Neurocutaneous features | 0.154 | 0.164 | 0.085 | ||||
| None | 122 (93.1) | 266 (85.0) | 171 (84.2) | 95 (86.4) | |||
| Capillary malformations | 0 | 3 (1.0) | 3 (1.5) | 0 | |||
| Hypopigmented macules | 1 (0.8) | 14 (4.5) | 7 (3.5) | 7 (6.4) | |||
| Hyperpigmented areas | 6 (4.6) | 22 (7.0) | 16 (7.9) | 6 (5.5) | |||
| Other | 2 (1.5) | 8 (2.6) | 6 (3.0) | 2 (1.8) | |||
| Any abnormal muscle tone | 121 (93.1) | 195 (62.3) | <0.001 | 121 (59.6) | <0.001 | 74 (67.3) | <0.001 |
| Normal | 9 (6.9) | 118 (37.7) | 82 (40.4) | 36 (32.7) | |||
| Diffuse hypotonia | 94 (72.3) | 112 (35.8) | 74 (36.5) | 38 (34.5) | |||
| Axial hypotonia and appendicular spasticity | 7 (5.4) | 60 (19.2) | 34 (16.7) | 26 (23.6) | |||
| Asymmetric increased tone | 0 | 9 (2.9) | 7 (3.5) | 2 (1.8) | |||
| Dystonia, persistent | 1 (0.8) | 2 (0.6) | 0 (0.0) | 2 (1.8) | |||
| Axial hypotonia only | 6 (4.6) | 8 (2.6) | 4 (2.0) | 4 (3.6) | |||
| Mixed | 13 (10.0) | 4 (1.3) | 2 (1.0) | 2 (1.8) | |||
| Any brain malformation | 1 (0.9) a | 67 (21.5) | <0.001 | 51 (25.3) | <0.001 | 16 (14.7) | <0.001 |
| Cortical dysplasia | 0 | 15 (4.8) | 11 (21.6) | 4 (3.7) | |||
| Complex malformation | 0 | 10 (3.2) | 8 (15.7) | 2 (1.8) | |||
| Post fossa/cerebellar | 0 | 7 (2.3) | 6 (11.8) | 1 (0.9) | |||
| Polymicrogyria | 0 | 6 (1.9) | 5 (9.8) | 1 (0.9) | |||
| Agenesis of corpus callosum | 0 | 5 (1.6) | 4 (7.8) | 1 (0.9) | |||
| Heterotopias | 0 | 3 (1.0) | 3 (5.9) | 0 | |||
| Other | 1 (0.9) | 21 (6.8) | 14 (27.5) | 7 (6.4) | |||
| Any systemic malformation | 0 c | 27 (8.6) | 0.013 | 14 (6.9) | 0.013 | 13 (11.8) | <0.001 |
| Cardiac malformation | 0 | 12 (3.8) | 0.022 | 4 (2.0) | 0.151 | 8 (7.3) | 0.001 |
| Extremity malformation | 0 | 3 (1.0) | 0.329 | 2 (1.0) | 0.517 | 1 (0.9) | 0.455 |
| Other malformation | 0 | 11 (3.5) | 0.021 | 5 (2.5) | 0.085 | 6 (5.5) | 0.007 |
| Gastrostomy tube | 55 (40.2) | 102 (32.6) | 0.122 | 63 (31.0) | 0.083 | 39 (35.4) | 0.450 |
| Tracheostomy | 2 (1.5) | 4 (1.3) | 1.000 | 3 (1.5) | 1.000 | 1 (0.9) | 0.772 |
| Metabolic findings | 5 (4.7) b | 35 (11.3) | 0.040 | 18 (9.0) | 0.255 | 17 (15.6) | 0.008 |
The p-values were calculated from χ2 or Fisher’s exact tests compared with the CDD cohort. Significant clinical features are set in bold type after Benjamini–Hochberg correction on the basis of a false discovery rate of 0.2.
Features with missing data >10% noted:
11–19% missing
20–29% missing;
30–39% missing.
Abbreviation: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5.
Statistical analysis
We compared the frequency of the clinical features between the CDD cohort and the comparison cohort, including the full cohort of individuals with epilepsy onset under 1 year of age with suspected genetic epilepsy and a subset of those individuals with an established genetic diagnosis. We compared the frequency of clinical features between the cohorts using χ2 or Fisher’s exact tests. For increased power, we collapsed complex variables into binary variables in some cases (e.g. epilepsy type, movement disorders, etc.). For age at seizure onset, we compared medians using a non-parametric Wilcoxon rank-sum test. We pre-set a significance level of 0.05 for p-values in Table 1. We corrected for multiple comparisons in Tables 2 to 4, using the Benjamini–Hochberg procedure with a false discovery rate of 0.2 (the false discovery rate is usually set as 0.05, 0.1, or 0.2, with 0.05 being most conservative and 0.2 being least conservative; 0.2 is selected to identify more potential differences between cohorts). Analyses were conducted using SAS, version 9.4 (SAS Institute, Cary, NC, USA) for observational statistics.
