\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[polish,english]{babel}



\usepackage{float}








\begin{document}

\title{ELECTRO-CLINICAL PATTERN OF EPILEPSY IN A CHILD WITH ANKRD11 MUTATION
ASSOCIATED WITH KBG SYNDROME: CASE REPORT OF DRUG-RESISTENT EPILEPSY}



\author[1]{Learta Alili Ademi}%
\author[1]{Blerim Ademi}%
\affil[1]{University Clinic for Children's Diseases}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{INTRODUCTION}

Epilepsy is a common neurological disorder affecting more than 70
million people around the world. It is the most common neurological
disorder in the pediatric population, affecting 1\% to 3\% of children,
and is defined as any disorder in which spontaneous recurrence of
unprovoked seizures is the main symptom. A seizure is usually defined as
a sudden alteration of behavior due to a temporary change in the
electrical functioning of the brain, that continuously generates tiny
electrical impulses in an orderly pattern. The etiology of epilepsy can
be different, including structural, genetic, infectious, metabolic, and
immune causes, but most often the cause is unknown, that is when it
refers to the so-called idiopathic epilepsy, which occurs in 40\% of
people with epilepsy. Despite the recent introduction of new
antiepileptic drugs (AEDs), about one-third of epilepsy patients have
drug-resistant (refractory) epilepsy, affecting about 30\% of children
with epilepsy.

Refractory epilepsy, which is the most severe form of epilepsy,
according to the International league against epilepsy (ILAE), is
defined as failure to control seizures when using two or more
appropriately chosen and tolerated antiepileptic drugs (as monotherapy
or in combination) during an appropriate period. Severe and refractory
epilepsies in children affect their cognitive function, leading to
worsening of the prognosis, serious psychosocial consequences,
difficulties in care and quality of life, anxiety in the family, as well
as an increase in the risk of death, including unexpected death in
epilepsy (SUDEP).

The expansion of genetic research and technologies in recent years and
the advances in next-generation sequencing (NGS) have shown that a large
proportion of unexplained epilepsies, especially idiopathic ones, have a
genetic basis. Numerous epilepsy genes helped the understanding of
mechanisms underlying epileptogenesis and guided the development of
treatments.

\emph{ANKRD11} gene functions as a co-regulator in the developing brain.
The role of the \emph{ANKRD11} gene in neurodevelopment was suggested by
subsequent reports of individuals with intellectual disability, facial
dysmorphism, and ASD. In 1975, \emph{Herrman et al.,} first described
the KBG syndrome, a neurodevelopmental autosomal dominant disorder,
caused by the haploinsufficiency of the \emph{ANKRD11} at 16q24.3 locus
due to heterozygous pathogenic variants or chromosomal
imbalances/rearrangement such as point mutations, duplications or
microdeletions involving this gene.

KBGS is characterized by global developmental delay (DD), intellectual
disability (ID), learning difficulties, neurobehavioral problems, short
stature, macrodontia, facial dysmorphism, skeletal anomalies, and
multiple congenital anomalies, sometimes associated with seizures,
delayed closing of fontanels and electroencephalographic (EEG)
abnormalities. So far, there have been reported more than 200 cases of
KBG syndrome.

The diagnosis of KBG syndrome is established, by the most commonly used
criteria of \emph{Skjei et al.} and \emph{Low et al} . A diagnosis of
epilepsy, a major criterion, according to \emph{Skjei et al} ., and a
minor criterion according to \emph{Low et al} . has been reported in
approximately 30\% of patients in a systematic review of 140 patients
with KBG syndrome. The onset of epilepsy is predominantly between
infancy and mid-teens and seizure remission occurred in the majority
after adolescence with good response to AEDs. Heterogeneous seizure
types have been reported, with tonic--clonic seizures, absences,
myoclonic seizures, and unclassified sleep-related seizures with motor
symptoms being most common, but no specific epilepsy syndrome has been
identified.

Detailed classification of the seizures, epilepsy type, or syndrome was
only made in 26 patients from 12 studies. Only two patients had an
epilepsy syndrome classification. No genotype--phenotype correlation
studies have been performed for the presence and type of epilepsy in
patients with KBG syndrome. Generalized epilepsy with febrile seizures
plus (GEFS+) is reported in a de novo mutation of the
\emph{ANKRD11}gene, with a clinical phenotype compatible with KBG
syndrome.

A systemic review of epilepsy and EEG anomalies in subjects with KBG
syndrome is deficient. \emph{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. 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 \emph{ANKRD11} gene, to
contribute to identifying a specific electroclinical pattern of KBG
syndrome.

