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King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
Division of Pediatric Neurology, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
Division of Pediatric Neurology, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
Division of Genetics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi ArabiaDepartment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaSaudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
Corresponding author at: Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Riyadh, PO Box 22490, Riyadh, 11426, Saudi Arabia.
King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
This is the largest case series of genetically confirmed EIEE in the region.
•
We identified 26 novel mutations in different genes causing EIEE.
•
We delineated the clinical phenotype of 26 types of EIEE.
•
Autosomal recessive EIEE could be more prevalent in consanguineous population.
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We provided a thorough functional classification of all EIEE registered in OMIM.
Abstract
Purpose
Epileptic encephalopathies (EE), are a group of age-related disorders characterized by intractable seizures and electroencephalogram (EEG) abnormalities that may result in cognitive and motor delay. Early infantile epileptic encephalopathies (EIEE) manifest in the first year of life. EIEE are highly heterogeneous genetically but a genetic etiology is only identified in half of the cases, typically in the form of de novo dominant mutations.
Method
This is a descriptive retrospective study of a consecutive series of patients diagnosed with EIEE from the participating hospitals. A chart review was performed for all patients. The diagnosis of epileptic encephalopathy was confirmed by molecular investigations in commercial labs. In silico study was done for all novel mutations. A systematic search was done for all the types of EIEE and their correlated genes in the literature using the Online Mendelian Inheritance In Man and PubMed databases.
Results
In this case series, we report 72 molecularly characterized EIEE from a highly consanguineous population, and review their clinical course. We identified 50 variants, 26 of which are novel, causing 26 different types of EIEE. Unlike outbred populations, autosomal recessive EIEE accounted for half the cases. The phenotypes ranged from self-limiting and drug-responsive to severe refractory seizures or even death.
Conclusions
We reported the largest EIEE case series in the region with confirmed molecular testing and detailed clinical phenotyping. The number autosomal recessive predominance could be explained by the society’s high consanguinity. We reviewed all the EIEE registered causative genes in the literature and proposed a functional classification.
Epileptic encephalopathies (EE), are disorders of the developing brain characterized by intractable seizures and electroencephalogram (EEG) abnormalities, that typically result in cognitive and motor delay, regression, and sometimes death. [
]. Early infantile epileptic encephalopathy (EIEE) have their onset during infancy and are highly variable in etiology and natural history. While seizure is the core symptom for all EIEE syndromes often accompanied by progressive cognitive delay, these disorders are highly variable in the age of onset, severity, type of the seizures, EEG patterns, other associated symptoms and outcome [
The classification of epilepsy, in general, is challenging. Many intersecting classification models were proposed based on the type of seizures, the electrical and imaging features, and the underlying etiology [
]. Historically, EIEE were classified into five main syndromes: Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and Landau-Kleffner syndrome [
EIEE are genetically heterogeneous, but despite the recent advances in molecular diagnostics, only around 50% of the cases have a recognizable underlying genetic cause [
], The identification of the genetic etiology of EIEE has greatly improved our understanding of the disease pathophysiology at the molecular level, however, the genotype/phenotype correlation remains poorly understood. Some epileptic syndromes have been correlated with certain genes like Dravet syndrome, in which around 80% of the cases are due to SCN1A gene mutations. Otahara syndrome was attributed to mutations in STXBP1 and ARX genes. The outcomes may range from self-limited and drug-responsive to severe debilitating syndromes [
In this study, we provide an extensive clinical and genetic characterization of 72 molecularly characterized EIEE patients from Saudi Arabia. Additionally, we reviewed all the reported genes causing EIEE and proposed a functional classification.
2. Methods
2.1 Patients
This is a descriptive retrospective study of a consecutive series of patients diagnosed with EIEE from the participating hospitals. A chart review was performed for all patients to record the following variables: perinatal history, developmental history, family history, magnetic resonance imaging (MRI), EEG findings, genetic testing, antiepileptic medications, and clinical outcome. Only patients with a genetic confirmatory test of EIEE were included.
