Autistic spectrum disorders in children with epilepsy

SUMMARY

The actuality of the subject. Autistic spectrum disorders (ASD) and epilepsy are pathologies with increasing incidence during the last years. Th e prevalence of ASD is about 14.7 per 1000 children. ASD and epilepsy often occur simultaneously, which is determined in 20-25% of cases. Data from other sources estimates that 44% of ASD children were diagnosed with epilepsy, and 54% of children with epilepsy were subsequently diagnosed with ASD. These pathologies are multifactorial, polygenic and overlap frequently. Recent research has demonstrated the involvement of genetic mechanisms in the pathogenesis of these diseases, for example: regulation of gene transcription, cell growth, function and structure of synaptic channels. Th e purpose of this study is to investigate and describe more genetic disorders in which ASD and epilepsy overlap; with the aim of improving the diagnosis of these pathologies. Th e study material consists in researching and analyzing data from the academic literature suggestive for epilepsy and ASD. Results. We analyzed the bibliographical sources referred on the interconnection between ASD and epilepsy in several genetic disorders and found out the most specifi c genes involved in the pathogenesis of ASD and epilepsy. Data from literature suggests that there are many genetic conditions associated with ASD and epilepsy. Among these we can mention the duplication 15q11-q13 maternally inherited – the most common chromosomal aberration reported in children with ASD (0.5-3%). Several genes encoding the GABA receptor subunits are located in this region, therefore mutations in these genes are associated with epilepsy. One of the most common genetic disorders – Down syndrome (DS), meets the ASD criteria in 5-9%, and epilepsy occurs in 8-13% of cases. Mutations in the DYRK1A gene located on chromosome 21 (21q22.13) cause the ASD phenotype and has an increased interest for DS pathogenesis. Fragile X syndrome is one of the most common monogenic disorders associated with ASD. Th is disease develops due to a dynamic mutation consisting in expansion of CGG nucleotides, thus inactivating the FMR1 gene. Epilepsy is reported in about 10-20% among children with Fragile X Syndrome. Other genes are also involved in ASD pathogenesis, for example: genes responsible of transcription regulation (MECP2, MEF2C, FOXG1), cell growth (TSC1, TSC2, PTEN), synaptic channels (SCN2A) and synaptic structure (CASK, CDKL5, FMR1, SHANK3). Conclusions. ASD and epilepsy overlap frequently, but the mechanisms underlying this interaction are still unclear. Th e geneticist and neurologist should work in a team and recognize the main features of ASD (defi cits in social behaviors, restricted interests, repetitive behavior patterns) and epilepsy. Data from the literature suggest that polygenic and monogenic disorders, as well as de novo mutations, can cause ASD and epilepsy. Due to the last advances in this fi eld, soon, will be easier to perform sequencing of the gene panels, as well as exon sequencing with the aim to prevent these pathologies. Continuing research into this fi eld will help scientists and doctors better understand these genetic disorders, establish an early diagnosis, introduce new therapies, and prevent the onset of ASD and epilepsy.

Keywords: Autistic spectrum disorders (ASD), epilepsy, genetic disorders (GD)

INTRODUCTION

Autistic spectrum disorders (ASD) are characterized by neurodevelopment disorders more often from early childhood, manifested by deficiencies in social interaction, limited communication with others, repetitive behavior, and stereotypical actions. ASD affect about 1 out of 68 children and is 3-4 times more common in boys than in girls [8]. ASD usually occur before the age of 3 years and persist during all life. Epilepsy is a condition defined by the occurrence of two and more unprovoked, recurrent seizures due to excessive and disordered neural discharge [15]. The association of ASD and epilepsy is not fully elucidated, but according to literature data the prevalence of epilepsy in children with ASD ranges from 5% to 46% [18]. Jokiranta et al. found that 44% of children with ASD were later diagnosed with epilepsy, and 54% of children with epilepsy were subsequently diagnosed with ASD. The age of onset of epilepsy in these children is bimodal distributed, with a peak between the age of 2-5 years and the other in adolescence. Intellectual deficiencies represent a risk factor for developing epilepsy within the ASD. The number of patients with ASD and intellectual deficiencies which suffer from epilepsy is approximately three times higher compared to those with whom the intellect is not affected [5]. At the moment, there are a few data regarding differences in the phenotype of autism in children with and without epilepsy. The onset of seizures can lead to further changes in brain function in children with ASD, which will erase the underlying clinical symptoms of autism. Thus, it is difficult to develop a good management for patients with vague clinical signs. In one study, Cuccaro et al. have investigated several groups of children suffering from ASD. The group with the highest rate of epilepsy was characterized by the early onset of ASD, repetitive use of objects, unusual sensory interests, and motor coordination deficiencies. Researchers have found that these symptoms reflect a significant delay in nervous system development at examined patients  [18]. Accumulation of knowledge and experience about the ASD-epilepsy phenotype in association with the evolution of genetic possibilities will open new horizons in treatment of these pathologies.

