Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome

Abstract

ObjectiveThe aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype–phenotype correlation.MethodsWe collected data on patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an “epilepsy group” or “non‐epilepsy group”. Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature.ResultsWe included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1%, RR 4.6 [95% CI 1.7–13.1]). Seizure onset in patients with KBG syndrome occurred at a median age of 4 years (range 12 months – 20 years), and the majority had generalized onset seizures (57.7%) with tonic–clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling the criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti‐seizure medication (ASM) for at least 1 year at the time of last assessment, but 26.9% of patients had drug‐resistant epilepsy (failure of ≥2 ASM). No genotype–phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics.SignificanceEpilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significantly poorer neurodevelopmental outcome compared with those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy.

Functional Assessment and Impact of Seizures on Cognitive Outcome in a Cohort of Individuals with KBG Syndrome

“…We recommend further research to delve more into types of seizures experienced. Buijsse et al 7 discovered that those with simultaneous KBG and epilepsy diagnoses more often had moderate to severe intellectual disability compared to those without a history of epilepsy. Their finding is significant given that seizures occur in a large portion of the KBG syndrome population (up to 33%), with onset occurring during infancy through mid-teens and often recurring at or shortly after adolescence.…”

“…These include a range of seizures such as focal and generalized seizures, tonic-clonic and absence seizures, myoclonic seizures, and unclassified sleep-related seizures. 7 Some individuals may exhibit electroencephalogram (EEG) abnormalities without clinically evident seizures. 8 Those with KBG syndrome are more susceptible to epilepsy, which occurs in a significant percentage of cases, 9 although epilepsy is not formally recognized as a defining characteristic of this condition.…”

Epileptic dyskinetic encephalopathy in KBG syndrome: Expansion of the phenotype

“…While epilepsy syndromes are uncommon in KBG syndrome, a recent multicentre study combining original and historical patients identified 12/63 (19%) epilepsy-affected KBG patients with an epilepsy syndrome (most were generalised epilepsy syndromes) and with associated developmental and/or epileptic encephalopathy (DEE) [10] . Here we describe a patient with LGS, a phenotype also described in three other patients with KBG syndrome [10] , [19] . KBG syndrome-affected patients with epilepsy have a significantly poorer neurodevelopmental outcome compared to those without epilepsy.…”

“…Seizures occur in KBG syndrome, mostly as part of a developmental encephalopathy [9] , [10] , [11] . Recently, Buijsse et al reported 26/75 patients with epilepsy (original and historical literature combined), most of whom were classified by International League Against Epilepsy (ILAE) criteria, as having generalized epilepsy (15/38 or 39 % patients), focal epilepsy 12/38 (31.6 %), or combined focal and generalized epilepsy (11/38 or 31.6 %) [10] . Distinctive epilepsy syndromes were identified in only few patients.…”

“…The median age of onset of seizures is approximately 3 to 4 years, with most patients reaching seizure remission. However, approximately one quarter of patients had a drug-resistant epilepsy [10] . While no genotype-phenotype correlation is clearly identified for the presence of epilepsy characteristics in KBG syndrome, those patients with epilepsy had worse developmental outcomes [10] .…”