2.2 Mutation identification
The diagnosis of epileptic encephalopathy was confirmed by whole exome sequencing (WES) of genomic DNA for most of the patients, while a few were diagnosed by relevant gene panels. All the molecular genetic studies were performed by accredited commercial labs. Cases are negative to customized gene panels were subjected to WES and performed as described elsewhere [
]. We strictly followed a criterion in reporting pathogenic variants from whole exome sequencing. For variants minor allele frequency <0.001 based on our internal database (2379 exomes), gnomad database and fully segregated within available family members. Whereas for dominant disease-causing variants considered de novo variants confirmed paternally and novel in our internal database and gnomad database. Loss of function variants (indels, nonsense and canonical splicing mutations) are considered as pathogenic. All the discovered variants were confirmed by Sanger sequencing. For missense mutation, in silico study analysis tools were used to predict the genetic damaging of the novel variants including Polyphen2 (http://www.genetics.bwh.harvard.edu/pph2/), SIFT (http://sift.bii.a-star.edu.sg/), and MutationTaster (http://www.mutationtaster.org/) for variants in coding regions. For intronic variants, Human Splicing Finder (HSF) (http://www.umd.be/HSF3/index.html) was used. To determine the novelty of the variant, we checked for the presence of the variants in HGMD and ClinVar databases.
2.3 EIEE literature review
We conducted a systematic search for all the types of EIEE and their correlated genes in the literature using the Online Mendelian Inheritance In Man (OMIM) and PubMed databases. A thorough literature review was conducted to summarize the functions of all the identified genes.
2.4 Ethical approval
The study was approved by the Institutional Review Board at King Abdullah International Medical Research Centre (KAIMRC) (Ref. RC 16/113R).
3. Results
A total of 72 patients from 59 unrelated families were identified as eligible and included in the study. Table 1, Table 2 provide a summary of the clinical and mutation information for all cases. The male to female ratio was almost 1:1. The age at onset of seizures ranged from one day to 2 years with average at 9.8 months. The current age ranges from 1 year to 22 years, with a mean of 6.8 years. Consanguinity was positive in 75% of the cases but was always noted in those with an autosomal recessive etiology.
Table 1Summary of the clinical features.
List
Patient Number
Gene and Mutation
Gender
Age at onset of seizures
Current age
Seizure pattern
AED
Consanguinity
Development
Clinical features
MRI
EEG
Outcome and seizure control
Hypotonia
Microcephaly
Ophthalmologic involvement
Genes responsible for the synapsis, neurotransmitters, and receptors:
Very active right sided centrotemporal epileptiform discharges. Other EEG showed epileptic discharges over both sides mainly over both frontal head regions
Still has eye myoclonus and GTC Unsteady gait, toe walking, became weaker
KCNQ2
24
KA1
KCNQ2 NM_172107.2 c.1464C > G (p.Asp488Glu)
F
2 m
16 y
GTC, tonic
No AED
N
Delayed
yes
No
No
Normal
Normal
No seizures for more than 4 years
25
KF110
KCNQ2 NM_172107.2 c.1744 A > T (p.Ile582Phe)
M
neonatal
3 y
focal + GTC
2 AED
Y
GDD
No
No
No
brain atrophy + delayed myelination
Epileptic Encephalopathy
Refractory to medications, still having seizure
26
KF140
KCNQ2 NM_172107.2 c.793 G > A (p.Ala265Thr)
F
birth
1 Y
focal + GTC
2 AED
N
GDD
Yes
No
No
high glycerin peak
Epileptic Encephalopathy
Refractory to medications, still having seizure
KCNT1
27
KA6
KCNT1 NM_020822.2 c.1130 G > C (p.Cys377Ser)
F
Day 20
2 y & 9 m
GTC, eye blinking, facial twitching
5 AED
N
Delayed
yes
yes
Poor eye contact
Delayed myelination
Diffuse slowing, multifocal spike, and wave discharges
Intractable seizures GERD Oropharyngeal dysphagia Esophagitis pseudoachalasia On GT feeding Mild ventricular dilatation and mild mitral regurgitation
28
KF138
KCNT1 NM_020822.2 c.862 G > A (p.Gly288Ser)
F
4 m
2 y
focal + GTC
2 AED
Y
ID, regression
No
No
Yes
abnormal shape of corpus callosum with verticalization of the splenium
multifocal
Refractory to medications, still having seizure
29
KF147
KCNT1 NM_020822.2 c.2800 G > A (p.Ala934Thr)
F
4 m
5 y
GTC, focal
2 AED
N
ID
No
Yes
No
Thin CC, prominent CDF Spaces in the frontal and parietal region.
