Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review

Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8780749/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background To investigate the clinical features, electroencephalography (EEG) findings, genetic basis, and therapeutic response of epilepsy in KBG syndrome patients and to explore its phenotypic spectrum. Methods A retrospective analysis was performed on four children with KBG syndrome presenting with epilepsy who were admitted to Hebei Children's Hospital between January 2023 and December 2025. Clinical data were collected, and a systematic database search identified 108 reported KBG syndrome patients with epileptic phenotypes. Results Among our 4 cases (3 males, 1 female), the median epilepsy onset age was 4 years. Focal and myoclonic seizures were predominant, and 1 patient presented with multiple seizure types. In accordance with the 2022 ILAE criteria, 1 patient presented with epilepsy with myoclonic-atonic seizures (EMAS), whereas another patient presented with a phenotype analogous to childhood occipital visual epilepsy (COVE). All patients exhibited abnormal electroencephalogram (EEG) findings, predominantly epileptiform discharges, whereas 2 patients presented nonspecific changes on cranial imaging. Pathogenic ANKRD11 mutations were detected in all the children, encompassing 2 transpositions, 1 nonsense, and 1 missense, with 3 de novo and 1 maternally inherited mutations. Two patients with focal epilepsy achieved seizure control with lacosamide, and 1 was diagnosed with refractory epilepsy. For the 108 literature cases, the male-to-female ratio was 1.7:1, and the median age at epilepsy onset was 3 years and 10 months. Bilateral tonic‒clonic seizures (n = 47) and focal seizures (n = 31) were most common, and 36.3% had multiple types. Seventeen patients met the criteria for epileptic syndrome, predominantly EMAS, which was the most common type. This is the first report of the association between COVE and KBG syndrome. The overall response to antiseizure medications (ASMs) was favorable, with the incidence of refractory epilepsy being 27.8%. Conclusion Epilepsy in KBG syndrome has significant phenotypic heterogeneity and a high incidence in childhood. EMAS is the most commonly associated epileptic syndrome, and COVE is a novel phenotypic association. This disease has a high rate of EEG abnormalities, while brain structural lesions are nonspecific. Lacosamide may be an effective drug for treating focal seizures. Given the limited sample sizes, the exact efficacy requires further verification in large-sample studies. KBG syndrome ANKRD11 gene Epilepsy Treatment Children Figures Figure 1 Figure 2 Figure 3 1 Introduction KBG syndrome (MIM #148050) is a rare autosomal dominant genetic disorder caused by mutations in the ankyrin repeat domain-containing protein 11 ( ANKRD11 ) gene or chromosomal microdeletions of 16q24.3 containing ANKRD11 . This syndrome is characterized by multisystem involvement, with typical clinical manifestations, including short stature, macrodontia of the permanent upper central incisors, dysmorphic facial features, and skeletal abnormalities. The nervous system is one of the major affected systems, and common neurological symptoms include varying degrees of developmental delay or intellectual disability, EEG abnormalities with or without seizures, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder. In addition, patients may also present with other systemic abnormalities, such as hearing loss, congenital heart defects, cryptorchidism, and feeding difficulties [ 1 ] . KBG syndrome was first described by Herrmann et al. in 1975 [ 2 ] , who reported the clinical features of seven patients from three families. The syndrome was named after the initial letters of the patients' surnames (K, B, and G). Since then, with the gradual deepening of clinical understanding, an increasing number of new cases have been reported. In recent years, the widespread application of high-throughput DNA sequencing technology has significantly improved the diagnostic rate of KBG syndrome, and its neurological manifestations have attracted increasing attention. Among these, epilepsy, a key clinical feature, is often the primary reason for patients to seek medical advice in the Department of Neurology. Research indicates that approximately one-third to one-half of patients with KBG syndrome may exhibit epileptic seizures, although the types and severity of these seizures show significant heterogeneity. They can manifest in various forms, including focal seizures, tonic‒clonic seizures, myoclonic seizures, and absence seizures. Only a minority of patients receive a definitive diagnosis of a specific epilepsy syndrome, such as Lennox‒Gastaut syndrome (LGS), epilepsy with myoclonic‒atonic seizures (EMAS), childhood absence epilepsy, or West syndrome [ 3 – 5 ] . Owing to the lack of specificity in the early clinical manifestations of KBG syndrome, some children are initially diagnosed with “epilepsy” or “developmental delay with epilepsy,” which can lead to delays in identifying the underlying cause. Therefore, we retrospectively analyzed the clinical and genetic data of four KBG syndrome patients with prominent epilepsy manifestations treated at our hospital. By reviewing the relevant literature, we explored the phenotypic characteristics of epilepsy associated with KBG syndrome, aiming to improve the clinical recognition and diagnostic accuracy of this condition. 2 Materials and methods 2.1 Source of the case series Four patients with KBG syndrome presenting with epilepsy as the prominent phenotype were selected from the Department of Neurology, Hebei Children's Hospital, between January 2020 and December 2025. All patients were confirmed to carry pathogenic variants in the ANKRD11 gene through genetic testing. Clinical data were collected for these four pediatric patients. Informed consent was obtained from the parents or legal guardians of all the participating children (Table 1 , Table 2 ). This study was approved by the Medical Research Ethics Committee of Hebei Children's Hospital (Approval No. 2025034-51). Table 1 Clinical phenotypes of the 4 patients Case Sex Ages at epilepsy onset Types of epilepsy ASMs Follow- up Characteristic facial dysmorphism Hand abnormalities short stature Other Abnormal birth history Abnormal family history Abnormal EEG Abnormal Cranial MRI Developmental delay 1 F 5y2m Focal LCM Seizure-free for 2 years + - + Congenital heart defect - - + + - 2 M 6y7m Focal VPA, LCM Seizure-free for 2 years + + + Hearing loss, cryptorchidism Term small for gestational age infant - + - + 3 M 1y3m myoclonic VPA, CLB, LGT, LEV Seizures persisted - + - - - - + + + 4 M 2y10m Myoclonic, atonic, myoclonic‒atonic VPA, CLB Seizure-free for a year + + - - - + + + + F: Female; M: Male; LCM: Lacosamide; VPA: Valproate; CLB: Clobazam; LTG: Lamotrigine; LEV: Levetiracetam Table 2 Genotypes of the 4 patients Case Gene Variant Locus Exon Mutation Type Zygosity Disease Inheritance Pattern Variant Origin Pathogenicity 1 ANKRD11 NM-013275.5 c.7183C๥T, p.Gln2395* 9 Nonsense Heterozygous KBG Syndrome AD De novo Pathogenic 2 ANKRD11 NM-01256182.1 c.7822C๥T, p.Arg2608Trp 13 Missense Heterozygous KBG Syndrome AD De novo Pathogenic 3 ANKRD11 NM-013275.5 c.1903-1907delAAACA, p.K635Qfs*26 9 Frameshift Heterozygous KBG Syndrome AD De novo Pathogenic 4 ANKRD11 NM-013275.6 c.6792dup, p.Ala2265Argfs*8 9 Frameshift Heterozygous KBG Syndrome AD Maternal Pathogenic 2.2 Diagnostic criteria 2.2.1 Diagnostic criteria for epilepsy The diagnosis and classification of epilepsy and epileptic syndromes followed the latest diagnostic framework standards published by the International League Against Epilepsy (ILAE) in 2017 and 2022. 2.2.2 Diagnostic criteria for KBG syndrome KBG syndrome can be diagnosed when two or more major diagnostic criteria are met or when one major criterion and two or more minor criteria are present [ 5 – 7 ] . The primary diagnostic criteria were as follows: macrodontia of permanent upper central incisors, developmental delay or mild/moderate intellectual disability or learning difficulty associated with behavioral issues, characteristic facial appearance, postnatal short stature, and 1st degree relative to KBG syndrome. The secondary diagnostic criteria were conductive hearing loss due to recurrent otitis media, palatal abnormalities, hair findings, delayed bone age, large anterior fontanelle with delayed closure, hand findings, costovertebral anomalies, scoliosis, EEG abnormalities with or without seizures, feeding difficulties, and cryptorchidism in males. 2.3 Case series Case 1 A 5-year-old girl with a 2-week history of recurrent seizures was admitted to our hospital. All seizures, characterized by sudden tachypnea, upward eye deviation, and unresponsiveness, occurred during sleep and lasted approximately one minute before spontaneously resolving. Seizures occurred at a frequency of approximately twice weekly, resulting in four episodes. No significant discomfort was reported postseizure, and no specific intervention was administered. She was the firstborn child of the family and was delivered at term via vaginal delivery, with a birth weight of 2.8 kg. She had no history of birth asphyxia, hypoxia, or resuscitation. Congenital heart disease (atrial septal defect, ventricular septal defect, and persistent left superior vena cava) was diagnosed immediately after birth. She underwent surgical repair of the atrial and ventricular septal defects at 2 months of age, with an uneventful postoperative recovery. Her intellectual development was normal; however, her physical growth was delayed compared with that of her age-matched peers. There was no relevant family history of neurological or genetic disorders. Physical examination revealed that the patient’s height was 106 cm, and her weight was 16 kg, both of which fell within the − 2SD to -1SD range for age- and sex-matched peers. Distinctive facial features: Triangular face, bushy eyebrows and macrodontia. Auxiliary Investigations: Video EEG showed sporadic left frontal spike‒and‒wave complexes during the interictal period; cranial magnetic resonance imaging (MRI) revealed mild enlargement of the bilateral ventricles and cisterna magna. Transthoracic echocardiography indicated findings consistent with postoperative changes following surgical repair of congenital heart disease (ventricular septal defects and atrial septal defects). An electrocardiogram revealed sinus rhythm with an otherwise normal waveform. Whole-exome sequencing (WES) identified a heterozygous de novo variant in the ANKRD11 gene: c.7183C > T (p.Gln2395*). Diagnosis: Epilepsy (focal seizures) and KBG syndrome. Treatment and Follow-up: Oral lacosamide was administered, with the maximum dose set at 50 mg twice daily (equivalent to 6.25 mg·kg − 1 ·d − 1 ). No significant adverse drug reactions were observed after medication initiation. During the 2-year follow-up period, no epileptic seizures occurred, and a repeat vEEG indicated a normal interictal background. Case 2 A 6-year and 7-month-old boy with a 3-month history of intermittent seizures was admitted to our hospital. The seizures manifested a cluster pattern, with 1 to 2 clusters documented per month. He frequently experienced paroxysmal visual blurring while awake; these episodes were accompanied or not accompanied by headache and vomiting, with consciousness preserved throughout the events, which resolved spontaneously within approximately 1 minute. Bilateral tonic‒clonic seizures were occasionally secondary to these episodes. Visual function returned to baseline following symptom resolution. During exacerbations, the episodes occurred more than ten times daily for several consecutive days before remission, with an overall disease course of 3 months. These symptomatic episodes were occasionally precipitated by febrile events. He was the firstborn child of his mother and was delivered at term via vaginal delivery, with a birth weight