TABLE 2.
Demographic data for individuals with CDD compared with those with other infantile-onset epilepsies with a suspected or defined genetic etiology
| Demographic feature | CDD | Other infantile-onset epilepsies | p | Other infantile-onset no genetic diagnosis | p | Other infantile-onset confirmed genetic epilepsies | p |
|---|---|---|---|---|---|---|---|
|
| |||||||
| n (%) | n (%) | n (%) | n (%) | ||||
| Total cohort | 137 | 313 | 203 | 110 | |||
| Sex | <0.001 | <0.001 | <0.001 | ||||
| Female | 110 (80.3) | 156 (49.8) | 105 (51.7) | 51 (46.4) | |||
| Male | 27 (19.7) | 157 (50.2) | 98 (48.3) | 59 (53.6) | |||
| Gestational age | 0.927 | 0.819 | 0.913 | ||||
| Preterm | 12 (10.7)a | 37 (12.1) | 25 (12.6) | 12 (11.1) | |||
| Full term | 100 (92.0) | 268 (87.3) | 173 (86.9) | 95 (88.0) | |||
| Post term | 0 | 2 (0.7) | 1 (0.5) | 1 (0.9) | |||
| Median age at epilepsy onset, months | 1.44 (IQR 0.72–2.04) | 3.96 (IQR 1.2–6.70) | <0.001 | 3.96 (IQR 2.04–7.00) | <0.001 | 3.96 (IQR 0.36–6) | <0.001 |
| Median age at last follow–up, years:months | 3:11 (IQR 2:1–11:8) | 5:2 (IQR 2:6–9:11) | 0.526 | 5:8 (IQR 2:8–10:6) | 0.223 | 4:6 (IQR 2:4–8:1) | 0.618 |
| Race | 0.041 | 0.035 | 0.128 | ||||
| American Indian/Alaska Native | 0 | 1 (0.3)a | 0 | 1 (0.9)a | |||
| Asian | 8 (5.8) | 24 (7.7) | 17 (8.3) | 7 (6.4) | |||
| Black or African American | 3 (2.2) | 24 (7.7) | 15 (7.4) | 9 (8.2) | |||
| Native Hawaiian or Other Pacific Islander | 0 | 2 (0.6) | 2 (1.0) | 0 (0.0) | |||
| White | 108 (78.8) | 212 (67.7) | 135 (66.5) | 77 (70.0) | |||
| More than one race | 4 (2.9) | 3 (1.0) | 2 (1.0) | 1 (0.9) | |||
| Unknown or not reported | 14 (10.2) | 47 (15.0) | 32 (15.8) | 15 (13.6) | |||
| Ethnicity | 0.108 | 0.024 | 0.886 | ||||
| Hispanic or Latino | 15 (10.0) | 40 (12.8)a | 27 (13.3) | 13 (11.8)a | |||
| Not Hispanic or Latino | 117 (85.4) | 245 (78.3) | 153 (75.4) | 92 (83,6) | |||
| Unknown or not reported | 5 (3.6) | 28 (8.9) | 23 (11.3) | 5 (4.6) | |||
| Mortality | 9 (6.6) | 18 (5.8)b | <0.001 | 9 (4.4)b | <0.001 | 9 (8.2) | <0.001 |
The p-values were calculated from χ2, Fisher’s exact, or Wilcoxon rank-sum tests with a significance threshold of 0.05 compared with the CDD cohort. Significant p-values and associated demographic features are set in bold type. Race and ethnicity are categories defined by the National Institute of Health in the US at the time of data collection.
Features with missing data >10% noted
11–19% missing
30–39% missing.
Abbreviations: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5; IQR, interquartile range.
TABLE 4.