Focal discharges
Refractory to medications, still having seizure
30
KF155
KCNT1 NM_020822.2 c.862 G > A (p.Gly288Ser)
F
4 m
2 years
focal, GTC
2 AED
Y
ID
No
No
Yes
thin CC, brain atrophy
multifocal
Refractory to medications, still having seizure
SCN1A
31
KA14
SCN1A NM_001165963.1 c.1244 T > C (p.Ile415Thr)
M
2 years
11 y
GTC
1 AED
N
Normal
No
No
No
Normal
generalized spike-wave
Partially controlled seizures Normal development.
32
KA17
SCN1A NM_001165963.1 c.1625 G > A (p.Arg542Gln)
F
3 m
16 m
GTC
1 AED
Y
Delay
Yes
Yes
No
Delayed myelination, Posterior fossa arachnoid cyst, and microcephaly.
The predominant type of seizure was generalized tonic-clonic (84.2%), one-third of them were accompanied by other types of seizures like focal seizures. The vast majority of patients (97.2%) were delayed in their developmental milestones. Microcephaly was noted in 22.2% of the patients, while 20.8% were hypotonic and 15.3% had ophthalmologic involvement. The most prevalent EEG pattern was the epileptic encephalopathy (29.1%) followed by Lennox-Gastaut Syndrome (LGS) and multifocal patterns (13.9% each). The brain MRI was normal in more than half of the patients (51.4%). The most commonly identified structural brain anomaly was brain atrophy (16.7%) followed by anomalies in the corpus callosum (8.3%), cerebellar hypoplasia (5.5%), and white matter hyperintensity (5.5%). The treatment with antiepileptic medications ranged from one medication (36.1%) to more than three medications (6.9%) with variable response to treatment. The majority of patients (61.1%) had poor seizure control, while 34.7% were well controlled. Most of the controlled patients (69.2%) required only one medication. Two patients had their seizures resolved without treatment. On the other hand, two patients died early at two months of age.
All the patients underwent molecular confirmatory investigations. In most of the patients, the diagnostic tool was the whole exome sequencing (WES). We identified 26 different types of EIEE including types 1–4, types 6–9, types 11–14, types 17,21,23, types 25–28, type 32, types 37–39, types 48, 49 and 52. The identified genes were ARX, CDKL, SLC25A22, STXBP1, SCN1A, KCNQ2, ARHGEF9, PCDH19, SCN2A, PLCB1, SCN8A, KCNT1, GNAO1, NECAP1, DOCK7, SLC13A5, KCNB1, GRIN2B, WWOX, KCNA2, FRRS1L, ARV1, SLC25A12, AP3B2, DENND5A, and SCN1B respectively. The age at diagnosis confirmation ranged from 3 months to 18 years with average at 4 years and 7 months. The most prevalent type in this cohort was EIEE type 25 caused by SLC13A5 mutation, which was found in 11 patients (15.2%). This was followed by type 11 and type 37, each of which was confirmed in seven patients (9.7%). We identified 50 variants, 26 of them were novel. All the identified novel variants were subjected to in silico prediction (Table 2). The types of mutations were as follows, 61.1% of the patients had missense mutations, 13.9% nonsense, 9.7% had deletion mutations, 6.9% had insertion mutations, 6.9% had intronic splice site mutations, and one patient (1.4%) had a synonymous mutation. The mode of inheritance was autosomal recessive (AR) in 50% of the patients, while 45.8% of the patients had an autosomal dominant (AD) mode of inheritance. Three patients had an X-linked mode of inheritance, one of them was dominant, the other was recessive and the third could not be determined (PCDH19 gene). In all the autosomal recessive cases, the parents were carriers. On the other hand, dominant cases were de novo, except in four cases where the mutation was inherited from an affected parent.
