Electroclinical features and outcome of ANKRD11-related KBG syndrome: A novel report and literature review

Abstract

KBG syndrome (OMIM #148050) is a rare autosomal dominant disorder, typically characterized by macrodontia of the upper central incisors, distinct craniofacial findings, short stature, and skeletal anomalies associated with neurological involvement including intellectual disability, behaviour difficulties, and epilepsy. KBG syndrome is associated with mutations in ANKRD11 gene that plays a chromatin regulator role of histone acetylation and gene expression during neurogenesis in the embryonic brain. [[1]Sirmaci A. Spiliopoulos M. Brancati F. et al.Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.Am J Hum Genet. 2011; 89: 289-294Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar] A systemic review of epilepsy and EEG anomalies in subjects with KBG syndrome is missing. Samanta first described in a patient an intermittent bisynchronous temporo-occipital rhythmic delta activity and episodes of staring spells with no EEG changes suggesting that these findings may be specific to KBG syndrome [[2]Samanta D. Willis E. Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene.Acta Neurol Belg. 2015; 115: 779-782Crossref PubMed Scopus (5) Google Scholar]. Here, we report a patient with a severe neurological phenotype of KBG syndrome associated with a novel heterozygous frame-shift de novo variant in the ANKRD11 (NM_013275.6) gene, to contribute to identify a specific electroclinical pattern of KBG syndrome. The proband is an Italian girl who at 13.8 years was referred to our Department for menstrual migraine and seizures. She was born to healthy unrelated parents at term by caesarean section, following a complicated pregnancy. Her postnatal clinical course was uneventful. Her birth weight was 2090 g, length 44 cm, and head circumference cc 31 cm. Her developmental milestones have been delayed. She spoke the first word at 15 months and walked unsupported at 18 months; currently, she is on speech and psychomotor therapy. Since 5 years of age she had vomiting and dizziness while travelling in the vehicle; also, the brushing or washing the hair-triggered an exaggerated pain reaction evoking allodynia condition. At the age of 13.5 years, the girl experienced a nocturnal seizure, characterized by focal right faciobrachial tonic-clonic movements associated with laryngeal symptoms lasting 2 min followed by nausea and headache. Wakefulness interictal EEG showed bilateral posterior 11−12 Hz alpha activity, reactive to eye opening, associated with occasional paroxysmal rhythmic 5−6 Hz activity in the right temporo-occipital region, lasting 20 s, and centrotemporal biphasic sharp wave discharges. Intermittent photic stimulation, hyperventilation, and sleep did not activate the background EEG and paroxysmal pattern. The attacks recurred every 3–4 months and some evolved into generalized tonic-clonic seizures that were mainly self-limited, while others needed of Diazepam treatment. Then, she was on Topiramate (4 mg/Kg/day) treatment which resulted in partial seizure control and reduction of pain intensity of menstrual migraine attacks. Unusually, the seizures were preceded by a dream activity followed by staring spells. In the following EEGs, we were so far unable to find the abnormal patterns above mentioned. The girl suffered from a headache that began with the menarche and the attacks occurred 2–3 days before and after menstruation associated with premonitory symptoms such as nausea, photophobia, phonophobia and allodynia. At last evaluation (17 yrs old), in addition, she displayed obesity associated with type 2 diabetes mellitus requiring metformin therapy. Finally, intellectual functioning and attention abilities were moderately impaired. At MRI, we did not detect any structural abnormalities of the central nervous system. A whole-exome sequencing (WES) showed a novel heterozygous de novo frame-shift variant of ANKRD11gene (NM_013275.6): (c.211_226 + 1del) likely resulting in a premature stop codon and subsequent nonsense mediated decay (NMD) degradation. The variant is absent in GnomAD (ver2.1.1) and ClinVar databases. The KBG syndrome was first identified in the 1975 based on only clinical features as above reported. The increasing use of next-generation sequencing (NGS) and WES technologies led to above 200 cases of KBG syndrome reported in the literature expanding the earlier phenotype. Recently, a neuropsychological study on a cohort of 18 KBG patients, showed a selective cognitive impairment on visuoconstruction, attention, inhibition, cognitive flexibility, and a behavior profile including impulsivity, hyperactivity, oppositional defiant behavior, and conduct problems. [[3]Van Dongen L.C.M. Wingbermühle E. van der Veld W.M. Vermeulen K. Bos-Roubos A.G. Ockeloen C.W. et al.Exploring the behavioral and cognitive phenotype of KBG syndrome.Genes Brain Behav. 2019; 18: e12553Crossref PubMed Scopus (7) Google Scholar] Our patient showed moderate intellectual disability and behavioral disorders that meet the criteria of ADHD syndrome with hyperactivity/impulsivity subtype in the school-age and inattentive subtype in adolescence. In addition, her phenotype included unusual symptoms as a menstrual migraine subtype associated with so-called "periodic childhood syndromes"/ kinetosis, and with a rarely reported condition of early-onset allodynia [[4]Marchese F. Rocchitelli L. Messina L.M. et al.Migraine in children under 6 years of age: a long-term follow-up study.Eur J Paediatr Neurol. 