Electroclinical syndromes for individuals with CDD compared with those with other infantile-onset epilepsies with a suspected or defined genetic etiology
| Clinical feature | CDD | Other infantile-onset epilepsies | p | Other infantile-onset no genetic diagnosis | p | Other infantile-onset confirmed genetic epilepsies | p |
|---|---|---|---|---|---|---|---|
|
| |||||||
| n (%) | n (%) | n (%) | n (%) | ||||
| Total cohort | 137 | 313 | 203 | 110 | |||
| Defined electroclinical syndrome | 28 (31.1)a | 95 (30.7) | 0.947 | 59 (29.7) | 0.802 | 36 (32.7) | 0.807 |
| Lennox–Gastaut syndrome | 21 (23.3) | 16 (5.2) | <0.001 | 14 (7.0) | 0.017 | 2 (1.8) | <0.001 |
| West syndrome | 7 (7.8) | 34 (11.0) | 0.051 | 29 (14.5) | 0.007 | 5 (4.5) | 1.000 |
| EIDEE (Ohtahara syndrome) | 0 | 11 (3.6) | 0.026 | 5 (2.5) | 0.085 | 6 (5.5) | 0.007 |
| Dravet Syndrome | 0 | 10 (3.2) | 0.034 | 1 (0.5) | 1.000 | 9 (8.2) | <0.001 |
| Epilepsy of infancy with migrating focal seizures | 0 | 5 (1.6) | 3 (1.5) | 3 (2.6) | |||
| Self-limited neonatal epilepsy | 0 | 4 (1.3) | 1 (0.5) | 3 (2.6) | |||
| Mesial temporal lobe epilepsy with hippocampal sclerosis | 0 | 4 (1.3) | 3 (1.5) | 1 (0.9) | |||
| Genetic epilepsy with febrile seizures plus | 0 | 3 (1.0) | 1 (0.5) | 2 (1.8) | |||
| Self-limited (non-familial) infantile epilepsy | 0 | 3 (1.0) | 1 (0.5) | 2 (1.8) | |||
| Hemiconvulsion–hemiplegia–epilepsy | 0 | 3 (1.0) | 2 (1.0) | 1 (0.9) | |||
| EIDEE (early myoclonic encephalopathy) | 0 | 2 (0.6) | 2 (1.8) | ||||
| Myoclonic epilepsy of infancy | 0 | 1 (0.3) | 1 (0.5) | 0 | |||
| Self-limited (familial) infantile epilepsy | 0 | 1 (0.3) | 0 | 1 (0.9) | |||
| Progressive myoclonus epilepsies | 0 | 1 (0.3) | 0 | 1 (0.9) | |||
| Epilepsy with generalized tonic–clonic seizures alone | 0 | 1 (0.3) | 0 | 1 (0.9) | |||
The p-values were calculated from χ2 or Fisher’s exact tests compared with the CDD cohort. Significant clinical features are set in bold type after Benjamini–Hochberg correction on the basis of a false discovery rate of 0.2.
Features with missing data >10% noted
30–39% missing.
Abbreviations: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5; EIDEE, early infantile developmental and epileptic encephalopathy.
RESULTS
CDD compared with other suspected or confirmed genetic epilepsies
Our CDD cohort included 137 individuals (110 females, 80.3%) with a median age at seizure onset of 1.4 months (interquartile range [IQR] 0.7–2.0). Details on CDKL5 variants are included in Table S2. Our comparison cohort included 313 individuals (156 females, 49.8%) with epilepsy onset under 1 year of age with suspected genetic etiology and a clinical epilepsy panel conducted from 2012 to 2019. This group had median age at seizure onset of 4.0 months (IQR 1.2–6.7), significantly older than those with CDD (Wilcoxon rank-sum test, p < 0.001). Both cohorts were primarily White and not Hispanic (Table 2). Known mortality occurred in 6.6% of individuals with CDD and in 5.8% of individuals in the comparison cohort (Table 2).
Individuals with data available at older than 1 year of age included 48 with CDD and 286 with other infantile-onset epilepsies. In these subsets, DEE, as defined in Table 1, was reported in 64.0% and 65.4% respectively (Figure 1 and Table 3).
FIGURE 1.
Key clinical features in individuals with CDD (n = 137) compared with those with other infantile-onset epilepsies with suspected or confirmed genetic etiology (n = 313). *A significant difference after Benjamini–Hochberg correction between a group and CDD (p calculated from χ2 or Fisher’s exact tests).
Abbreviations: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5; CVI, cerebral visual impairment; DEE, developmental and epileptic encephalopathy.
TABLE 3.
Epilepsy and seizure data for individuals with CDD compared with those with other infantile-onset epilepsies with a suspected or defined genetic etiology
| Clinical feature | CDD | Other infantile-onset epilepsies | p | Other infantile-onset no genetic diagnosis | p | Other infantile-onset confirmed genetic epilepsies | p | |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| n (%) | n (%) | n (%) | n (%) | |||||
| Total cohort | 137 | 313 | 203 | 110 | ||||
| Developmental and epileptic encephalopathy (≥1 year) | 71 (64.0) | 187 (65.4) | 0.815 | 125 (68.3) | 0.447 | 62 (6.2) | 0.576 | |
| Treatment-resistant epilepsy | 82 (95.3) b | 217 (70.5) | <0.001 | 138 (69.7) | <0.001 | 79 (71.8) | <0.001 | |
| History of status epilepticus | 6 (7.1) b | 91 (29.2) | <0.001 | 57 (28.2) | <0.001 | 34 (30.9) | <0.001 | |
| Epilepsy type | <0.001 | <0.001 | <0.001 | |||||