of 2 kg. He had no history of birth asphyxia, hypoxia, or resuscitation at birth. His mother remained healthy throughout the entire course of pregnancy. Postnatally, he was diagnosed with hearing impairment; cryptorchidism was identified when he was 1 year old. At the age of 2 years, he underwent cochlear implantation and orchidopexy. Since infancy, he has exhibited slow linear growth and weight gain. Motor development was age-appropriate, whereas language and intellectual development were delayed. There was no relevant family history of neurological or genetic disorders. Physical examination revealed that the height was 110 cm (between − 3 SD and − 2 SD), and the weight was 14 kg (<-3 SD). He has a triangular face, macrodontia and a small mandible. Bilateral short little fingers, clubbing of fingers and toes. Auxiliary Investigations: VEEG revealed slow background activity during the interictal period, with right posterior occipital spikes and spike-and-wave discharges observed across all sleep and wakefulness stages. A focal seizure originating in the right occipital and posterior temporal regions was detected (Fig. 1 ). Cranial MRI showed no obvious abnormalities. WES identified a de novo mutation in the ANKRD11 gene: c.7822C > T (p.Arg2608Trp*). Diagnosis: Epilepsy (focal seizures) and KBG syndrome. Treatment and Follow-up: The patient was switched to oral lacosamide therapy at a maximum dose of 50 mg twice daily (7.14 mg·kg − 1 ·d − 1 ), resulting in seizure control. Follow-up over 2 years showed no seizures, with normal vEEG findings. Case 3 A 1-year-3-month-old boy presented to our hospital with recurrent nodding episodes. He exhibited paroxysmal nodding movements that occurred once per episode, initially ranging from 1 to 2 times daily and then gradually increasing to dozens of times per day. He remained alert during the interictal periods. He was the second child, born at term via vaginal delivery, with a birth weight of 3 kg. There was no history of hypoxia, asphyxia, or resuscitation at birth. Physical development was normal prior to symptom onset. There was no relevant family history of neurological or genetic disorders. Physical examination revealed no characteristic facial dysmorphism; bilateral hypoplastic little fingers were observed. Neurological examination revealed no abnormalities. Auxiliary Investigations: VEEG revealed slow background activity, with widespread slow waves and spike-and-wave discharges during the interictal period, and generalized myoclonic seizures were detected (Fig. 2 ). Cranial MRI showed widened bilateral frontotemporal extraaxial spaces. The Gesell Developmental Diagnosis Scale assessment revealed the following developmental quotients (DQs): Adaptation 75, Gross Motor 80, Fine Motor 72, Language 70, and Personal-Social 72, which is consistent with mild developmental delay. WES identified a de novo variant in the ANKRD11 gene: c.1903_1907delAAACA (p.K635Qfs*26). Diagnosis: Epilepsy (myoclonic seizures), KBG syndrome. Treatment and Follow-up: Initial therapy with 4 ml of sodium valproate oral solution was given twice daily (32 mg·kg − 1 ·d − 1 ). Persistent frequent seizures led to the subsequent addition of clobazam, lamotrigine, and levetiracetam. Myoclonic seizures persisted at the 1-year follow-up. Case 4 A 2-year and 10-month-old boy presented to our hospital with intermittent seizure episodes over the past 2 weeks. There were two types of seizures: ① Sudden loss of consciousness during wakefulness, accompanied by blinking and upward eye deviation, lasting more than 10 seconds before resolution. This occurred twice initially. ② Episodic nodding, with or without a single-limb jerk, occurs 1 to 2 times daily initially and gradually increases to more than a dozen episodes per day. The child remained conscious during the interictal period. He was the first child of his parents and was born at term via vaginal delivery, with a birth weight of 3.4 kg. There was no history of hypoxia, asphyxia, or resuscitation at birth. The patient’s physical development was normal. His mother had distinctive facial features (triangular face, synophrys), megalodontia, and hearing impairment. The maternal grandmother had hearing impairment and an abnormal walking posture. Physical examination revealed a low anterior hairline, triangular face, protruding ears, high nasal bridge, missing maxillary central incisors, enamel hypoplasia, single transverse palmar crease on the right hand, and clinodactyly of the fifth finger. Auxiliary Investigations: EEG showed no obvious occipital dominant rhythm in the background activity; during both wakefulness and sleep, numerous paroxysmal and intermittent generalized spike waves, polyspike waves, spike-and-wave complexes/sharp-and-slow wave complexes, polyspike-and-slow wave complexes, and slow spike-and-slow wave complexes were observed. Multiple generalized myoclonic seizures, atonic seizures, and myoclonic‒atonic seizures were detected (Fig. 3 ). Cranial MRI revealed focal abnormal signals in both frontal lobes, suggestive of focal demyelination. The external temporal subarachnoid spaces on both sides were widened. Gesell Developmental Diagnosis Scale: Adaptation 80, Gross Motor 85, Fine Motor 80, Language 73, Personal-Social 72, consistent with mild developmental delay. WES revealed a maternal-derived ANKRD11 gene duplication at c.6792 (p.A2265Rfs*8). Diagnosis: Epilepsy (myoclonic seizures, atonic seizures, and myoclonic‒atonic seizures) and KBG syndrome. Treatment and Follow-up: Initially, sodium valproate oral solution was administered, with a maximum dose of 6 ml twice daily (equivalent to 32 mg·kg − 1 ·d − 1 ), which resulted in reduced seizures. Subsequently, clobazam was added at a dose of 2.5 mg twice daily, leading to a significant reduction in seizures until complete seizure cessation. During the 1-year follow-up, no epileptic seizures occurred. A repeat vEEG showed improved background activity compared with the previous one; interictal generalized spike waves, spike-and-wave complexes, and polyspike-and-slow wave complexes were observed, which were fewer than before. 2.4 Literature Review To systematically summarize the epileptic phenotype characteristics of patients with KBG syndrome, the terms “ ANKRD11 , epilepsy” or “KBG syndrome, epilepsy” were used as search terms in the PubMed database (2000 to December 2025). A total of 150 patients with KBG syndrome and documented epileptic phenotypes reported in the literature were included, and a pooled analysis was conducted on the clinical characteristics of 91 patients whose data were relatively complete. 3 Results 3.1 Case series This study included 4 patients with KBG syndrome presenting with epileptic seizures, comprising 3 males and 1 female. The median age at epilepsy onset was 4 years. The predominant seizure types were focal and myoclonic, and one patient had multiple seizure types. According to the 2022 ILAE Classification of Epilepsy Syndromes, two patients were highly consistent with the diagnostic criteria of specific epilepsy syndromes, with one classified as EMAS and the other conforming to COVE. With respect to other clinical phenotypes, three patients exhibited mild developmental delay, primarily characterized by language development delay. Additional systemic abnormalities included characteristic facial appearance (3 cases), macrodontia (2 cases) and enamel hypoplasia (1 case), hand abnormalities (3 cases), short stature (2 cases), congenital heart malformation (1 case), and hearing impairment with cryptorchidism (1 case). EEG revealed abnormalities in all 4 patients (Figs. 1 , 2 , 3 ). Interictal EEGs predominantly showed epileptiform discharges (4 cases), including focal discharges in 2 cases and generalized discharges in 2 cases. Additionally, 3 cases exhibited abnormal background activity. During seizures, multiple characteristic EEG patterns, corresponding to clinical seizure types (focal seizures, myoclonic seizures, atonic seizures, and myoclonic-atonic seizures), were recorded. Cranial MRI showed nonspecific abnormalities in 3 patients, manifested as focal demyelination, widened periventricular spaces, ventricular enlargement, and an enlarged foramen magnum. Genetic testing revealed that all patients harbored ANKRD11 gene variants, including one missense mutation, one nonsense mutation, and two frameshift mutations. Three mutations were de novo, whereas one was maternally inherited. The mother exhibited a distinctive facial appearance and hearing impairment but lacked an epileptic phenotype. All the variants were classified as “pathogenic” on the basis of the ACMG criteria. ASMs were administered to the 4 patients as follows: All patients received ASMs treatment. Case 1 achieved seizure freedom with lacosamide monotherapy. Case 2 had an inadequate initial response to valproate but achieved effective seizure control after switching to lacosamide. For Cases 3 and 4 , both with generalized seizures, valproate sodium was used as first-line treatment. Case 4 achieved partial control with valproate and achieved full seizure control after clobazam was added. Despite treatment with multiple ASMs, Case 3 continued to experience recurrent seizures and thus fulfilled the diagnostic criteria for drug-resistant epilepsy. 3.2 Literature Review Among the 150 patients with epilepsy associated with KBG syndrome included in the previous literature, 68 were male and 40 were female, yielding a male-to-female ratio of 1.7:1. The age at epilepsy onset ranged from birth to 51 years, with a median age of 3 years and 10 months. Among the 91 patients with documented seizure characteristics, marked heterogeneity was noted in terms of seizure phenotypes. Bilateral tonic‒clonic seizures were the most prevalent subtype (n = 39), with unclear seizure onset in some cases, followed by focal seizures (n = 32). Typical or atypical absence seizures (n = 17) and myoclonic seizures (n = 14) were also relatively common. The less frequently observed seizure types included atonic seizures (n = 6), epileptic spasms (n = 6), and myoclonic-atonic seizures (n = 4). The prevalence of status epilepticus was comparatively low (n = 6), with one case manifesting as absence status. With respect to the distribution of seizure subtypes, the majority of patients presented with a single seizure type, whereas 36.3% (33/91) of individuals presented with two or more distinct seizure types. Within this cohort, 17 patients exhibited clinical manifestations highly consistent with the diagnostic criteria for epilepsy syndromes, with the following subtype distributions: EMAS, 4 cases; LGS, 4 cases; childhood absence epilepsy, infantile spasms, infantile myoclonic epilepsy, and Jeavons syndrome, 2 cases each; and generalized epilepsy with febrile seizures plus (GEFS+), 1 case. Additionally, two sisters presented with clinical features compatible with the GEFS+. However, genetic testing revealed that both harbored mutations in the SCN9A gene in addition to the ANKRD11 mutation. This finding suggests that their phenotypic presentation may be linked to this SCN9A gene variant [ 8 ] . Of the four newly enrolled cases in this study, two fulfilled the diagnostic criteria for epilepsy syndrome. Prior studies have established that EMAS is the epilepsy subtype most strongly associated with KBG syndrome. The clinical phenotype of Case 4 in the present cohort was highly concordant with this conclusion, thereby further validating this core clinical feature. Notably, this study constitutes the first report of an association between COVE and KBG syndrome. This novel finding expands the phenotypic spectrum of epilepsy syndromes linked to KBG syndrome and provides additional evidence supporting the extensive clinical phenotypic heterogeneity of this disorder. In the clinical management of epilepsy associated with KBG syndrome, ASMs yield an overall favorable therapeutic response. Seizure activity in the majority of patients can be effectively or partially controlled via the judicious selection of ASMs. Among the 72 patients with documented treatment efficacy data, the prevalence of refractory epilepsy was approximately 27.8% (n = 20). Monotherapy achieved clinical efficacy in 37.5% (27/72) of cases. Valproate remains the first-line agent of choice for clinicians, with a monotherapy response rate of 32.3% (10/31). Lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and topiramate are also widely prescribed as first- or second-line treatment modalities. For refractory cases, adjunctive clobazam may confer clinical benefit in select patients. Accumulating evidence from the literature indicates that cannabidiol has a modest therapeutic effect on this epilepsy subtype [ 9 ] . Nonpharmacological interventions, including the ketogenic diet and vagus nerve stimulation (VNS), have also been validated to possess clinical utility in this patient population [ 3 , 10 , 11 ] . 