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.
ANKRD11 gene functions as a co-regulator in the developing brain.
The role of the ANKRD11 gene in neurodevelopment was suggested by
subsequent reports of individuals with intellectual disability, facial
dysmorphism, and ASD. In 1975, Herrman et al., first described
the KBG syndrome, a neurodevelopmental autosomal dominant disorder,
caused by the haploinsufficiency of the 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 Skjei et al. and Low et al . A diagnosis of
epilepsy, a major criterion, according to Skjei et al ., and a
minor criterion according to 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 ANKRD11gene, with a clinical phenotype compatible with KBG syndrome.
A systemic review of epilepsy and EEG anomalies in subjects with KBG
syndrome is deficient. 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 ANKRD11 gene, to
contribute to identifying a specific electroclinical pattern of KBG
syndrome.