| Focal | 10 (8.4) a | 103 (35.9) | 56 (30.8) | 47 (44.8) | ||||
| Generalized/mixed | 109 (91.6) | 184 (64.1) | 126 (69.2) | 58 (55.2) | ||||
| Seizures with multiple phases | 60 (45.8) | 18 (5.9) | <0.001 | 12 (6.1) | <0.001 | 6 (5.6) | <0.001 | |
| Seizure types | ||||||||
| Generalized motor | 113 (82.5) | 177 (56.9) | <0.001 | 123 (60.6) | <0.001 | 54 (50.0) | <0.001 | |
| Generalized non-motor | 16 (11.9) | 39 (12.6) | 0.851 | 24 (11.9) | 1.000 | 15 (13.8) | 0.672 | |
| Focal motor | 65 (48.5) | 181 (57.8) | 0.070 | 103 (50.7) | 0.688 | 78 (70.9) | <0.001 | |
| Focal non-motor | 15 (11.6) | 105 (33.8) | <0.001 | 63 (31.2) | <0.001 | 42 (38.5) | <0.001 | |
| Epileptic spasms (generalized, focal, or unknown) | 90 (65.7) | 131 (41.9) | <0.001 | 97 (47.8) | 0.001 | 34 (30.9) | <0.001 | |
| Any EEG encephalopathy pattern | 81 (87.1) b | 222 (71.8) | 0.003 | 150 (74.6) | 0.015 | 72 (66.7) | <0.001 | |
| Burst suppression | 3 (3.2) | 17 (5.5) | 0.143 | 9 (4.4) | 0.374 | 8 (7.4) | 0.067 | |
| Hypsarrhythmiad | 27 (30.0) | 63 (48.1) | 0.007 | 50 (51.5) | 0.003 | 13 (38.2) | 0.382 | |
| Generalized slowing with multifocal sharp waves | 42 (45.2) | 113 (36.6) | 0.263 | 77 (37.9) | 0.168 | 36 (33.3) | 0.728 | |
| Slow spike and wave with or without fast activity | 11 (11.8) | 10 (3.2) | 0.025 | 8 (3.9) | 0.148 | 2 (1.9) | 0.042 | |
| ESES | 0 | 1 (0.3) | 1.000 | 1 (0.5) | 1.000 | 0 | N/A | |
| Other | 33 (35.4) | 59 (19.1) | 0.205 | 34 (16.7) | 0.095 | 25 (23.1) | 0.802 | |
The p-values were calculated from χ2 or Fisher’s exact tests compared with the CDD cohort. Significant clinical features are set in bold type after Benjamini–Hochberg correction on the basis of a false discovery rate of 0.2.
Features with missing data >10% noted
11–19% missing
30–39% missing.
Rate of hypsarrhythmia was calculated only for those with reported spasms. Rates of other EEG patterns were calculated out of the total number with a known EEG encephalopathy pattern.
Abbreviations: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5; EEG, electroencephalogram; ESES, electrical status epilepticus during slow wave sleep; N/A, not applicable.
Individuals with CDD were more likely to have treatment-resistant epilepsy (95.3% vs 70.5%), but status epilepticus was less common (7.1% vs 29.2%). Sequential seizures (seizures with multiple phases as defined in Table 1) were reported in 45.8% of individuals with CDD compared with only 5.9% of those with other suspected or confirmed genetic epilepsies (Figure 1, including examples). Generalized or mixed epilepsy types were more common in CDD (91.6% vs 64.1%), including generalized motor seizures (82.5% vs 56.9%) and epileptic spasms (generalized, focal, or unknown; 65.7% vs 41.9%). However, individuals with CDD had a lower prevalence of focal non-motor seizures (11.6% vs 33.8%). Individuals with CDD were more likely to have defined electroencephalographic (EEG) encephalopathy patterns (87.1% vs 71.8%), most notably slow spike and wave with or without fast activity (11.8% vs 3.2%), consistent with higher rate of diagnosis of Lennox–Gastaut syndrome (23.3% in CDD and 5.2% in the comparison cohort). Among patients with epileptic spasms, hypsarrhythmia was less common in CDD than in the comparison cohort (30.0% vs 48.1%), consistent with a lower rate of diagnosis of the full triad of West syndrome (7.8% in CDD and 11.0% in the comparison cohort). Features suggesting Ohtahara syndrome and Dravet syndrome were not reported in any individuals with CDD, but occurred in 3.6% and 3.2% respectively of the comparison cohort (Table 4, one individual with a variant of uncertain significance in SCN1A).
Both intellectual disability, assessed at 5 years of age or older, and global developmental delay, assessed at 1 year of age or older, were present in all individuals with CDD, compared with 77.0% and 79.1%, respectively, of individuals with other infantile-onset epilepsies. In those with intellectual disability, severity was severe–profound in 98.4% of the CDD cohort compared with 67.3% of the comparison cohort. Developmental regression at any point occurred more frequently in CDD (52.3% vs 29.6%). Stereotypies were also more common in CDD than in other infantile-onset epilepsies (68.5% compared with 11.3%), as were paroxysmal movement disorder (28.8% vs 16.7%). In CDD, choreoathetosis (9%) and paroxysmal dystonia (11%) were the most common movement disorders. CVI, diagnosed at 2 years of age or older, was significantly higher in CDD (87.4%) compared with other infantile-onset epilepsies (28.0% overall, 38% of those with DEE) (p < 0.001) (Table 5).
TABLE 5.