4 Discussion Since the first proposal of the concept of KBG syndrome, new relevant cases have been reported, but unified diagnostic criteria for this disorder have not yet been established. To address this issue, scholars have proposed targeted clinical diagnostic protocols in which patients' clinical manifestations are systematically summarized. In 2007, Skjei et al. [ 6 ] conducted a detailed analysis of the clinical features of more than 50 patients with KBG syndrome, defining diagnostic criteria that include neurological involvement. Specifically, this neurological involvement manifests as epilepsy, generalized developmental delay, intellectual disability, and other conditions. In 2016, on the basis of reporting 31 new cases and systematically sorting out relevant literature, Low et al. [ 5 ] proposed a more refined diagnostic system, classifying the criteria into major diagnostic criteria and minor diagnostic criteria and categorizing epilepsy into the scope of minor diagnostic criteria. In 2017, Morel Swols et al. [ 7 ] further improved this diagnostic system, incorporating both epileptiform and nonepileptiform EEG abnormalities into the minor diagnostic criteria. Thus, there is a consensus that epilepsy is a common symptom when KBG syndrome patients have neurological involvement. A systematic review of the literature revealed a wide range of ages at epilepsy onset, with median ages of 3 years and 10 months. This finding is consistent with the median age of 4 years observed in the four patients in this study, supporting the clinical characteristic that epilepsy in KBG syndrome predominantly manifests during childhood. Regarding seizure types, bilateral tonic–clonic and focal seizures were the most common, followed by typical/atypical absence and myoclonic seizures. In this case series, focal and myoclonic seizures predominated, with additional manifestations of atonic and myoclonic-atonic seizures. Descriptions of associated epilepsy syndromes are scarce, among which EMAS and LGS are the most common epilepsy syndromes associated with KBG syndrome [ 10 – 13 ] . Case 4 in this study exhibited a phenotype highly consistent with EMAS, while Case 2 presented a COVE-related phenotype that is novel and has not been previously reported in KBG syndrome. These findings on epileptic phenotypes further confirm the remarkable diversity of seizure types in KBG syndrome patients with epilepsy, which may be consistent with the genetic heterogeneity and extensive neurological involvement of this disease. This study is the first to establish the association between COVE and KBG syndrome, enriching the phenotypic spectrum of epileptic syndromes in this disorder and providing new evidence supporting the diversity of its clinical phenotypes. With respect to treatment, three of the four included patients responded well to ASMs, which is consistent with the findings of previous studies. One patient remained refractory to standardized treatment with multiple ASMs, meeting the criteria for drug-resistant epilepsy; this incidence was consistent with the reported 27.8% prevalence of KBG syndrome. A review of prior cases indicated that valproate is the first-line treatment for KBG syndrome-associated epilepsy. In this study, the patient achieved only partial efficacy with sodium valproate monotherapy. However, effective seizure control was attained after the addition of clobazam. Currently, reports in the literature on the use of lacosamide in such patients are relatively scarce. Previous studies have shown that one patient with focal seizures achieved symptom remission with this drug [ 13 ] , whereas two other patients with drug-resistant epilepsy had suboptimal treatment efficacy [ 14 ] . In contrast, both patients with focal seizures in this study achieved definitive efficacy with lacosamide monotherapy. These findings not only enrich the clinical evidence for lacosamide in the treatment of KBG syndrome-associated focal epilepsy and provide a new practical basis for clinical diagnosis and treatment but also suggest that lacosamide monotherapy may serve as a potentially effective treatment strategy for this subset of patients. Previous cohort studies have characterized the neuroimaging features of KBG syndrome. Loberti L et al. [ 15 ] conducted a study of 32 patients with KBG syndrome and identified enlarged cisterna magna, which was the most prevalent structural abnormality, in 6 patients (18.7%). Peluso F et al. [ 16 ] analyzed imaging data from 53 patients with KBG syndrome, 41 of whom underwent cranial MRI, and only 3 cases yielded unremarkable findings. In this study, the prevalence of enlarged cisterna magna was as high as 63.6%, which was also among the most common structural anomalies. Additionally, incomplete hippocampal inversion was detected in up to 63.4% of cases; however, this finding is generally regarded as an anatomical variant that can also be observed in healthy individuals. Other reported neuroimaging abnormalities include ventricular structural anomalies, white matter signal alterations, corpus callosum morphological irregularities, optic nerve abnormalities, and olfactory bulb hypoplasia. All four patients enrolled in the present study underwent cranial MRI, and most presented with nonspecific radiological findings. An Enlarged cisterna magna was noted in Case 1 , whereas widened frontotemporal extraaxial spaces and focal myelination delay were observed in the two younger patients. These results are consistent with the findings reported in the literature. Genetic studies have conclusively established that KBG syndrome is closely associated with pathogenic mutations in the ANKRD11 gene (also known as ankyrin repeat-containing cofactor 1, ANCO-1 ). To date, no cases of ANKRD11 homozygous deficiency have been documented, and both in vitro experiments and animal model studies have corroborated the lethality of homozygous deficiency. In studies in which Ankrd11 -deficient Neuro-2a cells were used, all attempts to establish homozygous deficient cell lines were unsuccessful. In murine models, embryos with homozygous Ankrd11 deletion exhibited early embryonic lethality [ 17 ] . While the precise mechanisms by which ANKRD11 dysfunction elicits neurological abnormalities remain incompletely understood, numerous studies have addressed this knowledge gap. With respect to gene and protein characteristics, the ANKRD11 gene maps to chromosomal locus 16q24.3 and encodes ankyrin repeat domain-containing protein 11. This protein is a 298 kDa macromolecule comprising 2663 amino acids, with four distinct functional domains, an N-terminal ankyrin repeat domain, two transcriptional repressor domains, and one transcriptional activator domain. Current research suggests that ANKRD11 may function as a chromatin modifier that plays dual roles in transcriptional activation and repression. At the molecular level, members of the p160 nuclear receptor coactivator family interact with liganded nuclear receptors to potentiate target gene transcription. ANCO-1 (i.e., ANKRD11 ) is proposed to recruit histone deacetylase 3 (HDAC3) to the p160 coactivator/nuclear receptor complex, thereby abrogating ligand-dependent transactivation [ 18 ] . It can also form a complex with p53 and histone acetyltransferase (HAT), facilitating HAT-mediated acetylation of both p53 and histone H3 at the promoter loci of target genes (e.g., Trkb), which in turn augments the transcriptional activity of these genes. Histone acetylation serves as a core epigenetic regulatory switch that governs neural precursor proliferation, neuronal differentiation, and dendrite development during cerebral morphogenesis. HDACs (e.g., HDAC3) and HATs modulate histone acetylation levels to orchestrate the transcription of genes essential for nervous system development, laying a critical theoretical foundation for ANKRD11 -mediated regulation of neurodevelopment [ 19 , 20 ] . Neuroanatomical studies have demonstrated that ANKRD11 is widely expressed throughout the brain, with predominant localization to the nuclei of neurons and glial cells. Ankrd11 -knockout mouse models present a spectrum of neurodevelopmental abnormalities, including reduced proliferation of neural progenitor cells, impaired formation of leading processes in migrating neurons, decreased dendritic numbers, sparse branching, and abnormal dendritic spine morphology. Collectively, these abnormalities culminate in delayed radial migration of cortical neurons [ 17 ] . In summary, the ANKRD11 gene plays an indispensable role in neurodevelopment. Pathogenic mutations in this gene are likely to impair neuronal plasticity and disrupt the excitatory–inhibitory balance in neural circuits, and this represents the core mechanism underlying epileptiform discharges in KBG syndrome. Variants in the ANKRD11 gene exhibit high heterogeneity. Frameshift mutations and nonsense mutations are the most frequently detected subtypes in clinical practice, whereas missense mutations and splice-site mutations are relatively rare. Furthermore, de novo mutations represent the predominant form of variation in this gene. All four patients enrolled in the present study harbored ANKRD11 mutations, three of which were de novo. The variant types included two frameshift mutations, one nonsense mutation, and one missense mutation. Previous studies have indicated that the most common mutation sites of the ANKRD11 gene are concentrated in exon 9, which is the largest exon of the gene. Consistent with these reports, three out of the four patients in this study had mutations localized to exon 9. Notably, the c.1903_1907delAAACA mutation detected in Case 3 and the c.6792dup mutation identified in Case 4 have been previously reported multiple times [ 1 ] . Both variants are frameshift mutations that cause a shift in the gene's open reading frame, ultimately leading to the production of truncated proteins and impairment of normal protein structure and function. Collectively, the mutation characteristics observed in this study are generally consistent with those reported in the literature. 