4. Discussion
The latest definition of epileptic encephalopathy by the International League Against Epilepsy (ILAE) stated that “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time” [
Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009.
]. But it also highlights the underlying condition as an essential factor to determine the outcome and prognosis of the disease. In 2013, Bender, A. et al conducted a study on the Scn1a knocked-down murine model. Interestingly, they found that the gene defect per se was responsible for the animal cognitive impairment even without seizures [
]. This and other similar findings highlighted the essential role of the underlying genetic defect and its effect on the brain’s normal development and function with or without seizure activity.
The classification of the epileptic encephalopathy has been changing over time [
]. It was initially based particularly on the clinical features and the EEG patterns. Recently, in 2017, ILAE published a new classification for the epilepsies in general. The new classification emphasized the importance of the underlying genetic cause, if any, for the proper management and prognosis of the disease [
]. The recent advances in the molecular genetics field and the ability to overcome many genetic diagnostic hurdles impelled to redefine and reclassify many of the well-known diseases back again based on the identified underlying causes. Wang et al. and Zhou et al. presented functional classifications for multiple epilepsy-related genes, reported in their studies [
], In this study, we collected the clinical and molecular data for 72 patients diagnosed to have 26 out of 59 types of EIEE registered in OMIM database (from type 1 to type 61, except type 20 and 22, which do not exist). All the reported genes in the current study, including the ones with novel variants, are well known to cause EIEE if they harbored a pathogenic mutation. The genetic damaging effect of all the discovered novel variants was positively predicted using multiple in silico prediction tools. Furthermore, the vast majority of these novel variants were not found in general population databases like Exome Aggregation Consortium (ExAC) and 1000 Genome Project databases. The allele frequencies for the variants found in ExAC or 1000 G were extremely low, which goes with the predicted damaging effect on the genes’ functions.
To facilitate our review, we opted to classify our patients and all the remaining types of EIEE based on the responsible genes and their described functions (Fig. 1, Table S1, Figure S1). The genes were classified into six groups:
1
Genes responsible for the synapsis, neurotransmitters, and receptors: this group includes genes encoding for variable receptors like γ-Aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) and other receptors. It also includes the genes responsible for the neurotransmitters dynamics, like the release by vesicles and reuptake from the synaptic cleft. Finally, it includes the genes regulating the synapses.
2
Genes responsible for signal transduction: this group of genes control various types of intracellular signaling and signal transduction processes.
3
Genes responsible for ion channels: these genes encode for the different types of sodium, potassium, and calcium ion channels.
4
Genes regulating DNA and RNA: this group includes the genes responsible for DNA repair, regulation of the DNA and RNA (including tRNA), DNA synthesis and protection. None of our patients belongs to this group.
5
Genes responsible for the organelles and cell membrane: these genes exhibit variable structural and functional roles in the cellular organelles like Golgi apparatus, endoplasmic reticulum, and mitochondria. They also play a role in cell membrane function and characteristics like glycosylation.
6
Genes responsible for the development and growth of the neurons: this group includes the genes that control the cellular growth and cell cycle. Some of these genes play a pivotal role in neuronal development, like the myelination, and axons and dendrite development.
Fig. 1A: EIEE genes functional classification scheme. Genes annotated with "*" have multiple functions and can fit more than one group. Genes reported in the current study were highlighted in yellow. B: Scheme showing the distribution of EIEE among the proposed functional groups. C: Seizure semiology associated genes. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
4.1 Genes responsible for the synapsis, neurotransmitters, and receptors
Fifteen patients in our study were diagnosed to have mutations in genes that belong to this group. Three patients from two unrelated families had mutations in AP3B2 gene. All of them had refractory seizures and demonstrated cerebellar atrophy in brain MRI. Assoum et al. reported 12 patients with AP3B2 gene mutations. The majority of them were resistant to antiepileptic medications. Four out of six had structural brain findings in the brain MRI. However, none of the current patients had optic atrophy, which was reported previously [
Autosomal-recessive mutations in AP3B2, adaptor-related protein complex 3 Beta 2 subunit, cause an early-onset epileptic encephalopathy with optic atrophy.
