Epileptic encephalopathy with spike‐and‐wave activation in sleep associated with Tatton–Brown–Rahman syndrome responsive to highly purified cannabidiol

Tatton-Brown–Rahman syndrome (TBRS) is a congenital overgrowth disorder caused by DNMT3A mutations, marked by overgrowth and intellectual disability, with variable features including facial dysmorphism, hypotonia, autism, psychiatric comorbidities, orthopedic, and cardiac abnormalities.1 Approximately 20% of affected individuals have epilepsy; however, as TBRS was first described in 2014, seizure-related data remain limited.2 Here, we describe a 10-year-old patient with TBRS, confirmed by whole-exome sequencing, and developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), who demonstrated an electroclinical response to cannabidiol (Epidiolex). The patient was born at term after an uncomplicated pregnancy and later showed developmental delay, walking at 15 months with ongoing coordination and fine motor difficulties. Early language milestones were appropriate, with 50 words and two-word phrases by 24 months and sentence speech by 3 years. Growth parameters were consistently greater than the 90th percentiles. Examination revealed hypotonia, joint hypermobility, and facial features consistent with TBRS. At 2.5 years, she developed focal impaired consciousness seizures associated with throat clearing and left facial and arm clonic movements, sometimes progressing to bilateral tonic–clonic seizures. EEG showed occasional bilateral central-parietal epileptiform discharges in awake and sleep states (EEGs are depicted in Figure 1). Brain MRI demonstrated incomplete right hippocampal inversion (Figure 2). By 3.5 years, seizures increased to monthly frequency, and sleep EEG showed >80% bilateral centrotemporal–parietal spike-and-wave activity consistent with DEE-SWAS. Neuropsychological testing revealed mild intellectual disability. Multiple antiseizure medications (clobazam, sulthiame, ethosuximide) were ineffective or poorly tolerated, accompanied by marked developmental regression, including loss of sphincter control, fine motor and gait skills, and language decline from sentences to single words, with overall functioning approximating a 2-year level. Clinical seizure freedom was achieved by age 6 years with divalproex sodium and lamotrigine; however, DEE-SWAS persisted and developmental progress remained limited. By ages 7–8 years, she functioned at a 4-year-old level despite ongoing supports. At 9.5 years, cannabidiol (10 mg/kg/day) was initiated. Within 5 months, marked cognitive and language improvements were noted, including increased alertness, situational awareness, and use of short phrases rather than single words. Ambulatory EEG showed complete DEE-SWAS resolution at 5 and 17 months. Neuropsychological testing, 10 months after DEE-SWAS resolution, demonstrated moderate intellectual disability, suggesting cumulative neurodevelopmental impact of prolonged DEE-SWAS. She continues to have gross and fine motor difficulties but now participates in therapeutic horseback riding and attends full school days with support. This case demonstrates cannabidiol response in TBRS-associated DEE-SWAS, underscoring the epileptic burden in overgrowth–intellectual disability syndromes and potential for mechanism-based therapies. Resolution of DEE-SWAS suggests cannabidiol effects beyond seizure suppression alone. Given TBRS is newly recognized, seizure prevalence and characteristics may be underestimated.1 The Overgrowth Syndromes Alliance (2023) identified seizures as a high-priority shared challenge, with diagnostic delays often attributable to limited phenotype characterization.2 In TBRS, patients typically demonstrate relatively preserved verbal abilities compared with nonverbal reasoning.3 Therefore, our patient's language decline was atypical and attributable to DEE-SWAS. TBRS is caused by pathogenic variants in DNMT3A, encoding DNA methyltransferase 3A, a key regulator of DNA methylation during neurodevelopment. Haploinsufficiency likely results in global hypomethylation and dysregulated gene expression. Epigenetic regulatory genes have increasingly been implicated in epilepsy, with DNA methylation changes contributing to epileptogenesis, neuroinflammation, ion channel dysfunction, and altered synaptic plasticity.4 To our knowledge, there are no prior reports of cannabidiol efficacy in DNMT3A-related epilepsy or TBRS-associated DEE-SWAS. However, cannabidiol has benefited a small number of patients with DEE-SWAS.5-7 Cannabidiol may act through reduced hyperexcitability (via GPR55 inhibition, TRPV1 desensitization, and adenosine reuptake blockade) and anti-inflammatory effects mediated by CB2 receptor interactions that lower TNF-α and IL-6.6 Given that DEE-SWAS often responds to corticosteroids and is associated with elevated inflammatory cytokines (TNF-α, IL-6, IL-1α), an immune-mediated component is likely.8 Notably, cannabidiol induces epigenomic changes, as one study demonstrated thousands of differentially methylated loci identified in the mouse hippocampus after short-term exposure, affecting genes involved in synaptic function and neurodevelopment.9 These effects raise the possibility that cannabidiol may partially counteract methylation dysregulation due to DNMT3A haploinsufficiency. Notably, valproic acid, a histone deacetylase inhibitor, helped control clinical seizures.10 This report broadens the TBRS seizure phenotype and supports further investigation of cannabidiol for DEE-SWAS, including its potential as a mechanism-informed therapy in TBRS and other disorders of chromatin remodeling and DNA methylation. The author has nothing to report. The author has received speaker honoraria from Jazz Pharmaceuticals. She has served on an advisory board for Knight and Acadia Pharmaceuticals. The author declares no other conflicts of interest. The patient provided consent to publish the case. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Cannabadiol has an antiseizure effects via all of the following mechanisms, except: Which of the following statements regarding TBRS-related epilepsy are FALSE? Which of the following statements regarding cannabidiol and epilepsy is CORRECT? Answers may be found in the supporting information.