5 Conclusions In summary, epilepsy in KBG syndrome patients exhibits marked clinical heterogeneity, characterized by a broad spectrum of seizure semiologies encompassing generalized tonic–clonic, focal, myoclonic, and mixed-type seizures, with onset predominantly concentrated in early childhood. ANKRD11 gene mutations are hypothesized to disrupt neurodevelopmental trajectories, thereby acting as the core pathogenic driver of epileptogenesis in patients with KBG syndrome. Therefore, for pediatric patients who present with epilepsy as the initial symptom, especially those with concurrent multisystem involvement, a high index of suspicion for KBG syndrome is warranted, and priority should be given to ANKRD11 genetic testing. Defining the etiological basis not only provides a precise framework for formulating individualized therapeutic regimens but also enables evidence-based prognostic stratification, ultimately optimizing long-term clinical management outcomes for affected individuals. Abbreviations EMAS Epilepsy with myoclonic-atonic seizures COVE Childhood occipital visual epilepsy EEG Electroencephalogram ASMs Antiseizure medications ANKRD11 Ankyrin repeat domain-containing protein 11 ADHD Attention deficit hyperactivity disorder ILAE International League Against Epilepsy LGS Lennox–Gastaut syndrome MRI Magnetic resonance imaging WES Whole-exome sequencing GEFS+ Generalized epilepsy with febrile seizures plus VNS Vagus nerve stimulation Declarations Author information Authors and Affiliations First Department of Neurology, Hebei Children’s Hospital, Shijiazhuang, China Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li & Suzhen Sun Hebei Provincial Clinical Research Center for Child Health and Disease, Shijiazhuang, China Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li & Suzhen Sun Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders, Shijiazhuang, China Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li & Suzhen Sun Contributions Conception and design of the work: XFL, JJL; Data collection: LYP, PHY, FF; Supervision: XL, SZS; Analysis and interpretation of the data: JZ, FC; Drafting the manuscript: XFL, JJL; Critical revision of the manuscript: all authors; Approval of the final manuscript: all authors. Corresponding authors Correspondence to Xin Li or Suzhen Sun. Ethics declarations Ethics approval and consent to participate This study was performed in accordance with the principles of the Declaration of Helsinki. The study was approved by the Hebei Children's Hospital Ethics Committee. The Hebei Children's Hospital's Institutional Review Board also approved the study after consulting with its ethics committee (approval number: 2025034-51). Written informed consent was obtained from the parents or legal guardians of all participants under 16 years of age for their participation in this study. Consent for publication Written informed consent for publication of the clinical details and/or clinical images was obtained from the parents or legal guardians of all cases under 18 years of age included in this study. Conflict of interest The authors have no conflicts of interest to declare. Funding This work was supported by the Medical Science Research Project of Hebei (20260885), China. Author Contribution Conception and design of the work: XFL, JJL; Data collection: LYP, PHY, FF; Supervision: XL, SZS; Analysis and interpretation of the data: JZ, FC; Drafting the manuscript: XFL, JJL; Critical revision of the manuscript: all authors; Approval of the final manuscript: all authors. Acknowledgement I would like to express my deepest gratitude to the patient and his parents, who provided the data and significantly contributed to the development of human health. Data Availability The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request. References Martinez-Cayuelas E, Blanco-Kelly F, Lopez-Grondona F, Swafiri ST, Lopez-Rodriguez R, et al. Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients. J Med Genet. 2023;60(7):644–54. 10.1136/jmg-2022-108632 . Herrmann J, Pallister PD, Tiddy W, Opitz JM. The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser. 1975;11(5):7–18. Buijsse N, Jansen FE, Ockeloen CW, van Kempen MJA, Zeidler S, et al. Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome. Epilepsia Open. 2023;8(4):1300–13. 10.1002/epi4.12799 . Parenti I, Mallozzi MB, Hüning I, Gervasini C, Kuechler A, et al. ANKRD11 variants: KBG syndrome and beyond. Clin Genet. 2021;100(2):187–200. 10.1111/cge.13977 . Low K, Ashraf T, Canham N, Clayton-Smith J, Deshpande C, et al. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A. 2016;170(11):2835–46. 10.1002/ajmg.a.37842 . Skjei KL, Martin MM, Slavotinek AM. KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. Am J Med Genet A. 2007;143A(3):292–300. 10.1002/ajmg.a.31597 . Morel Swols D, Foster JJ, Tekin M. KBG syndrome. Orphanet J Rare Dis. 2017;12(1):183. 10.1186/s13023-017-0736-8 . Alves RM, Uva P, Veiga MF, Oppo M, Zschaber FCR, et al. Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report. BMC Med Genet. 2019;20(1):16. 10.1186/s12881-019-0745-7 . Kleyner R, Malcolmson J, Tegay D, Ward K, Maughan A, et al. KBG syndrome involving a single-nucleotide duplication in ANKRD11. Cold Spring Harb Mol Case Stud. 2016;2(6):a001131. 10.1101/mcs.a001131 . Whitney R, Komar M, Yoganathan S, Costain G, Jain P. Epilepsy in KBG Syndrome: Report of Additional Cases. Pediatr Neurol. 2024;151:138–42. 10.1016/j.pediatrneurol.2023.12.006 . Donnellan EP, Gorman KM, Shahwan A, Allen NM. Epileptic dyskinetic encephalopathy in KBG syndrome: Expansion of the phenotype. Epilepsy Behav Rep. 2024;25:100647. 10.1016/j.ebr.2024.100647 . Samanta D, Willis E. Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene. Acta Neurol Belg. 2015;115(4):779–82. 10.1007/s13760-014-0413-9 . Auconi M, Serino D, Digilio MC, Gnazzo M, Conti M, et al. Epilepsy in KBG syndrome. Dev Med Child Neurol. 2023;65(5):712–20. 10.1111/dmcn.15428 . Guo L, Park J, Yi E, Marchi E, Hsieh TC, et al. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients. Eur J Hum Genet. 2022;30(11):1244–54. 10.1038/s41431-022-01171-1 . Loberti L, Bruno LP, Granata S, Doddato G, Resciniti S, et al. Natural history of KBG syndrome in a large European cohort. Hum Mol Genet. 2022;31(24):4131–42. 10.1093/hmg/ddac167 . Peluso F, Caraffi SG, Contrò G, Valeri L, Napoli M, et al. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature. J Med Genet. 2023;60(12):1224–34. 10.1136/jmg-2023-109141 . Gallagher D, Voronova A, Zander MA, Cancino GI, Bramall A, et al. Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. Dev Cell. 2015;32(1):31–42. 10.1016/j.devcel.2014.11.031 . Zhang A, Yeung PL, Li CW, Tsai SC, Dinh GK, et al. Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. J Biol Chem. 2004;279(32):33799–805. 10.1074/jbc.M403997200 . Zhang A, Li CW, Chen JD. Characterization of transcriptional regulatory domains of ankyrin repeat cofactor-1. Biochem Biophys Res Commun. 2007;358(4):1034–40. 10.1016/j.bbrc.2007.05.017 . Sashiyama S, Nakagawa T, Nakagawa M, Hosogane M, Watanabe Y, et al. KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation. iScience. 2025;28(6):112699. 10.1016/j.isci.2025.112699 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8780749","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591576323,"identity":"be84a5a4-1def-4e2d-a340-b638debd2911","order_by":0,"name":"Xuefang Liu","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuefang","middleName":"","lastName":"Liu","suffix":""},{"id":591576324,"identity":"d0a8cccf-c49d-480d-b448-694acf17c6d1","order_by":1,"name":"Jingjie Li","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jingjie","middleName":"","lastName":"Li","suffix":""},{"id":591576325,"identity":"e5067caa-65a9-45e8-8587-e56ecd957c42","order_by":2,"name":"Jing Zhang","email":"","orcid":"","institution":"Hebei Provincial Clinical Research Center for Child Health and Disease","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhang","suffix":""},{"id":591576326,"identity":"c3bff966-e364-4c41-960a-106da9c4180f","order_by":3,"name":"Lingyu Pang","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lingyu","middleName":"","lastName":"Pang","suffix":""},{"id":591576327,"identity":"8903f28b-1a9c-41b3-ab29-9dc024a4754c","order_by":4,"name":"Panhui Yu","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Panhui","middleName":"","lastName":"Yu","suffix":""},{"id":591576328,"identity":"57df0cbb-4631-42a7-8946-cd7507ff8d5c","order_by":5,"name":"Fan Feng","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Feng","suffix":""},{"id":591576329,"identity":"8438f690-2c1c-4495-82c7-08021b648d71","order_by":6,"name":"Hongru Lu","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongru","middleName":"","lastName":"Lu","suffix":""},{"id":591576330,"identity":"f0b204df-1227-4c3c-b79e-4f42817cd75f","order_by":7,"name":"Liyao Ma","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Liyao","middleName":"","lastName":"Ma","suffix":""},{"id":591576331,"identity":"386d9b29-b46c-4567-b761-34392f6afee1","order_by":8,"name":"Xin Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIie2PsQrCMBCGrwQytXaTiNC8QoqrD5MuncTFJZsOks1d6Us4Ol4RdMkDCO1Q8QUCroJaHAWT0SHfdAf38d8PEAj8Kdip55LyG6JVvoo0RA6gLOqt8Y0pNJEZzCbHZO1xnVab6zuFzikYi8kKeDrE3wprzwKlihc02uxxdIB8V0lHzKXsu7BIk2SPuQEpGofCe6XQItI07t6DhyI+iix0HAPWPkrenvrHcEIZFfXKMHeXrNHEWoUZ35Lb/aGmPB07FGA/Vx8lEAgEAt+8AL3yTKGQIqrOAAAAAElFTkSuQmCC","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":591576332,"identity":"6be8edeb-d5be-4385-9fad-8b1054a1ffb6","order_by":9,"name":"Fang Chen","email":"","orcid":"","institution":"First Department of Neurology, Hebei Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2026-02-04 01:53:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8780749/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8780749/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102940268,"identity":"079bc7a4-98d7-4e97-a615-80defa2d6d5c","added_by":"auto","created_at":"2026-02-18 17:05:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1612955,"visible":true,"origin":"","legend":"\u003cp\u003eEEG findings of Case 2: (a) slow background activity, (b) interictal right posterior cranial spikes and spike-wave complexes, and (c–f) process of a single focal seizure\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8780749/v1/8311fa78b1c99b5081e9c456.jpg"},{"id":102940266,"identity":"40128baf-7de7-49dd-8e25-251c27dd58c8","added_by":"auto","created_at":"2026-02-18 17:05:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2902945,"visible":true,"origin":"","legend":"\u003cp\u003eEEG findings of Case 3: (a) slow background activity, (b) interictal generalized spike-wave complex discharges, and (c) myoclonic seizures\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8780749/v1/e26f701bc2ad186631cd9cec.jpg"},{"id":102940267,"identity":"c06800a0-196c-478a-9605-f5adb586b463","added_by":"auto","created_at":"2026-02-18 17:05:02","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3526312,"visible":true,"origin":"","legend":"\u003cp\u003eEEG findings of Case 4: (a) Interictal generalized spike-wave complex discharges and (b) myoclonic, atonic, and myoclonic-atonic seizures\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8780749/v1/4c0d000a47cbe4bffb740d86.jpg"},{"id":103049582,"identity":"ab1a6ae2-f36a-4b48-9b64-dd41399a60ed","added_by":"auto","created_at":"2026-02-20 07:42:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8863385,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8780749/v1/5ee45fb4-d62b-470f-af2f-c5a7b3cf988b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eKBG syndrome (MIM #148050) is a rare autosomal dominant genetic disorder caused by mutations in the ankyrin repeat domain-containing protein 11 (\u003cem\u003eANKRD11\u003c/em\u003e) gene or chromosomal microdeletions of 16q24.3 containing \u003cem\u003eANKRD11\u003c/em\u003e. This syndrome is characterized by multisystem involvement, with typical clinical manifestations, including short stature, macrodontia of the permanent upper central incisors, dysmorphic facial features, and skeletal abnormalities. The nervous system is one of the major affected systems, and common neurological symptoms include varying degrees of developmental delay or intellectual disability, EEG abnormalities with or without seizures, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder. In addition, patients may also present with other systemic abnormalities, such as hearing loss, congenital heart defects, cryptorchidism, and feeding difficulties\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. KBG syndrome was first described by Herrmann et al. in 1975\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, who reported the clinical features of seven patients from three families. The syndrome was named after the initial letters of the patients' surnames (K, B, and G). Since then, with the gradual deepening of clinical understanding, an increasing number of new cases have been reported. In recent years, the widespread application of high-throughput DNA sequencing technology has significantly improved the diagnostic rate of KBG syndrome, and its neurological manifestations have attracted increasing attention. Among these, epilepsy, a key clinical feature, is often the primary reason for patients to seek medical advice in the Department of Neurology.