]. All our patients had the same mutation, c.1837del (p.Glu613Serfs*182), that was described previously in Saudi population, which might reflect a founder effect.
In our study, we found seven patients from two unrelated families with mutations in FRRS1L gene. All of them have the same mutation, c.961C>T (p.Gln321*), which was reported before in other Saudi patients [
]. All of them share the previously reported phenotype including the developmental regression and poor response to antiepileptic medications, however, none of them had chorea [
The GRIN2B mutation, c.2429 G > A (p.Ser810Asn), was reported previously by Platzer et al. Although the current patient's seizures were controlled, she manifested the previously reported features of global developmental delay, microcephaly, and polymicrogyria in the brain MRI [
The deletion (9q33.3 to 9q34.11), which involves eight genes including STXBP1 gene was reported twice in the literature to be associated with epileptic encephalopathy and intellectual disability [
Regarding the current patient with ARHGEF9 mutation, his presentation is consistent with the genotype/phenotype correlation proposed by Wang et al. The patient’s seizures were well controlled, which could be because the mutation c.1476T>G (p.Phe492Leu), is located outside the three domains of the protein. Seizures improved in eight out of the twelve cases reported in Wang et al. review [
]. Although the three patients had the same brain MRI findings, brain atrophy and dysgenesis of the corpus callosum, as the patient presented here, however, they had severe intractable seizures while our patient’s seizures were well controlled with three antiepileptic medications.
Regarding the GNAO1 gene mutations, there is a wide variation in the clinical presentations and outcomes in the literature ranging from well controlled to intractable seizures. The genotype/phenotype may not be correlated for this gene [
]. The presence of developmental delay, hypotonia, and microcephaly in patients with well-controlled epilepsy, may reflect the considerable effect of the underlying genetic mutation on the patients' phenotype.
The previously reported cases with PLCB1 gene mutation had truncating deletion mutations involving multiple exons leading to drug-resistant epilepsy. The fourth case reported in the literature was responding to medication, however, ended up with severe developmental delay [
]. Herein we reported the first nonsense mutation in PLCB1, c.550C > T (p.Arg184*), which causes a very early termination and loss of all the protein domains. The patients were found to have brain atrophy, which was a common feature in most of the reported cases [
The KCNA2 mutations of the patients KF108 and KF109 (p.Thr374Ala and p.Arg297Gln) are located in the intramembrane domains, however, the patient KF151 mutation (p.Glu422Glyfs*21) is located in the intracellular domain near to the C terminal, which could explain the milder phenotype and better control of the seizures. The same was reported previously regarding the variant p.Pro405Leu [
]. The gain of function mutation, p.Arg297Gln and p.Thr374Ala are among the most commonly reported mutations. Although two of the previously reported seven patients with p.Arg297Gln mutation had a favorable outcome, our patient was resistant to all AED and is still seizing [
Like the patient KA4, none of the previously reported patients with KCNB1 mutations had a seizure control. The patient’s mutation (p.Pro408Ser) is novel and involves the S6 domain of the protein, which could affect the function of the protein significantly. Normal brain MRI was reported previously in two patients [
The patient (KA1) has a benign familial neonatal epilepsy presentation caused by KCNQ2 mutation like what was reported by Soldovieri, MV. (2014), where 13 out of 16 patients had a favorable outcome and normal cognition and development [
Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.
]. Alternatively, some patients were found to have intractable seizures with a global developmental delay like the two other patients (KF110 and KF140). The inheritance from currently asymptomatic mother of our patient KA1 mimics the familial inheritance reported previously [
Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.