Developmental and other neurological disorders diagnosed in individuals with CDD compared with those with other infantile-onset epilepsies with a suspected or defined genetic etiology
| Clinical feature | CDD | Other infantile-onset epilepsies | p | Other infantile-onset no genetic diagnosis | p | Other infantile-onset confirmed genetic epilepsies | p |
|---|---|---|---|---|---|---|---|
|
| |||||||
| n (%) | n (%) | n (%) | n (%) | ||||
| Total cohort | 137a | 313b | 203c | 110d | |||
| Autism (≥3 years) | 10 (14.7)f | 54 (25.6) | 0.069 | 40 (28.4) | 0.037 | 14 (20.0) | 0.502 |
| Intellectual disability (≥5 years) | 64 (100) | 104 (77.0) e | <0.001 | 78 (78.0) e | <0.0001 | 26 (74.3) f | <0.001 |
| Mild/moderate | 1 (1.6) | 28 (26.9) | <0.001 | 19 (24.4) | <0.0001 | 9 (34.6) | <0.001 |
| Severe/profound | 63 (98.4) | 70 (67.3) | 54 (69.2) | 16 (61.5) | |||
| Unknown | 0 | 6 (5.8) | 5 (6.4) | 1 (3.8) | |||
| Development | <0.001 | <0.001 | <0.001 | ||||
| Normal development | 0 | 47 (15.2) | 34 (16.9) | 13 (11.9) | |||
| Global developmental delay | 133 (100) | 240 (77.4) | 154 (76.6) | 86 (78.9) | |||
| Delays in one area only | 0 | 23 (7.4) | 13 (6.5) | 10 (9.2) | |||
| Global developmental delay (≥1 year) | 121 (100) | 227 (79.1) | <0.001 | 144 (78.3) | <0.001 | 83 (80.6) | <0.001 |
| Any developmental regression | 69 (52.3) | 89 (29.0) | <0.001 | 57 (28.6) | <0.001 | 32 (29.6) | <0.001 |
| No regression | 63 (47.7) | 218 (71.0) | 142 (71.4) | 76 (70.4) | |||
| Yes, independent of seizures/change in EEG | 13 (9.8) | 10 (3.3) | 6 (3.0) | 4 (3.7) | |||
| Yes, in the setting of epileptic encephalopathy | 35 (26.5) | 73 (23.8) | 50 (25.1) | 23 (21.3) | |||
| Yes, unknown setting | 21 (15.9) | 6 (2.0) | 1 (0.5) | 5 (4.6) | |||
| Stereotypies | 89 (68.5) | 35 (11.3) | <0.001 | 22 (10.9) | <0.001 | 13 (12.0) | <0.001 |
| Any movement disorder | 34 (28.8) f | 52 (16.7) | 0.005 | 28 (13.8) | 0.001 | 24 (22.0) | 0.241 |
| Choreoathetosis | 11 (9.3) | 14 (4.5) | 7 (3.5) | 7 (6.2) | |||
| Dystonia (paroxysmal) | 13 (11.0) | 12 (3.8) | 6 (3.0) | 6 (5.3) | |||
| Tremors | 3 (2.5) | 7 (2.2) | 4 (2.0) | 3 (2.7) | |||
| Dyskinesias | 6 (5.1) | 8 (2.6) | 4 (2.0) | 4 (3.5) | |||
| Tics | 0 | 3 (1.0) | 2 (1.0) | 1 (0.9) | |||
| Non-epileptic myoclonus | 1 (0.8) | 8 (2.6) | 5 (2.5) | 3 (2.7) | |||
| Ataxia | 1 (0.8) | 4 (1.3) | 2 (1.0) | 2 (1.8) | |||
| Other | 4 (3.4) | 4 (1.3) | 3 (1.5) | 1 (0.9) | |||
| Cerebral visual impairment (≥2 years) | 90 (87.4) | 71 (28.0) | <0.001 | 49 (29.3) | <0.001 | 22 (25.3) | <0.001 |
The p-values were calculated from χ2 or Fisher’s exact tests compared with the CDD cohort. Significant clinical features are set in bold type after Benjamini–Hochberg correction on the basis of a false discovery rate of 0.2.
Numbers for cohorts with age cutoffs: ≥1 year = 123, ≥2 years = 105, ≥3 years = 89, ≥5 years = 64.
Numbers for cohorts with age cutoffs: ≥1 year = 288, ≥2 years = 260, ≥3 years = 218, ≥5 years = 163.
Numbers for cohorts with age cutoffs: ≥1 year = 185, ≥2 years = 169, ≥3 years = 147, ≥5 years = 115.
Numbers for cohorts with age cutoffs: ≥1 year = 103, ≥2 years = 91, ≥3 years = 71, ≥5 years = 48.
Features with missing data >10% noted
11–19% missing
20–29% missing.
Abbreviations: CDD, CDKL5 deficiency disorder; CDKL5, cyclin-dependent kinase-like 5; EEG, electroencephalogram.