\u003c/p\u003e \u003cp\u003eResearch indicates that approximately one-third to one-half of patients with KBG syndrome may exhibit epileptic seizures, although the types and severity of these seizures show significant heterogeneity. They can manifest in various forms, including focal seizures, tonic‒clonic seizures, myoclonic seizures, and absence seizures. Only a minority of patients receive a definitive diagnosis of a specific epilepsy syndrome, such as Lennox‒Gastaut syndrome (LGS), epilepsy with myoclonic‒atonic seizures (EMAS), childhood absence epilepsy, or West syndrome\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Owing to the lack of specificity in the early clinical manifestations of KBG syndrome, some children are initially diagnosed with \u0026ldquo;epilepsy\u0026rdquo; or \u0026ldquo;developmental delay with epilepsy,\u0026rdquo; which can lead to delays in identifying the underlying cause. Therefore, we retrospectively analyzed the clinical and genetic data of four KBG syndrome patients with prominent epilepsy manifestations treated at our hospital. By reviewing the relevant literature, we explored the phenotypic characteristics of epilepsy associated with KBG syndrome, aiming to improve the clinical recognition and diagnostic accuracy of this condition.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Source of the case series\u003c/h2\u003e \u003cp\u003eFour patients with KBG syndrome presenting with epilepsy as the prominent phenotype were selected from the Department of Neurology, Hebei Children's Hospital, between January 2020 and December 2025. All patients were confirmed to carry pathogenic variants in the \u003cem\u003eANKRD11\u003c/em\u003e gene through genetic testing. Clinical data were collected for these four pediatric patients. Informed consent was obtained from the parents or legal guardians of all the participating children (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This study was approved by the Medical Research Ethics Committee of Hebei Children's Hospital (Approval No. 2025034-51).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical phenotypes of the 4 patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"15\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAges at epilepsy onset\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTypes of epilepsy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eASMs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFollow- up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCharacteristic facial dysmorphism\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHand abnormalities\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eshort stature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eAbnormal birth history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAbnormal family history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eAbnormal\u003c/p\u003e \u003cp\u003eEEG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eAbnormal\u003c/p\u003e \u003cp\u003eCranial MRI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003eDevelopmental delay\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5y2m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeizure-free for 2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCongenital heart defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6y7m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVPA, LCM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeizure-free for 2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHearing loss, cryptorchidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTerm small for gestational age infant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1y3m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003emyoclonic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVPA, CLB, LGT, LEV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeizures persisted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2y10m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMyoclonic, atonic, myoclonic‒atonic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVPA, CLB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeizure-free for a year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"15\"\u003eF: Female; M: Male; LCM: Lacosamide; VPA: Valproate; CLB: Clobazam; LTG: Lamotrigine; LEV: Levetiracetam\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotypes of the 4 patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVariant Locus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExon\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMutation Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZygosity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDisease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eInheritance Pattern\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eVariant Origin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathogenicity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eANKRD11 NM-013275.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.7183C๥T, p.Gln2395*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNonsense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKBG Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eANKRD11 NM-01256182.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.7822C๥T, p.Arg2608Trp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMissense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKBG Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eANKRD11 NM-013275.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1903-1907delAAACA, p.K635Qfs*26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKBG Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eANKRD11 NM-013275.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.6792dup, p.Ala2265Argfs*8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKBG Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Diagnostic criteria\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1 Diagnostic criteria for epilepsy\u003c/h2\u003e \u003cp\u003eThe diagnosis and classification of epilepsy and epileptic syndromes followed the latest diagnostic framework standards published by the International League Against Epilepsy (ILAE) in 2017 and 2022.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.2.2 Diagnostic criteria for KBG syndrome\u003c/h2\u003e \u003cp\u003eKBG syndrome can be diagnosed when two or more major diagnostic criteria are met or when one major criterion and two or more minor criteria are present\u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe primary diagnostic criteria were as follows: macrodontia of permanent upper central incisors, developmental delay or mild/moderate intellectual disability or learning difficulty associated with behavioral issues, characteristic facial appearance, postnatal short stature, and 1st degree relative to KBG syndrome.\u003c/p\u003e \u003cp\u003eThe secondary diagnostic criteria were conductive hearing loss due to recurrent otitis media, palatal abnormalities, hair findings, delayed bone age, large anterior fontanelle with delayed closure, hand findings, costovertebral anomalies, scoliosis, EEG abnormalities with or without seizures, feeding difficulties, and cryptorchidism in males.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Case series\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003eA 5-year-old girl with a 2-week history of recurrent seizures was admitted to our hospital. All seizures, characterized by sudden tachypnea, upward eye deviation, and unresponsiveness, occurred during sleep and lasted approximately one minute before spontaneously resolving. Seizures occurred at a frequency of approximately twice weekly, resulting in four episodes. No significant discomfort was reported postseizure, and no specific intervention was administered.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eShe was the firstborn child of the family and was delivered at term via vaginal delivery, with a birth weight of 2.8 kg. She had no history of birth asphyxia, hypoxia, or resuscitation. Congenital heart disease (atrial septal defect, ventricular septal defect, and persistent left superior vena cava) was diagnosed immediately after birth. She underwent surgical repair of the atrial and ventricular septal defects at 2 months of age, with an uneventful postoperative recovery. Her intellectual development was normal; however, her physical growth was delayed compared with that of her age-matched peers. There was no relevant family history of neurological or genetic disorders.\u003c/p\u003e \u003cp\u003ePhysical examination revealed that the patient\u0026rsquo;s height was 106 cm, and her weight was 16 kg, both of which fell within the \u0026minus;\u0026thinsp;2SD to -1SD range for age- and sex-matched peers. Distinctive facial features: Triangular face, bushy eyebrows and macrodontia.\u003c/p\u003e \u003cp\u003eAuxiliary Investigations: Video EEG showed sporadic left frontal spike‒and‒wave complexes during the interictal period; cranial magnetic resonance imaging (MRI) revealed mild enlargement of the bilateral ventricles and cisterna magna. Transthoracic echocardiography indicated findings consistent with postoperative changes following surgical repair of congenital heart disease (ventricular septal defects and atrial septal defects). An electrocardiogram revealed sinus rhythm with an otherwise normal waveform. Whole-exome sequencing (WES) identified a heterozygous de novo variant in the \u003cem\u003eANKRD11\u003c/em\u003e gene: c.7183C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gln2395*).\u003c/p\u003e \u003cp\u003eDiagnosis: Epilepsy (focal seizures) and KBG syndrome.\u003c/p\u003e \u003cp\u003eTreatment and Follow-up: Oral lacosamide was administered, with the maximum dose set at 50 mg twice daily (equivalent to 6.25 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;d\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). No significant adverse drug reactions were observed after medication initiation. During the 2-year follow-up period, no epileptic seizures occurred, and a repeat vEEG indicated a normal interictal background.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003eA 6-year and 7-month-old boy with a 3-month history of intermittent seizures was admitted to our hospital. The seizures manifested a cluster pattern, with 1 to 2 clusters documented per month. He frequently experienced paroxysmal visual blurring while awake; these episodes were accompanied or not accompanied by headache and vomiting, with consciousness preserved throughout the events, which resolved spontaneously within approximately 1 minute. Bilateral tonic‒clonic seizures were occasionally secondary to these episodes. Visual function returned to baseline following symptom resolution. During exacerbations, the episodes occurred more than ten times daily for several consecutive days before remission, with an overall disease course of 3 months. These symptomatic episodes were occasionally precipitated by febrile events. He was the firstborn child of his mother and was delivered at term via vaginal delivery, with a birth weight of 2 kg. He had no history of birth asphyxia, hypoxia, or resuscitation at birth. His mother remained healthy throughout the entire course of pregnancy. Postnatally, he was diagnosed with hearing impairment; cryptorchidism was identified when he was 1 year old. At the age of 2 years, he underwent cochlear implantation and orchidopexy. Since infancy, he has exhibited slow linear growth and weight gain. Motor development was age-appropriate, whereas language and intellectual development were delayed. There was no relevant family history of neurological or genetic disorders.