2020; https://doi.org/10.1016/j.ejpn.2020.04.005Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Although epilepsy and EEG anomalies were frequently reported in many series of KBG patients, so far, literature data are limited and incomplete (Table 1) and do not allow to identify a distinct epileptic profile nor the clinical outcome (see references in Supplementary data). We show the electroclinical pattern of epilepsy associated with KBG and outline the clinical features of the epileptic seizures and the EEG feature of this patient.Table 1Comparative data on epilepsy and EEG of patients with ANKRD11 mutation.Our patientAlves et al.(2019)Low et al.(2016)Goldenberg et al. (2016)Samanta et al. (2015)Kim et al. (2015)Lo-Castro et al.(2013)Skjei et al.(2007)Brancati et al. (2004)SeizureAt 13.5yrs right focal and generalized tonic-clonic seizures.From 9mths to 4.8yrs frequent myoclonus-atonic seizures with and without fever.pts 14/32 epilepsy with variable onset and heterogeneous seizure type: absences, grand mal, myoclonic jerks, nocturnal seizures, staring episodes, infantile seizures, febrile fits.pts 10/38 epilepsy: -7 ptsgeneralized / partial seizures in childhood; -pt 16severe complex generalized seizures with onset at 9 mths; -pt 21severe generalized epilepsy; -pt 25myoclonic epilepsy.At 1−3yrs episodes of unresponsiveness along with picking of his clothes for 1–2 min. Frequent focal seizures but intermittent seizure-free state up to 9mths. Occasional secondarily generalized tonic–clonic seizures.All 3 pts without seizures.pt 2 generalized tonic– clonic seizures from 4 to14 yrs.-pt 1.At 8 yrs partial complex seizures and long lasting absences treated with AED -pt2 At 8 yrs partial complex seizures and long lasting absences treated with AED; at 9 ½ yrs 2 Grand Mal seizures.pts10: -pt2 transient pubertal seizures; -pt10 grand mal seizures.EEG findingsAt 13.5yrs centrotemporal biphasic sharp wave discharges and occasional paroxysmal rhythmic 5−6 Hz activity in the right temporo-occipital region.At 1 yr focal centro-temporal spikes. At 4yrs theta rhythm (4−5 Hz) in temporo-occipital regions. At 6 yrs persistence of bursts of generalized polyspike-wave and spike-wave discharge.NA2pts non-specific and isolated EEG anomalies.At 5−7 yrs epileptiform discharges in right centroparietal area, and intermittent bisynchronous temporooccipital 3 cps rhythmic delta activity. At 7yrs disappearance of epileptiform discharges in right centroparietal area.-pt 1At 11mths occasional non-specific slowing in both occipital lobes. -pt 2 At 23mths occasional non-specific slowing in both occipital lobes. -pt 3 At 37yrs non-specific fast activity in both frontal lobes.-pt 1 poorly organized background activity; -pt 2 slow epileptiform abnormalities in left temporo parietal regions, with a tendency to became diffuse during waking and sleeping.pt 1 At 9yrs sharp waves of uncertain significance. At 10 yrs asymmetric rhythmic build-up of alpha over the midline,>left side, prior 2 partial complex seizures.6/10 pts non-specific EEG anomalies.Response to AEDsTPM with partial seizure control.VPA responsive.NA−7pts responsive to AEDs -pt 16 politerapy; -pt 21refractory to AEDs.OXC + TPM responsive_pt 2 VPA responsive-pt 1partial seizure control: -pt 2 partial seizure control.NAEpilepsy outcomepartial seizure control.seizure free <4.8yrs.NANAintermittent staring spells._pt 2 seizure free <14 yrs.pts 1,2 unfavorable.NAOther neurological findingsheadachesproband and her sister carriers of SCN9A mutation.pt1headachesDOI10.1186/s12881−019-0745−710.1002/ajmg.a.3784210.1002/ajmg.a.3787810.1007/s13760−014-0413−910.1016/j.ejmg.2014.11.00310.1002/ajmg.b.3211310.1002/ajmg.a.3159710.1002/ajmg.a.30292 Open table in a new tab The girl suffered from focal to bilateral tonic- clonic seizures, mainly on awaking and self-limited, with onset at 13.5 years of age, always followed by catamenial migraine treated with Topiramate that was effective for both headache and seizure control. The comparison of our findings with the available data in literature shows that epilepsy has a low penetrance and an onset between 9 months and 13.5 years as well as the focal to bilateral tonic- clonic attacks could be the prevalent seizure type (Table 1). The comparison of our findings with a few EEG recordings, previously reported, suggests that the slowing pattern in the posterior regions was constant, it may be lateral or bilateral and the frequency band ranges from 3−6 Hz, being lower in infancy and higher in adolescent patients (Fig. 1 and Table 1). As such EEG feature was no longer noticed after 14 years, it is likely that it may be an age-dependent pattern. Thus, our video-EEG documents the lack of clinical paroxysmal events simultaneous with slowing bioelectric activity. However, we hypothesize that the slowing bioelectric activity, although without a clinical correlation, may more likely represent an EEG pattern which, together with the facial anomalies and intellectual disability, may help to characterize the phenotype of KBG syndrome. Of course, we are aware that our results cannot conclusive as they come from the study of small size sample, so we hope that future studies, focusing more on these issues, can confirm or refine this electroclinical pattern in larger series of patients with KBG syndrome. All authors have seen and approved the final version of the manuscript being submitted. They warrant that the article is the authors' original work, hasn't received prior publication and isn't under consideration for publication elsewhere.