THE AIM OF THE STUDY

Is to investigate and describe more genetic disorders (GD) in which ASD and epilepsy overlap.

THE STUDY MATERIAL

Consists in researching and analyzing data from the specialized literature suggestive for epilepsy and ASD with the aim of improving the diagnosis of these pathologies.

RESULTS AND DISCUSSIONS

ASD and epilepsy are multifactorial, polygenic pathologies that overlap frequently. Literature data suggest that there are many genetic disorders associated with these conditions. Recent research has shown that many genes are also involved in ASD pathogenesis, for example genes responsible for: transcriptional regulation (MECP2, MEF2C, FOXG1), cell growth (TSC1, TSC2, PTEN), genes encoding for synaptic structures, CDKL5, FMR1, SHANK3) and synaptic channels (GABR, SCN2A) [8]. In this article, we will describe several genetic disorders in which ASD and epilepsy occur simultaneously.

Fragile X syndrome (FXS) is the most common X-dominant genetic disorder with intellectual disabilities that overlap with autism in approximately a third of cases. The prevalence of FXS is estimated to be about 1 of 4,000 boys [8]. Patients with FXS have a dynamic mutation in the FMR1 gene that consists in the repetition of the CGG triplet over 200 times. At these individuals is methylated the CGG repeated expansion and FMR1 gene promoter, which leads to lack of the protein product. This methylation in the Xq27.3 region leads to the constriction of the X chromosome that appears “fragile” under the microscope, where the name of the syndrome comes from [10]. In FXS laboratory mice was detected disturbance in excitatory synapses formation, reducing the expression of the GABA receptor subunits and receptor N-methyl-D-aspartate (NMDA) [3].

FXS is characterized by the phenomenon of anticipation, as was described in 1985 Sherman paradox which states that the next generations are affected with a higher frequency compared to their parents, who are carriers of mutations. In women this pathology is rare, but those showing complete mutations in the FMR1 gene can have an easier phenotype than men due to variability in X chromosome inactivation [10]. FXS is considered to be the main monogenic disorder associated with ASD, according to literature data 15-60% of patients with FXS also suffer from ASD. The physical appearance of these patients is characterized by their long and narrow face, macrocephaly, large ears, hyperflexible fingers and large testicles. Patients suffering from FXS show hyperactivity, anxiety, and socialization difficulties. It has been found that indifference and avoidance tendencies in individuals with FXS are a predictor of the ASD onset. When autism overlaps with FXS, a more pronounced language deficiency and a lower IQ are observed than in children suffering only from FXS [10].

People with FXS have a higher risk of developing seizures, which are observed in 10-20% of cases. These tend to be partial, not very frequent, and usually are not resistant to drug treatment [5]. After the investigation of a group of 13 people with FXS and seizures, abnormal electroencephalography (EEG) routes were reported in 10 patients, and at 6 of them – EEG routes showed peaks characteristic for benign childhood focal seizures. In addition, 23% of individuals with FXS, but without clinically manifested seizures, had abnormal EEG [15].Duplication of the 15q11.2-q13.1 chromosomal region, maternally inherited, is the most common chromosomal aberration among ASD patients (0.53%). The deletion of this region is characteristic for the Prader-Willi and Angelman syndromes. Patients with 15q11.2-q13.1 duplication have intellectual disorders, a high incidence of infantile spasms and in some children Lennox-Gastaut syndrome has been reported. In the duplicated 15q11.2-q13.1 region are localized several genes encoding for the GABAA receptor subunits, suggesting that the impairments of the inhibitory synapses are the basis of ASD and epilepsy pathogenesis [8].

GABAA receptors (GABAAR) are heteropentameric chloride channels, essential for maintaining inhibitory tonus. However, it was found that GABAergic transmission in early development is excitatory [15]. The transition from excitatory type to inhibitory type is associated with expression of the K+/Cl–cotransporter (KCC2), which causes a significant decrease of intracellular chloride. This excitatory/inhibitory balance is a complex process, being regulated by GABAAR activation.