\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePhysical examination revealed that the height was 110 cm (between \u0026minus;\u0026thinsp;3 SD and \u0026minus;\u0026thinsp;2 SD), and the weight was 14 kg (\u0026lt;-3 SD). He has a triangular face, macrodontia and a small mandible. Bilateral short little fingers, clubbing of fingers and toes.\u003c/p\u003e \u003cp\u003eAuxiliary Investigations: VEEG revealed slow background activity during the interictal period, with right posterior occipital spikes and spike-and-wave discharges observed across all sleep and wakefulness stages. A focal seizure originating in the right occipital and posterior temporal regions was detected (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cranial MRI showed no obvious abnormalities. WES identified a de novo mutation in the \u003cem\u003eANKRD11\u003c/em\u003e gene: c.7822C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg2608Trp*).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDiagnosis: Epilepsy (focal seizures) and KBG syndrome.\u003c/p\u003e \u003cp\u003eTreatment and Follow-up: The patient was switched to oral lacosamide therapy at a maximum dose of 50 mg twice daily (7.14 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;d\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), resulting in seizure control. Follow-up over 2 years showed no seizures, with normal vEEG findings.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 3\u003c/strong\u003e \u003cp\u003eA 1-year-3-month-old boy presented to our hospital with recurrent nodding episodes. He exhibited paroxysmal nodding movements that occurred once per episode, initially ranging from 1 to 2 times daily and then gradually increasing to dozens of times per day. He remained alert during the interictal periods. He was the second child, born at term via vaginal delivery, with a birth weight of 3 kg. There was no history of hypoxia, asphyxia, or resuscitation at birth. Physical development was normal prior to symptom onset. There was no relevant family history of neurological or genetic disorders.\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePhysical examination revealed no characteristic facial dysmorphism; bilateral hypoplastic little fingers were observed. Neurological examination revealed no abnormalities.\u003c/p\u003e \u003cp\u003eAuxiliary Investigations: VEEG revealed slow background activity, with widespread slow waves and spike-and-wave discharges during the interictal period, and generalized myoclonic seizures were detected (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cranial MRI showed widened bilateral frontotemporal extraaxial spaces. The Gesell Developmental Diagnosis Scale assessment revealed the following developmental quotients (DQs): Adaptation 75, Gross Motor 80, Fine Motor 72, Language 70, and Personal-Social 72, which is consistent with mild developmental delay. WES identified a de novo variant in the \u003cem\u003eANKRD11\u003c/em\u003e gene: c.1903_1907delAAACA (p.K635Qfs*26).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDiagnosis: Epilepsy (myoclonic seizures), KBG syndrome.\u003c/p\u003e \u003cp\u003eTreatment and Follow-up: Initial therapy with 4 ml of sodium valproate oral solution was given twice daily (32 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;d\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). Persistent frequent seizures led to the subsequent addition of clobazam, lamotrigine, and levetiracetam. Myoclonic seizures persisted at the 1-year follow-up.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 4\u003c/strong\u003e \u003cp\u003eA 2-year and 10-month-old boy presented to our hospital with intermittent seizure episodes over the past 2 weeks. There were two types of seizures: ① Sudden loss of consciousness during wakefulness, accompanied by blinking and upward eye deviation, lasting more than 10 seconds before resolution. This occurred twice initially. ② Episodic nodding, with or without a single-limb jerk, occurs 1 to 2 times daily initially and gradually increases to more than a dozen episodes per day. The child remained conscious during the interictal period. He was the first child of his parents and was born at term via vaginal delivery, with a birth weight of 3.4 kg. There was no history of hypoxia, asphyxia, or resuscitation at birth. The patient\u0026rsquo;s physical development was normal. His mother had distinctive facial features (triangular face, synophrys), megalodontia, and hearing impairment. The maternal grandmother had hearing impairment and an abnormal walking posture.\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePhysical examination revealed a low anterior hairline, triangular face, protruding ears, high nasal bridge, missing maxillary central incisors, enamel hypoplasia, single transverse palmar crease on the right hand, and clinodactyly of the fifth finger.\u003c/p\u003e \u003cp\u003eAuxiliary Investigations: EEG showed no obvious occipital dominant rhythm in the background activity; during both wakefulness and sleep, numerous paroxysmal and intermittent generalized spike waves, polyspike waves, spike-and-wave complexes/sharp-and-slow wave complexes, polyspike-and-slow wave complexes, and slow spike-and-slow wave complexes were observed. Multiple generalized myoclonic seizures, atonic seizures, and myoclonic‒atonic seizures were detected (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Cranial MRI revealed focal abnormal signals in both frontal lobes, suggestive of focal demyelination. The external temporal subarachnoid spaces on both sides were widened. Gesell Developmental Diagnosis Scale: Adaptation 80, Gross Motor 85, Fine Motor 80, Language 73, Personal-Social 72, consistent with mild developmental delay. WES revealed a maternal-derived \u003cem\u003eANKRD11\u003c/em\u003e gene duplication at c.6792 (p.A2265Rfs*8).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDiagnosis: Epilepsy (myoclonic seizures, atonic seizures, and myoclonic‒atonic seizures) and KBG syndrome.\u003c/p\u003e \u003cp\u003eTreatment and Follow-up: Initially, sodium valproate oral solution was administered, with a maximum dose of 6 ml twice daily (equivalent to 32 mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;d\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), which resulted in reduced seizures. Subsequently, clobazam was added at a dose of 2.5 mg twice daily, leading to a significant reduction in seizures until complete seizure cessation. During the 1-year follow-up, no epileptic seizures occurred. A repeat vEEG showed improved background activity compared with the previous one; interictal generalized spike waves, spike-and-wave complexes, and polyspike-and-slow wave complexes were observed, which were fewer than before.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Literature Review\u003c/h2\u003e \u003cp\u003eTo systematically summarize the epileptic phenotype characteristics of patients with KBG syndrome, the terms \u0026ldquo;\u003cem\u003eANKRD11\u003c/em\u003e, epilepsy\u0026rdquo; or \u0026ldquo;KBG syndrome, epilepsy\u0026rdquo; were used as search terms in the PubMed database (2000 to December 2025). A total of 150 patients with KBG syndrome and documented epileptic phenotypes reported in the literature were included, and a pooled analysis was conducted on the clinical characteristics of 91 patients whose data were relatively complete.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Case series\u003c/h2\u003e \u003cp\u003eThis study included 4 patients with KBG syndrome presenting with epileptic seizures, comprising 3 males and 1 female. The median age at epilepsy onset was 4 years. The predominant seizure types were focal and myoclonic, and one patient had multiple seizure types. According to the 2022 ILAE Classification of Epilepsy Syndromes, two patients were highly consistent with the diagnostic criteria of specific epilepsy syndromes, with one classified as EMAS and the other conforming to COVE. With respect to other clinical phenotypes, three patients exhibited mild developmental delay, primarily characterized by language development delay. Additional systemic abnormalities included characteristic facial appearance (3 cases), macrodontia (2 cases) and enamel hypoplasia (1 case), hand abnormalities (3 cases), short stature (2 cases), congenital heart malformation (1 case), and hearing impairment with cryptorchidism (1 case).\u003c/p\u003e \u003cp\u003eEEG revealed abnormalities in all 4 patients (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Interictal EEGs predominantly showed epileptiform discharges (4 cases), including focal discharges in 2 cases and generalized discharges in 2 cases. Additionally, 3 cases exhibited abnormal background activity. During seizures, multiple characteristic EEG patterns, corresponding to clinical seizure types (focal seizures, myoclonic seizures, atonic seizures, and myoclonic-atonic seizures), were recorded. Cranial MRI showed nonspecific abnormalities in 3 patients, manifested as focal demyelination, widened periventricular spaces, ventricular enlargement, and an enlarged foramen magnum. Genetic testing revealed that all patients harbored \u003cem\u003eANKRD11\u003c/em\u003e gene variants, including one missense mutation, one nonsense mutation, and two frameshift mutations. Three mutations were de novo, whereas one was maternally inherited. The mother exhibited a distinctive facial appearance and hearing impairment but lacked an epileptic phenotype. All the variants were classified as \u0026ldquo;pathogenic\u0026rdquo; on the basis of the ACMG criteria.\u003c/p\u003e \u003cp\u003eASMs were administered to the 4 patients as follows: All patients received ASMs treatment. Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e achieved seizure freedom with lacosamide monotherapy. Case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e had an inadequate initial response to valproate but achieved effective seizure control after switching to lacosamide. For Cases \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, both with generalized seizures, valproate sodium was used as first-line treatment. Case \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e achieved partial control with valproate and achieved full seizure control after clobazam was added. Despite treatment with multiple ASMs, Case \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e3\u003c/span\u003e continued to experience recurrent seizures and thus fulfilled the diagnostic criteria for drug-resistant epilepsy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Literature Review\u003c/h2\u003e \u003cp\u003eAmong the 150 patients with epilepsy associated with KBG syndrome included in the previous literature, 68 were male and 40 were female, yielding a male-to-female ratio of 1.7:1. The age at epilepsy onset ranged from birth to 51 years, with a median age of 3 years and 10 months.\u003c/p\u003e \u003cp\u003eAmong the 91 patients with documented seizure characteristics, marked heterogeneity was noted in terms of seizure phenotypes. Bilateral tonic‒clonic seizures were the most prevalent subtype (n\u0026thinsp;=\u0026thinsp;39), with unclear seizure onset in some cases, followed by focal seizures (n\u0026thinsp;=\u0026thinsp;32). Typical or atypical absence seizures (n\u0026thinsp;=\u0026thinsp;17) and myoclonic seizures (n\u0026thinsp;=\u0026thinsp;14) were also relatively common. The less frequently observed seizure types included atonic seizures (n\u0026thinsp;=\u0026thinsp;6), epileptic spasms (n\u0026thinsp;=\u0026thinsp;6), and myoclonic-atonic seizures (n\u0026thinsp;=\u0026thinsp;4). The prevalence of status epilepticus was comparatively low (n\u0026thinsp;=\u0026thinsp;6), with one case manifesting as absence status. With respect to the distribution of seizure subtypes, the majority of patients presented with a single seizure type, whereas 36.3% (33/91) of individuals presented with two or more distinct seizure types.