\textbf{CASE REPORT}

We report on a 16-year-old boy, referred to our department for afebrile
unprovoked seizures. He was born at term by spontaneous vaginal
delivery, of healthy unrelated parents, and with uneventful perinatal
and postnatal clinical course. He did not experience febrile
convulsions, traumatic brain injury, or central nervous system
infections. Over time he was found to have a mild global learning
difficulty that improved over time with occupational therapy. He was
reported by the parents to be a very shy, quite timid, reticent, and
solitary person. Also, stereotype and behavioral changes were noted.
Emotional and social difficulties were reported by the family. During
clinical assessment, craniofacial dysmorphic features of KBG syndrome
were noted. Regarding the neurologic and behavioral aspects, the patient
had mild intellectual disability, learning difficulties, and
neurobehavioral problems such as attention deficit hyperactivity
disorder (ADHD) since childhood. However, he was able to participate in
normal school life without any help.

Targeted exome sequencing (TES) of 4800 clinically significant genes was
performed and a pathogenic heterozygous variant, NM\_001256183.2:
c.4407dupG, frameshift, was identified in ANKRD11, c.4407dupG, (p.
Arg1470GlufsTer84). As the parental genetic tests revealed that the
parents did not have this frameshift, the variation was identified as a
de novo variant. This variant was categorized as pathogenic by the
American College of Medical Genetics and Genomics (ACMG) guideline
(PVS1, PS1, PS2, and PM2) and has not been reported earlier. The variant
is absent from control sequences (Genome Aggregation Database (gnomAD)
and no alternative plausible variants or known mutations were identified
as competing possibilities in this patient.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Seizure type}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{EEG abnormalities}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{AEDs}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Seizure frequency}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GTCS\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Multifocal discharges\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 yo\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VPA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
First seizure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
GTCS + FS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Focal/ multifocal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
9 yo\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
VPA+ LTG (ex, ar) + ACZ\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1-2 /month\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stabilization\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
No abnormalities\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9-11 yo\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VPA + ACZ\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
GTCS One FS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Focal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
11 yo\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
VPA+ ACZ + LEV\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1-2 /week\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GTCS\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Focal /multifocal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12 yo\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VPA + ACZ + LEV\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1/month\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
FS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Multifocal paroxysmal discharges\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
13-15 yo\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
VPA + ACZ + LEV LEV -- ex\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1/week\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
GTCS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Multifocal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
15 yo\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
OXC (ex,ar)+ TPM VPA -- ex ACZ -- ex\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1/week\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
GTCS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Multifocal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 yo\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
TPM - ex + LTG\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2-3/month\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
GTCS\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Multifocal bursts\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
nowadays\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LTG\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2-3/year\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 1} : Electroclinical characteristics of epilepsy

Abbreviations: Generalized tonic-clonic seizures= GTCS, focal seizures=
FS

Sodium valproate/valproic acid=VPA, Lamotrigine=LTG, Acetazolamide=ACZ,
Topiramate=TPM, Levetiracetam=LEV, Oxcarbazepine= OXC

Allergic reaction=ar, years old=yo, excluded=ex

His first seizure was a generalized tonic-clonic seizure by description
and occurred at the age of 8 years, when he was admitted in our clinic,
department of neurology. The first wakefulness interictal EEG showed
regular alpha activity, associated with occasional multifocal paroxysmal
bursts of high voltage spike-wave complexes (\emph{see} picture 1).
Treatment with sodium valproate was started. Initially, there were 1-2
generalized tonic-clonic seizures per month on average, by the age of 9.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\emph{Picture 1.} Wakefulness interictal EEG showing occasional
multifocal paroxysmal bursts of high voltage spike-wave complexes.

Stabilization of seizures was not achieved, there were also focal
seizures. Therefore, a second AED, lamotrigine, was added to the
treatment. Regarding the allergic reaction due to lamotrigine, it was
discontinued, and the treatment included acetazolamide. During this
period the EEG findings in wakefulness and post-hyperventilation, showed
occasional multifocal mainly bitemporal bursts of spike-and-waves, while
on sleep EEG revealed occasional multifocal left-sided frontotemporal
and parietooccipital spike-and-waves bursts (\emph{see} pictures 2, 3,
4).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\emph{Picture 2.} Wakefulness EEG showing occasional focal bitemporal
bursts of spike-and-waves.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\emph{Picture 3.} Sleep EEG showing occasional multifocal left-sided
frontotemporal and parietooccipital spike-and-waves bursts.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\emph{Picture 4.} Post-hyperventilation EEG showing occasional
multifocal mainly bitemporal bursts of spike-and-waves.