Mutations in GABAAR genes (GABRA1-A6, GABRB1-B3, GABRG1-G3, GABRD) modify GABAergic functions, thus being associated with epilepsy. This occurs through two mechanisms: damaging of the channel assembly or transport through channel; or modification of receptor functions (kinetic, binding or channel closure). Numerous studies have described several single nucleotide polymorphisms (SNPs) of the GABR gene associated with ASD. The GABRB3 gene was the first to be associated with Angelman’s syndrome by analyzing the linkage disequilibrium within the 15q11-13 region. Moreover, SNPs have been identified in three GABR genes (GABRB3, GABRG3 and GABRA5) with loci on this chromosome. The alleles of GABRB3 and GABRA5 genes are associated with increased risk for ASD and epilepsy [4]. Delahanty et al. have been reported that P11S polymorphism in the GABRB3 gene is associated with absence epilepsy and autism. The GABRB3 gene encodes the chloride channel subunit β3 that serves as receptor for gamma-aminobutyric acid [16]. Thus, the identified polymorphism will lead in low synthesis of β3 subunit on the cell surface.

The deletion 2q24.2-24.3 containing the SCN2A gene was first identified in a child with ASD and intellectual disabilities. The presence of mutations in this gene is associated with cerebral hyperexcitability [18]. The SCN2A gene encodes the alpha subunit from the voltage-dependent sodium channels that are responsible for generation and spread of action potentials in neurons and muscle cells. The channels change their conformation and form another channel for selective transport of sodium ions that are transported according to the electrochemical gradient. The allelic variants of this gene are associated with seizures and ASD. It has been found that the presence of nonsense mutations leading to the formation of a premature STOP codon is associated with the most severe phenotypes [8].

In a 29-year-old Japanese woman with delayed onset of the early infantile epileptic encephalopathy, Kamiya et al. identified a de novo 304C>T mutation (transition) in the SCN2A gene, resulting in the formation of a STOP codon, causing the synthesis of the protein to cease before the first transmembrane domain. The patient presented seizures for the first time at 1 year and 7 months, after which she was diagnosed with autism. Initial EEGs did not notice any pathological changes, but spikes were observed after 3 years. Epileptic seizures persisted during childhood and were treatment resistant.

The patient had severe psychomotor retardation. Cerebral MRI showed moderate diffuse atrophy of the brain, and electrophysiological studies showed that mutant R102X protein was not functional [6]. In another clinical case, Tavassoli et al. reported a de novo mutation in intron structure at a 7-year-old boy with ASD and absence epilepsy. This mutation, namely c.476+1G>A, was located in intron number 4, and led to abnormal splicing, because enzymes were not able to recognize the GU sequence within the intron and remove it. In the cDNA sequence was found that exons 3 and 4 were removed, that changed the reading phase of the messenger RNA and resulted in a premature STOP codon formation. Clinically, the boy had a compulsive behavior, he was closing and opening the doors continuously, also, he was often clapping his hands, he did not allow being touched and had a particular interest in toys that emit sounds. The patient presented severe verbal retardation, he started to pronounce some simple words from 4 years. These reports confirm that mutations in the SCN2A gene are a risk factor for ASD, but also for epilepsy [17]. Down syndrome (DS) is one of the most common chromosomal abnormalities, caused by supernumerary chromosome 21. The incidence of trisomy 21 is about 1:700 newborns, thus it is a genetic disorder with high actuality. Although patients with DS are considered to be friendly, about 5-9% of DS individuals meet the ASD criteria [8]. It is difficult to put the diagnosis of ASD in children with DS and remains a challenge for physicians due to coexisting intellectual disabilities. Children with ASD and DS have an impaired brain function and an increased risk to develop seizures [15]. The prevalence of epilepsy in patients with DS is approximately 8-13% [8]. The clinical presentations of patients with DS and epilepsy is very heterogeneous, and have been reported cases of progressive myoclonus epilepsy associated with dementia, infantile spasm (West syndrome) and Lennox-Gastaut syndrome [5]. DS pathogenesis referred to brain development remains uncertain, but there is an increased interest for DYRK1A protein activity, which is a double-tyrosine kinase. It is autophosphorylated by interaction with serine/threonine and tyrosine residues. It has a significant role in regulating the proliferation and differentiation of cells. DYRK1A is involved in brain development and in the pathogenesis of mental retardation and Alzheimer’s disease.