The prevalence of microcephaly or macrocephaly versus normal head size and neurocutaneous features did not differ significantly across groups (Table 6). Examination features identified more commonly in individuals with CDD than those with other infantile-onset epilepsies included short stature (18.2% vs 10.9%), dysmorphic features (31.8% vs 16.3%), and abnormal muscle tone (93.1% compared with 62.3%). Dysmorphic features in the CDD cohort included, most commonly, broad forehead, high hairline, deep-set eyes, bulbous nose, prominent or large ears, broad or depressed nasal bridge, mouth large, and widely spaced teeth. In CDD, diffuse hypotonia was most frequent (72.3%), followed by mixed tone (e.g. variable limb dystonia, spasticity, and hypotonia) in 10%. In individuals with a suspected or confirmed genetic epilepsy, the range of tone abnormalities was broader (diffuse hypotonia in 35.8%, axial hypotonia with appendicular spasticity in 19.2%). Individuals with CDD were more likely to experience failure to thrive than those with other infantile-onset epilepsies (38.1% vs 22.4%), and less likely to have systemic malformations (0 vs 8.6%), or brain malformations (e.g. thick corpus callosum in one individual with CDD, 0.9% vs 21.5%, Table 6). Metabolic laboratory abnormalities were less common in the CDD cohort (4.7% vs 11.3%, Table 6). Individuals with CDD compared with other infantile-onset epilepsies had similar rates of gastrostomy tube placement (40.2% vs 32.6%) and tracheostomy (1.5% vs 1.3%, Table 6).
CDD compared with other confirmed genetic epilepsies
Of the 313 individuals in the comparison cohort, 35.1% (n = 110) had a specific genetic etiology identified on epilepsy gene panels or other relevant genetic testing for epilepsy: SCN1A (n = 13), KCNQ2 (n = 12), PRRT2 (n = 9), SCN2A (n = 6), SCN8A (n = 4), STXBP1 (n = 4), PNPO (n = 3), TSC2 (n = 3) (Figure 2). This group included 79 individuals with heterozygous variants in autosomal genes, 10 with hemizygous or heterozygous X-linked variants (three male, seven female), and 13 with homozygous or compound heterozygous variants. Of the heterozygous or hemizygous variants, 47 of 89 were de novo (Table S3).
FIGURE 2.
The non-CDKL5 (cyclin-dependent kinase-like 5) comparison cohort consisted of 313 individuals, 110 of whom had a clinical genetic diagnosis. The most common genetic etiologies are included.
This subset of the comparison cohort had a median age at epilepsy onset of 4.0 months (IQR 0.36–6), which was significantly higher than in CDD (Wilcoxon rank-sum test, p < 0.001) but the same as the subset of the comparison cohort without genetic diagnosis (Table 2). The differences in seizure and epilepsy data between CDD and those with other infantile-onset epilepsy with genetic diagnosis were similar to those between CDD and the broader comparison cohort. However, the presence of focal motor seizures was higher in those with other infantile-onset genetic epilepsies (70.9% vs 48.5% in CDD). The rate of burst suppression on EEG was also higher in other infantile-onset genetic epilepsies compared with CDD (7.4% vs 3.2%, Table 3), while the rate was similar to CDD in the sub-cohort without genetic etiology (4.4%). The rate of hypsarrhythmia for those with reported epileptic spasms was similar across groups with genetic diagnosis (38.2% in other genetic epilepsies vs 30.0% in CDD) (Table 3 and Figure 1). In contrast, the rate of hypsarrhythmia for those with reported epileptic spasms was higher in the subset of the comparison cohort without genetic diagnosis (51.5%) and the rate of West syndrome was similarly higher (14.5%, Table 4).
The CDD cohort and the comparison group with established genetic diagnosis had similar rates of movement disorders (28.8% vs 22.0%, Table 5); the rate was lower in the comparison group without genetic diagnosis (13.8%). Movement disorders in this subset of the comparison cohort were reported in patients with pathogenic or likely pathogenic variants in the following genes: ARX, ATP1A3, BRAT1, CACNA1A, CACNA1E, COL4A1, CPLANE1, FOXG1, FRRS1L, GNAO1, GABRB2, KCNQ2, KCNT1, POLG, PRRT2, SCN1A, SCN1B, SCN8A, STXBP1, TBL1XR1, trisomy 21, and two chromosomal translocations. Individuals with and without CDD were equally likely to experience failure to thrive and short stature (38.1% compared with 28.4%, and 18.2% compared with 12.8% respectively) (Table 6). Brain malformations were identified at a higher rate in those without compared with those with genetic diagnosis in the comparison cohort (25.3% vs 14.7%, Table 6).