A period of seizure freedom occurred from age 9 to 11 occurred after
commencing acetazolamide. There was no history of absence seizures or
myoclonic seizures, meanwhile, episodes of staring spells with no EEG
changes were noted. The follow-up wakefulness EEG findings showed
stabilization, meaning a regular brain activity of alpha rhythm with
isolated right-sided spike-and-wave bursts.

Thereafter, followed a period of frequent twice-a-week generalized
tonic-clonic seizures and one focal epileptic seizure. Levetiracetam was
included in the antiepileptic treatment. Repeat wakefulness EEG findings
showed focal bursts of left-sided parieto-occipital and temporal
spike-wave discharges. (\emph{see} picture 5). Epilepsy protocol
magnetic resonance imaging of the brain was normal.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\emph{Picture 5.} Wakefulness EEG findings showing focal bursts of
left-sided parieto-occipital and temporal spike-wave discharges.

During a period of a year, the boy had one tonic-clonic generalized
seizure per month, and no focal seizures were noted. The wakefulness EEG
findings revealed basic brain activity of regular alpha rhythm with
intermittent photic stimulation and hyperventilation activation of focal
bursts of frontal and temporal spike-and-waves.

A round two-year period of focal seizures followed, and the wakefulness
EEG findings showed regular alpha activity with multifocal bilateral
paroxysmal discharges of spike-and-wave 2 c/s, lasting 3-4 seconds
(\emph{see} picture 6).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\emph{Picture 6.} Wakefulness EEG findings showing multifocal bilateral
paroxysmal discharges of spike-and-wave 2 c/s, lasting 3-4 seconds.

The patient was not seizure-free for a long period of time. He had
tonic-clonic generalized epileptic seizures once a week in the following
years. In the epileptic treatment another AED, oxcarbazepine, was added.
The EEG findings during this period showed focal bursts of right-sided
spike-and-wave. After a short period of time, exactly a two-week period,
oxcarbazepine was excluded, due to allergic reaction regarding the drug,
and topiramate was added. Valproate was excluded from the treatment.

The period that followed was characterized by 2-3 tonic-clonic
generalized epileptic seizures per month. Topiramate was excluded and
lamotrigine was added. No allergic reaction was noted. For a short
period of a few months, he was seizure-free. Now the patient is on
treatment with lamotrigine, he is not seizure-free completely, but
stabilized and has only a few seizures per year. The follow-up
wakefulness EEG findings showed regular beta rhythm with right-sided
multifocal bursts of spike-and-slow waves.

His seizures proved difficult to control from age 12 when generalized
tonic-clonic seizures recurred reaching a frequency of up to 2-3
seizures per month, despite trials of lamotrigine, levetiracetam, and
topiramate. A trial of topiramate in combination with lamotrigine led to
a marked reduction in seizure frequency, reducing to three generalized
tonic-clonic seizures in the year following treatment initiation.

\textbf{DISCUTION AND CONCLUSION}

Epilepsy and EEG abnormalities are frequently reported in KBG patients.
Most often present with generalized or combined generalized and focal
epilepsy with onset in childhood. Literature data are limited,
incomplete, and inconclusive to identify a specific electroclinical
pattern. Various seizure types have been reported in the literature,
with tonic-clonic generalized seizures being the most frequent seizure
types. Focal seizures are also rarely noted. Moreover, many cases of
generalized and focal EEG abnormalities without clinically evident
seizures have been reported. In most of the KBG syndrome patients with
epilepsy, seizures are drug-resistant. Moreover, epilepsy in patients
with KBG syndrome is associated with poorer developmental outcomes.

We report a boy presenting with a drug-resistant, monogenic epilepsy
syndrome, due to ANKRD11 pathogenic de novo variant found by TES
associated with the KGB syndrome. This variant has never been reported
so far in the literature. The reassessment of phenotypic features
confirmed that he fulfilled the proposed diagnostic criteria for KBG
syndrome.

We outline the electroclinical pattern of epilepsy in KBGs, types of the
epileptic seizures and EEG features of this patient. He suffered from
focal to tonic-clonic seizures, treated with various AEDs, making a
drug-resistant epilepsy diagnosis. Even though our result cannot be
conclusive, we hypothesize that the represented EEG pattern together
with the epilepsy and seizure type, dysmorphic facial features, ID, and
behavioral disorders, may help to characterize the phenotype of KBG
syndrome. Future studies regarding these issues may outline the
electroclinical pattern in a larger series of patients with KBG
syndrome.

\textbf{AUTHORS CONTRIBUTIONS}

LAA had main contribution in literature search, writing and drafting the
manuscript. All authors contributed in the diagnosing, treatment, and
follow-up of the patient, edited the manuscript. All authors approved
the final version.