A recent cohort of 12 patient with KCNT1 gene mutation delineated the phenotypic features, which goes with the clinical characteristics of the patients in the current study. Seven out of the twelve reported patients didn't respond to any antiepileptic medications similar to the current patients. The reported brain MRI features included mainly cerebral and cerebellar atrophy, however, the main MRI finding in the current cases was the thinning of the corpus callosum [
Five of the patients in our study harbored mutations in the SCN1A gene, encoding the voltage-gated sodium channel. These patients had a variable course of the disease; while two patients (KA14 and KF150) had a mild course and spontaneous resolution of the seizures, the other three (KA17, KF133, and KF157) had refractory seizures and cognitive impairment. Their described mutations (p.Ile415Thr, p.Leu224Trp, p.Arg542Gln, p.Arg500Trp, and p.Glu1238Asp) are expected to affect variable domains of the expressed protein, which might exhibit a variable impact on the protein function, and consequently a great variation of the phenotype [
The patient KF159 is the second reported case in the literature up to our knowledge with the SCN1B gene intronic mutation c.449-2A > G. He has a similar presentation like the case reported by Trujillano et al. [
The matched clinical presentation of the patients in the current study with SCN2A mutation and the previously reported cases supports the genotype/phenotype correlation proposed by Sanders et al [
]. The patient KA12 had other associated symptoms like sleep disturbance, spasticity, scoliosis, and gastro-esophageal reflux disease. Scoliosis was reported previously in three patients in the literature and one patient had scoliosis with GERD [
All the current patients with SCN8A mutations had a global developmental delay. Although the patients KF114, KF115, and KF127 have the same mutation c.82C > T (p.Arg28Cys), they had marked differences in the phenotype, response to treatment and MRI findings. This could reflect the effect of other factors on the outcome of the disease.
4.4 Genes responsible for the organelles and cell membrane
The first reported patient with ARV1 gene mutation had neurodegenerative disease and blindness [
], however, none of the patients in our study had any brain MRI findings nor ophthalmologic involvement. The second reported case in the literature had an early onset and very severe phenotype and died at the age of 12 months. The patient had a splice site mutation and demonstrated hyperintensity on brain MRI in the posterior pons [
]. Interestingly, all patients in the current study had ataxia, which was not reported previously.
Although the patient KA2 with the PCDH19 mutation has a novel mutation that involves the most distal part of the intracellular domain of the protein, the patient shares the same clinical presentation with a recently reported series including the intractable seizure, and global developmental delay. This may reflect the critical role of the intracellular domain in the protein function [
]. PCDH19 mutation was reported in the literature to have a unique type of inheritance, where the disease appeared to affect heterozygous females and mosaic hemizygous males [
]. It was called “female-limited epilepsy” as some of the affected females inherited the mutations from their healthy fathers. However, in some cases, the mutation was inherited from hemizygous father, who was reported to have neuropsychiatric symptoms without commenting on the presence of mosaicism, while some carrier mothers were asymptomatic [
The most common type of EIEE in our study was type 25 caused by SLC13A5 gene mutation, which encodes for the sodium citrate transporter. Five out of the six mutations discovered in this study were novel. The most commonly found mutation was c.1227dupC (p.Ile410Hisfs*13), which was described in three unrelated families, raising the possibility of being a founder mutation in the Saudi population. All patients had a profound developmental delay and were resistant to medical treatment except one patient, who had partial control of her seizures. Teeth hypoplasia was reported previously in patients with SLC13A5 mutations, [
]. All the currently reported patients share a comparable course of the disease and outcome. Although one of them (KA11) did not develop any seizure in the last five years, she has a profound cognitive delay, which further support the effect of the underlying genetic mutation on the patients’ outcome in addition to the seizure effect.