\u003c/p\u003e \u003cp\u003eWithin this cohort, 17 patients exhibited clinical manifestations highly consistent with the diagnostic criteria for epilepsy syndromes, with the following subtype distributions: EMAS, 4 cases; LGS, 4 cases; childhood absence epilepsy, infantile spasms, infantile myoclonic epilepsy, and Jeavons syndrome, 2 cases each; and generalized epilepsy with febrile seizures plus (GEFS+), 1 case. Additionally, two sisters presented with clinical features compatible with the GEFS+. However, genetic testing revealed that both harbored mutations in the \u003cem\u003eSCN9A\u003c/em\u003e gene in addition to the \u003cem\u003eANKRD11\u003c/em\u003e mutation. This finding suggests that their phenotypic presentation may be linked to this \u003cem\u003eSCN9A\u003c/em\u003e gene variant\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Of the four newly enrolled cases in this study, two fulfilled the diagnostic criteria for epilepsy syndrome. Prior studies have established that EMAS is the epilepsy subtype most strongly associated with KBG syndrome. The clinical phenotype of Case \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e in the present cohort was highly concordant with this conclusion, thereby further validating this core clinical feature. Notably, this study constitutes the first report of an association between COVE and KBG syndrome. This novel finding expands the phenotypic spectrum of epilepsy syndromes linked to KBG syndrome and provides additional evidence supporting the extensive clinical phenotypic heterogeneity of this disorder.\u003c/p\u003e \u003cp\u003eIn the clinical management of epilepsy associated with KBG syndrome, ASMs yield an overall favorable therapeutic response. Seizure activity in the majority of patients can be effectively or partially controlled via the judicious selection of ASMs. Among the 72 patients with documented treatment efficacy data, the prevalence of refractory epilepsy was approximately 27.8% (n\u0026thinsp;=\u0026thinsp;20). Monotherapy achieved clinical efficacy in 37.5% (27/72) of cases. Valproate remains the first-line agent of choice for clinicians, with a monotherapy response rate of 32.3% (10/31). Lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and topiramate are also widely prescribed as first- or second-line treatment modalities. For refractory cases, adjunctive clobazam may confer clinical benefit in select patients. Accumulating evidence from the literature indicates that cannabidiol has a modest therapeutic effect on this epilepsy subtype\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Nonpharmacological interventions, including the ketogenic diet and vagus nerve stimulation (VNS), have also been validated to possess clinical utility in this patient population\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eSince the first proposal of the concept of KBG syndrome, new relevant cases have been reported, but unified diagnostic criteria for this disorder have not yet been established. To address this issue, scholars have proposed targeted clinical diagnostic protocols in which patients' clinical manifestations are systematically summarized. In 2007, Skjei et al.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e conducted a detailed analysis of the clinical features of more than 50 patients with KBG syndrome, defining diagnostic criteria that include neurological involvement. Specifically, this neurological involvement manifests as epilepsy, generalized developmental delay, intellectual disability, and other conditions. In 2016, on the basis of reporting 31 new cases and systematically sorting out relevant literature, Low et al.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e proposed a more refined diagnostic system, classifying the criteria into major diagnostic criteria and minor diagnostic criteria and categorizing epilepsy into the scope of minor diagnostic criteria. In 2017, Morel Swols et al.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e further improved this diagnostic system, incorporating both epileptiform and nonepileptiform EEG abnormalities into the minor diagnostic criteria. Thus, there is a consensus that epilepsy is a common symptom when KBG syndrome patients have neurological involvement.\u003c/p\u003e \u003cp\u003eA systematic review of the literature revealed a wide range of ages at epilepsy onset, with median ages of 3 years and 10 months. This finding is consistent with the median age of 4 years observed in the four patients in this study, supporting the clinical characteristic that epilepsy in KBG syndrome predominantly manifests during childhood. Regarding seizure types, bilateral tonic\u0026ndash;clonic and focal seizures were the most common, followed by typical/atypical absence and myoclonic seizures. In this case series, focal and myoclonic seizures predominated, with additional manifestations of atonic and myoclonic-atonic seizures. Descriptions of associated epilepsy syndromes are scarce, among which EMAS and LGS are the most common epilepsy syndromes associated with KBG syndrome\u003csup\u003e[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Case \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e in this study exhibited a phenotype highly consistent with EMAS, while Case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presented a COVE-related phenotype that is novel and has not been previously reported in KBG syndrome. These findings on epileptic phenotypes further confirm the remarkable diversity of seizure types in KBG syndrome patients with epilepsy, which may be consistent with the genetic heterogeneity and extensive neurological involvement of this disease. This study is the first to establish the association between COVE and KBG syndrome, enriching the phenotypic spectrum of epileptic syndromes in this disorder and providing new evidence supporting the diversity of its clinical phenotypes.\u003c/p\u003e \u003cp\u003eWith respect to treatment, three of the four included patients responded well to ASMs, which is consistent with the findings of previous studies. One patient remained refractory to standardized treatment with multiple ASMs, meeting the criteria for drug-resistant epilepsy; this incidence was consistent with the reported 27.8% prevalence of KBG syndrome. A review of prior cases indicated that valproate is the first-line treatment for KBG syndrome-associated epilepsy. In this study, the patient achieved only partial efficacy with sodium valproate monotherapy. However, effective seizure control was attained after the addition of clobazam. Currently, reports in the literature on the use of lacosamide in such patients are relatively scarce. Previous studies have shown that one patient with focal seizures achieved symptom remission with this drug\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, whereas two other patients with drug-resistant epilepsy had suboptimal treatment efficacy\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In contrast, both patients with focal seizures in this study achieved definitive efficacy with lacosamide monotherapy. These findings not only enrich the clinical evidence for lacosamide in the treatment of KBG syndrome-associated focal epilepsy and provide a new practical basis for clinical diagnosis and treatment but also suggest that lacosamide monotherapy may serve as a potentially effective treatment strategy for this subset of patients.\u003c/p\u003e \u003cp\u003ePrevious cohort studies have characterized the neuroimaging features of KBG syndrome. Loberti L et al.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e conducted a study of 32 patients with KBG syndrome and identified enlarged cisterna magna, which was the most prevalent structural abnormality, in 6 patients (18.7%). Peluso F et al.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e analyzed imaging data from 53 patients with KBG syndrome, 41 of whom underwent cranial MRI, and only 3 cases yielded unremarkable findings. In this study, the prevalence of enlarged cisterna magna was as high as 63.6%, which was also among the most common structural anomalies. Additionally, incomplete hippocampal inversion was detected in up to 63.4% of cases; however, this finding is generally regarded as an anatomical variant that can also be observed in healthy individuals. Other reported neuroimaging abnormalities include ventricular structural anomalies, white matter signal alterations, corpus callosum morphological irregularities, optic nerve abnormalities, and olfactory bulb hypoplasia. All four patients enrolled in the present study underwent cranial MRI, and most presented with nonspecific radiological findings. An Enlarged cisterna magna was noted in Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, whereas widened frontotemporal extraaxial spaces and focal myelination delay were observed in the two younger patients. These results are consistent with the findings reported in the literature.\u003c/p\u003e \u003cp\u003eGenetic studies have conclusively established that KBG syndrome is closely associated with pathogenic mutations in the \u003cem\u003eANKRD11\u003c/em\u003e gene (also known as ankyrin repeat-containing cofactor 1, \u003cem\u003eANCO-1\u003c/em\u003e). To date, no cases of \u003cem\u003eANKRD11\u003c/em\u003e homozygous deficiency have been documented, and both in vitro experiments and animal model studies have corroborated the lethality of homozygous deficiency. In studies in which \u003cem\u003eAnkrd11\u003c/em\u003e-deficient Neuro-2a cells were used, all attempts to establish homozygous deficient cell lines were unsuccessful. In murine models, embryos with homozygous \u003cem\u003eAnkrd11\u003c/em\u003e deletion exhibited early embryonic lethality\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile the precise mechanisms by which \u003cem\u003eANKRD11\u003c/em\u003e dysfunction elicits neurological abnormalities remain incompletely understood, numerous studies have addressed this knowledge gap. With respect to gene and protein characteristics, the \u003cem\u003eANKRD11\u003c/em\u003e gene maps to chromosomal locus 16q24.3 and encodes ankyrin repeat domain-containing protein 11. This protein is a 298 kDa macromolecule comprising 2663 amino acids, with four distinct functional domains, an N-terminal ankyrin repeat domain, two transcriptional repressor domains, and one transcriptional activator domain. Current research suggests that \u003cem\u003eANKRD11\u003c/em\u003e may function as a chromatin modifier that plays dual roles in transcriptional activation and repression. At the molecular level, members of the p160 nuclear receptor coactivator family interact with liganded nuclear receptors to potentiate target gene transcription. \u003cem\u003eANCO-1\u003c/em\u003e (i.e., \u003cem\u003eANKRD11\u003c/em\u003e) is proposed to recruit histone deacetylase 3 (HDAC3) to the p160 coactivator/nuclear receptor complex, thereby abrogating ligand-dependent transactivation\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. It can also form a complex with p53 and histone acetyltransferase (HAT), facilitating HAT-mediated acetylation of both p53 and histone H3 at the promoter loci of target genes (e.g., Trkb), which in turn augments the transcriptional activity of these genes. Histone acetylation serves as a core epigenetic regulatory switch that governs neural precursor proliferation, neuronal differentiation, and dendrite development during cerebral morphogenesis. HDACs (e.g., HDAC3) and HATs modulate histone acetylation levels to orchestrate the transcription of genes essential for nervous system development, laying a critical theoretical foundation for \u003cem\u003eANKRD11\u003c/em\u003e-mediated regulation of neurodevelopment\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Neuroanatomical studies have demonstrated that \u003cem\u003eANKRD11\u003c/em\u003e is widely expressed throughout the brain, with predominant localization to the nuclei of neurons and glial cells. \u003cem\u003eAnkrd11\u003c/em\u003e-knockout mouse models present a spectrum of neurodevelopmental abnormalities, including reduced proliferation of neural progenitor cells, impaired formation of leading processes in migrating neurons, decreased dendritic numbers, sparse branching, and abnormal dendritic spine morphology. Collectively, these abnormalities culminate in delayed radial migration of cortical neurons\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. In summary, the \u003cem\u003eANKRD11\u003c/em\u003e gene plays an indispensable role in neurodevelopment. Pathogenic mutations in this gene are likely to impair neuronal plasticity and disrupt the excitatory\u0026ndash;inhibitory balance in neural circuits, and this represents the core mechanism underlying epileptiform discharges in KBG syndrome.