DISCUSSION
Although previous literature differentiates CDD from Rett syndrome and FOXG11,4,7,10 and identifies the key clinical features of the disorder,1,3,5,6 this is the first study to our knowledge to directly compare CDD with the broad group of other infantile-onset epilepsies associated with suspected or confirmed genetic etiologies. Highly prevalent features that characterize CDD, and are present more often than in other early-life genetic epilepsies, include refractory seizures, seizures with multiple motor phases, diffuse hypotonia, stereotypies, paroxysmal movement disorders, and CVI. These features are consistent with those reported in case series,2–4,6,8,22–24 although we noted a particularly high rate of movement disorders, possibly reflecting the lack of dedicated ascertainment for this feature in past studies. Intellectual disability was more likely to be severe/profound, and short stature and failure to thrive were also more common in the CDD cohort. Head size was not a differentiating feature. Epileptic spasms without hypsarrhythmia was more common in CDD relative to the overall comparison cohort but not relative to the subset with genetic diagnosis. This comparison of clinical characteristics relative to other early infantile DEEs is limited in some cases by ascertainment bias from the longitudinal clinic-based nature of the CDD cohort, which led to more consistent collection of certain features such as movement disorders and CVI. However, in the CDD and comparison cohorts, data were collected during clinical care. The findings of this study inform differentiation of non-acquired early-infantile DEEs.
Consistent with previous reports, we show that individuals with CDD are more likely to have generalized or mixed seizures and epileptic spasms, although with lower rates of hypsarrhythmia, and have higher rates of treatment-resistant epilepsy than other infantile-onset suspected or confirmed genetic epilepsies.1–3,6,23,25 The higher rate of treatment-resistant epilepsy is consistent with a recent report of increased risk in the setting of infants with focal seizures who have an abnormal neurological examination, cognitive impairment, epileptic spasms, and younger age at onset.25 Seizures with multiple phases are another distinguishing feature, with a large proportion with mixed motor pattern seizures as commonly reported in CDD.6,8 Other early-onset genetic DEEs have also been reported to have sequential seizure types, as seen in our series (Figure 1).26 Although there may have been ascertainment bias in assessing for these seizure types in CDD, we reviewed the detailed seizure semiology for all individuals on the basis of medical records. Detailed clinical characterization of complex seizure patterns from video–EEG data will help to further distinguish CDD from other infantile DEEs.
Previous literature suggests that the EEG can be relatively normal at onset of symptoms in CDD with evolution of encephalopathy patterns over time.1,8,27 Given the substantially lower median age at onset of epilepsy in CDD (1.4 months) than in the comparison cohort (4.0 months, p < 0.001), it is most relevant to differentiate CDD from other genetic DEEs with typical onset in the first 1 to 2 months of life. Compared with other commonly identified genetic causes of neonatal-onset DEE, such as KCNQ2, SCN2A, and STXBP1, CDD is only rarely associated with burst suppression or Ohtahara syndrome.27–29 Rates of burst suppression were low in both the CDD and comparison cohorts in our study, although higher in the confirmed genetic subset. Hypsarrhythmia was less common in CDD than the overall comparison cohort, possibly explaining the lower rate of West syndrome, but similar to those with other genetic diagnoses. Thus spasms without hypsarrhythmia is not a clear differentiating feature.6 Rates of slow spike and wave and Lennox–Gastaut syndrome were higher in the CDD than in the comparison cohort. These patterns reflect variability in evolution through age-dependent electroclinical syndromes.
The high observed rates of CVI in individuals with CDD (94.9%), consistent with previous reports that include subsets of this same cohort,3,6,22 reinforces the observation that CVI is one of CDD’s defining features. This feature was specifically ascertained as part of our clinic-based research in CDD at CDKL5 Centers of Excellence, and patients with CDD are often referred to ophthalmologists and appropriate educational supports. The ascertainment and referral bias may account, at least in part, for the substantially higher rate of CVI in CDD compared with other infantile-onset epilepsies, because it is a well-recognized feature of DEEs more broadly.
Our comparison cohort was heterogeneous, with SCN1A-, KCNQ2-, and PRRT2-related epilepsies being the most common diagnoses (Figure 2). On the basis of the differences in presentation depending on diagnosis, it is not surprising that the CDD phenotypes in our report are distinct from these other gene-associated syndromes. While SCN1A was the most commonly implicated gene, rates of diagnosis were lower than in previously reported cohorts.9,13 However, many in our comparison cohort had variants in genes that were not associated with specific seizure or epilepsy syndromes; it is perhaps in reference to this subset that our delineation of the CDD phenotypic features is most relevant. We emphasize the need for future research to continue to differentiate genetic etiologies of infantile-onset DEEs, ideally with parallel clinical studies to avoid ascertainment bias.
This study was limited by its retrospective design. Because Boston Children’s Hospital and the CDKL5 Centers of Excellence provide quaternary care, individuals in both cohorts were followed for variable amounts of time and did not always receive primary medical care at the center gathering data. Additionally, data acquisition across cohorts differed because individuals with CDD were enrolled in a clinic-based research study, with all data collected in the course of routine clinical visits that may have differed at different institutions. This probably led to ascertainment bias for some features, including subtle dysmorphisms (e.g. broad nasal bridge, prominent ears, deep-set eyes, etc.), stereotypies, and milder or transient movement disorders. Both dysmorphic features and movement disorders were nearly twice as prevalent, and stereotypies were six times as prevalent in CDD in this study.22,30,31 Long-term motor outcomes including rates of ambulation in CDD have been captured in previous studies.22,30,31 Furthermore, the comparison cohort was from a single center, broad in its composition, and included self-limited epilepsy syndromes and malformations. Indeed, the comparison cohort was chosen carefully to capture a sample with an age at presentation within the range of CDD and before knowledge on course over time.