\textbf{ACKNOWLEDGEMENTS}

The authors are grateful to the patient and his family for generously
permitting usage of clinical information.

\textbf{CONFLICT OF INTEREST}

None of the authors have any conflict of interest to disclose.

\textbf{FUNDING}

No funding was obtained for this case report.

\textbf{AVAILABILITY OF DATA}

The data of the current case report are available from the corresponding
author on reasonable request.

\textbf{CONSENT}

The case report protocol was performed in accordance with the
Declaration of Helsinki.

\textbf{INFORMED CONSENT}

Written informed consent was obtained from the patient's parent to
publish this report in accordance with the journal's patient consent
policy.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Parenti I, et al. ANKRD11 variants: KBG syndrome and beyond. Clin
  Genet. 2021 Aug;100(2):187-200.
\item
  Loberti L, et al. Natural history of KBG syndrome in a large European
  cohort. Hum Mol Genet. 2022 Dec 16;31(24):4131-4142.
\item
  Auconi M, Serino D, Digilio MC, Gnazzo M, Conti M, Vigevano F, Fusco
  L. Epilepsy in KBG syndrome. Dev Med Child Neurol. 2023
  May;65(5):712-720
\item
  Buijsse N, et al. Epilepsy is an important feature of KBG syndrome
  associated with poorer developmental outcome. Epilepsia Open. 2023 Jul
  27.
\item
  Miao P, Feng J, Guo Y, Wang J, Xu X, Wang Y, Li Y, Gao L, Zheng C,
  Cheng H. Genotype and phenotype analysis using an epilepsy-associated
  gene panel in Chinese pediatric epilepsy patients. Clin Genet. 2018
  Dec;94(6):512-520.
\item
  Goldenberg A, et al. Clinical and molecular findings in 39 patients
  with KBG syndrome caused by deletion or mutation of ANKRD11. Am J Med
  Genet A. 2016 Nov;170(11):2847-2859.
\item
  Low K, et al; DDD Study; Smithson S. Clinical and genetic aspects of
  KBG syndrome. Am J Med Genet A. 2016 Nov;170(11):2835-2846
\item
  Alves RM, 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 Jan 14;20(1):16.
\item
  Nardello R, Mangano GD, Antona V, Fontana A, Striano P, Giorgio E,
  Brusco A, Mangano S, Salpietro V. Electroclinical features and outcome
  of ANKRD11-related KBG syndrome: A novel report and literature review.
  Seizure. 2021 Feb; 85: 151-154.
\item
  Kutkowska-Ka\selectlanguage{polish}ź\selectlanguage{english}mierczak A, et al. Wide Fontanels, Delayed Speech
  Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG
  Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants
  Involving the~\emph{ANKRD11} Gene or Submicroscopic Chromosomal
  Rearrangements of 16q24.3. Genes (Basel). 2021 Aug 17;12(8):1257.
\item
  Kim SJ, Yang A, Park JS, Kwon DG, Lee JS, Kwon YS, Lee JE. Two Novel
  Mutations of~\emph{ANKRD11} ~Gene and Wide Clinical Spectrum in KBG
  Syndrome: Case Reports and Literature Review. Front Genet. 2020 Nov
  11; 11: 579805.
\item
  Murphy MJ, McSweeney N, Cavalleri GL, Greally MT, Benson KA, Costello
  DJ. KBG syndrome mimicking genetic generalized epilepsy. Epilepsy
  Behav Rep. 2022 Apr 20; 19: 100545.
\item
  Shneker BF, Fountain NB. Epilepsy. Dis Mon. 2003 Jul;49(7):426-78.
\item
  Milligan TA. Epilepsy: A Clinical Overview. Am J Med. 2021
  Jul;134(7):840-847.
\item
  Tang, F., Hartz, A., \& Bauer, B. (2017). Drug-Resistant Epilepsy:
  Multiple Hypotheses, Few Answers.~Frontiers in neurology,~8, 301.
\item
  Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N,
  Resnick T, Benbadis SR. The consequences of refractory epilepsy and
  its treatment. Epilepsy Behav. 2014 Aug; 37:59-70.
\item
  Knupp, K., Koh, S., \& Park, K. (2012). Pediatric epilepsy: Five new
  things.~Neurology. Clinical practice,~2(1), 40--47.
\item
  Aneja S, Jain P. Refractory epilepsy in children. Indian J Pediatr.
  2014 Oct;81(10):1063-72.
\end{enumerate}

\selectlanguage{english}
\FloatBarrier
\end{document}