\u003c/p\u003e \u003cp\u003eVariants in the \u003cem\u003eANKRD11\u003c/em\u003e gene exhibit high heterogeneity. Frameshift mutations and nonsense mutations are the most frequently detected subtypes in clinical practice, whereas missense mutations and splice-site mutations are relatively rare. Furthermore, de novo mutations represent the predominant form of variation in this gene. All four patients enrolled in the present study harbored \u003cem\u003eANKRD11\u003c/em\u003e mutations, three of which were de novo. The variant types included two frameshift mutations, one nonsense mutation, and one missense mutation. Previous studies have indicated that the most common mutation sites of the \u003cem\u003eANKRD11\u003c/em\u003e gene are concentrated in exon 9, which is the largest exon of the gene. Consistent with these reports, three out of the four patients in this study had mutations localized to exon 9. Notably, the c.1903_1907delAAACA mutation detected in Case \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and the c.6792dup mutation identified in Case \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e have been previously reported multiple times\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Both variants are frameshift mutations that cause a shift in the gene's open reading frame, ultimately leading to the production of truncated proteins and impairment of normal protein structure and function. Collectively, the mutation characteristics observed in this study are generally consistent with those reported in the literature.\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eIn summary, epilepsy in KBG syndrome patients exhibits marked clinical heterogeneity, characterized by a broad spectrum of seizure semiologies encompassing generalized tonic\u0026ndash;clonic, focal, myoclonic, and mixed-type seizures, with onset predominantly concentrated in early childhood. \u003cem\u003eANKRD11\u003c/em\u003e gene mutations are hypothesized to disrupt neurodevelopmental trajectories, thereby acting as the core pathogenic driver of epileptogenesis in patients with KBG syndrome. Therefore, for pediatric patients who present with epilepsy as the initial symptom, especially those with concurrent multisystem involvement, a high index of suspicion for KBG syndrome is warranted, and priority should be given to \u003cem\u003eANKRD11\u003c/em\u003e genetic testing. Defining the etiological basis not only provides a precise framework for formulating individualized therapeutic regimens but also enables evidence-based prognostic stratification, ultimately optimizing long-term clinical management outcomes for affected individuals.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpilepsy with myoclonic-atonic seizures\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOVE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChildhood occipital visual epilepsy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEEG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectroencephalogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASMs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntiseizure medications\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eANKRD11\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnkyrin repeat domain-containing protein 11\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAttention deficit hyperactivity disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eILAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational League Against Epilepsy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLennox\u0026ndash;Gastaut syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhole-exome sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGEFS+\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGeneralized epilepsy with febrile seizures plus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVagus nerve stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003e \u003cb\u003eAuthor information\u003c/b\u003e \u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e \u003cp\u003eFirst Department of Neurology, Hebei Children\u0026rsquo;s Hospital, Shijiazhuang, China\u003c/p\u003e \u003cp\u003eXuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li \u0026amp; Suzhen Sun\u003c/p\u003e \u003cp\u003eHebei Provincial Clinical Research Center for Child Health and Disease, Shijiazhuang, China\u003c/p\u003e \u003cp\u003eXuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li \u0026amp; Suzhen Sun\u003c/p\u003e \u003cp\u003eHebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders, Shijiazhuang, China\u003c/p\u003e \u003cp\u003eXuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li \u0026amp; Suzhen Sun\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eContributions\u003c/strong\u003e \u003cp\u003eConception and design of the work: XFL, JJL; Data collection: LYP, PHY, FF; Supervision: XL, SZS; Analysis and interpretation of the data: JZ, FC; Drafting the manuscript: XFL, JJL; Critical revision of the manuscript: all authors; Approval of the final manuscript: all authors.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCorresponding authors\u003c/strong\u003e \u003cp\u003eCorrespondence to Xin Li or Suzhen Sun.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003e \u003cb\u003eEthics declarations\u003c/b\u003e \u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was performed in accordance with the principles of the Declaration of Helsinki. The study was approved by the Hebei Children's Hospital Ethics Committee. The Hebei Children's Hospital's Institutional Review Board also approved the study after consulting with its ethics committee (approval number: 2025034-51). Written informed consent was obtained from the parents or legal guardians of all participants under 16 years of age for their participation in this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eWritten informed consent for publication of the clinical details and/or clinical images was obtained from the parents or legal guardians of all cases under 18 years of age included in this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the Medical Science Research Project of Hebei (20260885), China.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConception and design of the work: XFL, JJL; Data collection: LYP, PHY, FF; Supervision: XL, SZS; Analysis and interpretation of the data: JZ, FC; Drafting the manuscript: XFL, JJL; Critical revision of the manuscript: all authors; Approval of the final manuscript: all authors.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eI would like to express my deepest gratitude to the patient and his parents, who provided the data and significantly contributed to the development of human health.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMartinez-Cayuelas E, Blanco-Kelly F, Lopez-Grondona F, Swafiri ST, Lopez-Rodriguez R, et al. 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KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation. iScience. 2025;28(6):112699. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.isci.2025.112699\u003c/span\u003e\u003cspan address=\"10.1016/j.isci.2025.112699\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"KBG syndrome, ANKRD11 gene, Epilepsy, Treatment, Children","lastPublishedDoi":"10.21203/rs.3.rs-8780749/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8780749/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo investigate the clinical features, electroencephalography (EEG) findings, genetic basis, and therapeutic response of epilepsy in KBG syndrome patients and to explore its phenotypic spectrum.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis was performed on four children with KBG syndrome presenting with epilepsy who were admitted to Hebei Children's Hospital between January 2023 and December 2025. Clinical data were collected, and a systematic database search identified 108 reported KBG syndrome patients with epileptic phenotypes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong our 4 cases (3 males, 1 female), the median epilepsy onset age was 4 years. Focal and myoclonic seizures were predominant, and 1 patient presented with multiple seizure types. In accordance with the 2022 ILAE criteria, 1 patient presented with epilepsy with myoclonic-atonic seizures (EMAS), whereas another patient presented with a phenotype analogous to childhood occipital visual epilepsy (COVE). All patients exhibited abnormal electroencephalogram (EEG) findings, predominantly epileptiform discharges, whereas 2 patients presented nonspecific changes on cranial imaging. Pathogenic \u003cem\u003eANKRD11\u003c/em\u003e mutations were detected in all the children, encompassing 2 transpositions, 1 nonsense, and 1 missense, with 3 de novo and 1 maternally inherited mutations. Two patients with focal epilepsy achieved seizure control with lacosamide, and 1 was diagnosed with refractory epilepsy. For the 108 literature cases, the male-to-female ratio was 1.7:1, and the median age at epilepsy onset was 3 years and 10 months. Bilateral tonic‒clonic seizures (n\u0026thinsp;=\u0026thinsp;47) and focal seizures (n\u0026thinsp;=\u0026thinsp;31) were most common, and 36.3% had multiple types. Seventeen patients met the criteria for epileptic syndrome, predominantly EMAS, which was the most common type. This is the first report of the association between COVE and KBG syndrome. The overall response to antiseizure medications (ASMs) was favorable, with the incidence of refractory epilepsy being 27.8%.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEpilepsy in KBG syndrome has significant phenotypic heterogeneity and a high incidence in childhood. EMAS is the most commonly associated epileptic syndrome, and COVE is a novel phenotypic association. This disease has a high rate of EEG abnormalities, while brain structural lesions are nonspecific. Lacosamide may be an effective drug for treating focal seizures. Given the limited sample sizes, the exact efficacy requires further verification in large-sample studies.\u003c/p\u003e","manuscriptTitle":"Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-18 17:04:55","doi":"10.21203/rs.3.rs-8780749/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-01T19:52:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-25T20:21:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226471970044746932864430039399507207759","date":"2026-02-15T08:51:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49790297746947931750712914972543949654","date":"2026-02-13T08:10:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-13T00:56:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-13T00:54:02+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-11T05:04:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-10T02:29:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-02-10T02:22:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"676c40d7-24a4-4af5-a9c8-47a049ca7381","owner":[],"postedDate":"February 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-18T17:04:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-18 17:04:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8780749","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8780749","identity":"rs-8780749","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}