In contrast to early literature but consistent with more recent data, head size did not differentiate CDD (microcephaly in 18%) from other infantile-onset epilepsies (microcephaly in 21%).2,8 The median head circumference z-score of participants with CDD in the National Institutes of Health-funded Natural History Study of Rett syndrome and Related Disorders (NCT02738281) was −1.8 (IQR −2.6 to −0.9).11
Identifying core features in individuals with CDD will help to raise early suspicion for the disorder and prompt exhaustive genetic evaluation. Although the present phenotype may not be specific enough to indicate single-gene testing, having a high level of suspicion for CDD may lead to repeating or expanding previous genetic testing or to reinterpreting data. For example, initial testing or evaluation could miss a deletion, a variant in an alternative transcript or a non-coding region, or a mosaic variant not reaching detection threshold.32,33 Comparisons between CDD and other infantile-onset epilepsies emphasize common and disease-specific features, which contribute to a better characterization of their natural history and management (e.g. health surveillance).
Furthermore, precision diagnosis affects precision treatment. In CDD, there have been disease-specific clinical trials including those for ganaxolone (now approved by the US Food and Drug Administration for CDD), fenfluramine, cannabidiol, and ataluren.8,34–36 Additionally, gene replacement therapy, antisense oligonucleotides, and gene-editing approaches in development give hope for disease-modifying therapies on the horizon.8,35,36 Accurate diagnosis is critical for enrollment in clinical trials, and even more so for approaches targeting the gene specifically.
In conclusion, our study defines core features of CDD relative to other suspected or confirmed genetic epilepsies with onset in the first year of life. Key features include refractory generalized and mixed epilepsy with complex mixed motor seizures, diffuse hypotonia, CVI, and movement disorders, in particular choreoathetosis and dystonia. Notably, in contrast to conventional wisdom, microcephaly and spasms without hypsarrhythmia are not distinguishing features from other genetic etiologies. Understanding the typical clinical features of CDD relative to other genetic epilepsies affects clinical diagnosis and care, including eligibility for disease-specific treatments and trials.
Supplementary Material
Table S1: CDKL5 working group author affiliations.
Appendix S1: Conflict of interest statement.
Table S2: CDKL5 variants for 137 individuals.
Table S3: Summary of genetic variants in 110 individuals with infantile-onset epilepsy with a defined genetic etiology identified on epilepsy gene panel, exome sequencing, or other genetic testing or chromosomal microarray or karyotype.
What this paper adds.
Epileptic spasms, sequential seizures, and Lennox–Gastaut syndrome are more common in CDKL5 deficiency disorder (CDD).
Hypsarrhythmia is less common in association with epileptic spasms in CDD.
Cerebral visual impairment has a high prevalence in CDD.
Paroxysmal movement disorders, particularly dystonia, are more prevalent in CDD.
Hypotonia and failure to thrive are more common in CDD.
ACKNOWLEDGMENTS
The members of the CDKL5 study group are as follows: Lindsay Swanson, Jamie Love-Nichols, Christelle Moufawad El Achkar, Rochelle M Witt, Walter E Kaufmann, David N Lieberman, Kristina Julich, Siddharth Srivastava, Duyu A Nie, Xiaoming Zhang, Ahsan N Moosa, Jacqueline Drew, Andrea Fidell, Isabel Haviland, Jenna Lucash (affiliations are listed in Table S1). We thank all of the individuals and families followed in our CDKL5 Centers of Excellence and our Boston Children’s Hospital Epilepsy Genetics Program who participated in our research studies.
Funding information
Funding for the CDKL5 Centers of Excellence by the International Foundation for CDKL5 Research. HO is supported by the National Institute of Neurologic Disorders and Stroke (NINDS K23 NS107646-05 and 3K23NS107646-05S1). TAB is funded by the Ponzio Family Chair in Neurology Research through Children’s Hospital Colorado Foundation.
Abbreviations:
- CDD
CDKL5 deficiency disorder
- CDKL5
cyclin-dependent kinase-like 5
- CVI
cerebral visual impairment
- DEE
developmental and epileptic encephalopathy
Footnotes
CONFLICT OF INTEREST
The authors’ conflict of interest statement is given in Appendix S1.
DATA AVAILABLILITY STATEMENT
The data that support the findings of this study are available in de-identified form from the corresponding author upon reasonable request. The data are not publicly available owing to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: CDKL5 working group author affiliations.
Appendix S1: Conflict of interest statement.
Table S2: CDKL5 variants for 137 individuals.
Table S3: Summary of genetic variants in 110 individuals with infantile-onset epilepsy with a defined genetic etiology identified on epilepsy gene panel, exome sequencing, or other genetic testing or chromosomal microarray or karyotype.
Data Availability Statement
The data that support the findings of this study are available in de-identified form from the corresponding author upon reasonable request. The data are not publicly available owing to privacy or ethical restrictions.