All the previously reported cases with SLC25A22 gene mutation experienced their first seizure at a very early age of their neonatal life [
]. Alternatively, the patient KF129 presented later at 18 months of age. Although he has a global developmental delay, his seizures were controllable with the use of three antiepileptic medications. Hypotonia and microcephaly were found in patient KA5, which goes with the phenotype of the previously reported patients [
4.5 Genes responsible for the development and growth of the neurons
We reported one patient with a novel mutation in ARX gene. The patient’s mutation is located in the DNA binding homeobox, the site at which most of the severe ARX mutations are clustered [
]. Although the p.Ala40Val mutation was reported before, the p.Ala40Glu mutation, which was found in the current patient was not reported. Both variants share the same phenotype of tonic seizures, refractory to treatment and developmental delay [
The DOCK7 mutations were described for the first time in 2014 by Perrault, I. et al in three female patients from two unrelated families. These patients had refractory seizures, intellectual disability, and cortical blindness. All the reported mutations were truncating, two of the patients had compound heterozygous mutations and one had a stop codon mutation, (p.Asp837Alafs*48), (p.Arg1237*), and (p.Ser328*) respectively [
]. Although the patient in our study had a truncating mutation (p.Lys295Argfs*15) and microcephaly, she had a milder course with controllable seizures, normal development, and unremarkable ophthalmological examination and normal brain MRI.
In this report, we add another two patients with c.606-1G > A mutation in WWOX gene to the previously reported patients by our group [
]. The two patients had the same course of the disease with premature death. Which supports the severity of this intronic mutation. These two siblings presented with arthrogryposis, which was not reported in the previous cases [
]. A third patient with an intronic mutation in WWOX was presented here (KA8) has a global developmental delay, refractory seizures, hypotonia, and poor eye contact. His brain MRI showed cerebral atrophy, which goes with the previously reported cases of WWOX gene mutations [
Identifying the underlying genetic cause for all EIEE cases is of utmost importance not only for the personalized management and prognostic prediction but also for proper genetic counseling. Four of our patients had inherited autosomal dominant mutations, one of them (KA14), had a similar phenotype of his affected father. The second and third patients (KA15 and KA17), had severe phenotypes in comparison to the affected fathers. Alternatively, the fourth patient (KA1), the carrier mother was completely asymptomatic. Incomplete penetrance and variable expressivity were reported in cases with SCN1A related seizures, which might be challenging for the counseling of these families [
]. Although the autosomal dominant epileptic encephalopathy is expected to be the most common,7 in our study the autosomal recessive cases were slightly more than the autosomal dominant, 50% and 45.8% respectively. This could be attributed to the high consanguinity rate in Saudi society, which explains the high incidence of AR diseases [
]. Of note, the discovered de novo mutations in autosomal dominant EIEE should be taken with extreme caution as some of the previously reported genes were found warrant further functional studies to proof their pathogenicity and correlation with EIEE phenotype [
], most of the patients in this study (61.1%) were resistant to all the antiepileptic medications given. The clinical course of our cases, as well as the EEG patterns and brain MRI characteristics, were quite heterogeneous even for the same genes. However, intrafamilial homogeneity is noted. Some genes showed certain seizure semiology summarized in Fig. 1C.
The functional classification can be applied to other types of epilepsy syndromes. Additionally, it would be easy to add newly discovered genes either to the same proposed groups or to add new ones. As expected, some of the genes were included in more than one group of the classification, as they have multiple functions. It is important to bear in mind that this classification was based on the discovered functions of the genes, which could change or expand in the future. Certainly, knowing the pathophysiology of the underlying gene defect will help the clinicians in the personalized management for their patients and will pave the way for possible future treatments [
We reported the largest EIEE case series in the region with confirmed molecular testing and detailed clinical phenotyping. The AR outweighed the AD cases in this study, which could be expected in other societies with high consanguinity. The clinical manifestations of EIEE are widely variable. The breakthrough in molecular genetics led to the discovery of the underlying causes in a significant number of patients. A scrutinized look at the patient's genotype is of utmost importance for proper personalized management, prognostic prediction, and for genetic counseling. The functional classification of the disease might solve the dilemma of the existing classifications and would sort the patients easily and clearly. Although it is still a challenge to reach for the genetic diagnosis in all the EIEE patients, we are on the right way.
Funding sources
No funding for this article from any institution or agency.
Conflicts of interests
None declared.
Acknowledgments
We are grateful to patients and their families involved in this study.
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ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology.
Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009.
Autosomal-recessive mutations in AP3B2, adaptor-related protein complex 3 Beta 2 subunit, cause an early-onset epileptic encephalopathy with optic atrophy.
Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.
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