The DYRK1A gene is located on chromosome 21 (21q22.13) and it is considered a candidate gene for learning disabilities associated with DS [7]. In addition, after the genome sequencing, were identified mutations in DYRK1A gene in several children with ASD and microcephaly. Tuberous Sclerosis (TS) is a multisystem disorder characterized by brain, heart, lung, kidney and skin hamartomas, caused by mutations in the TSC1 and TSC2 genes.

Their protein products, hamartin and tuberin together form a protein complex involved in regulation of the mammalian target of rapamycin (mTOR) signaling pathway. These proteins are tumor growth suppressors and regulate proliferation and differentiation of cells. TS is an autosomal dominant disorder characterized by variable expressivity and incomplete penetrance [8]. Neurological manifestations of TS are varied, including epilepsy, ASD, intellectual disabilities, and various malformations of the brain such as subependymal nodules and subependymal giant cell astrocytoma. Approximately 80-90% of patients with TS suffer from epilepsy. Types of seizures vary and are often resistant to pharmacological treatment. In future drug therapy, mTOR inhibitory substances will be of particular interest [5]. ASD are estimated to be in 20-60% of TS patients. According to some sources, intellectual deficiencies, infantile spasm and the presence of temporal lobe lesions are considered risk factors for ASD in patients with TS [18].

PTEN is a tumor suppressor gene encoding a phosphatase that stops the G1 phase of the cell cycle and inhibits the PI3K/AKT/mTOR pathway. The protein product of the PTEN gene plays a significant role in cellular energy metabolism, accelerating the ATP synthesis [8]. Mutations in this gene lead to cancerogenesis, most notably breast cancer, thyroid gland cancer, and endometrial cancer. In some children with macrocephaly and ASD, were detected mutations in the PTEN gene. Seizures have also been reported in patients with mutations in this gene, including a number of patients with focal cortical dysplasia. Epilepsy is considered to be a part of the phenotype of patients with megaloencephaly and PI3K/AKT/mTOR pathway disorder, but the exact role of mutations in PTEN gene in seizure and ASD pathogenesis is still unclear [15].

Mutations in the MECP2 gene located on chromosome Xq28 are associated with Rett Syndrome. Women are predominantly affected and the clinical picture is characterized by intellectual disabilities, microcephaly, language disorders and stereotypical hand movements [8]. The protein product of the MECP2 gene is involved in the regulation of transcription, through methylation of promoter of other genes. Patients with MECP2-related disorders present ASD, respiratory abnormalities, walking disorders and various cardiac complications. Also, among these patients, about 50-90% have convulsions. Their severity usually decrease after adolescence. Two mutations in the MECP2 gene associated with epilepsy were identified, namely p.T158M and p.R106W (T-threonine, M-methionine, R-arginine, W-tryptophan) [19]. FOXG1 is a protein involved in neurogenesis, namely telencephalon, and it is a repressor of transcription.

Mutations in the locus of this gene (14q12) were associated with Rett syndrome. Overexpression of FOXG1 in the frontal region of the brain is associated with neuroepithelial thickening, and recent data suggest that it is involved in differentiation of neural progenitor cells. Children with FOXG1 gene duplication on chromosome 14q12 frequently suffer from infantile spasms [8]. Although most are undergoing drug treatment and remission is observed with EEG normalization, patients have features from the autistic spectrum.

In contrast, children with the 14q12 deletion exhibit microcephaly, corpus callosum hypoplasia and choreiform movements. It was found that in patients with FOXG1 gene deletion, the onset of epilepsy was observed at about 22 months, and those with duplication of this region – at the age of 7 months. The mechanisms by which mutations in this gene lead to epilepsy and neurodevelopment disorders are not known at this time [2].

In patients with mutations in the MEF2C gene located on chromosome 5q14.3, severe intellectual disabilities, epilepsy and stereotypical movements were detected. Also, the phenotype presenting autistic features was described and some similarities were found with the disorders associated with the MECP2 gene [19]. The protein product of this gene (MEF2C polypeptide) is a transcription enhancer. It plays an essential role in the learning process and hippocampus-dependent memory. It is crucial for normal neuronal development and electrical activity of neocortex [8]. Patients with mutations in the MEF2C gene have a variety of clinical signs related to the evolution and type of epilepsy. Thus, 20% of the patients have infantile spasms, 33% – myoclonic epilepsy in infancy, 24% – generalized epilepsy and about 23% – without epilepsy. The reason for this clinical variability is not fully elucidated, but it was found that patients with partial deletions of MEF2C are less likely to develop epilepsy [9]. Phelan-McDermid syndrome is characterized by deletion of 22q13.3 that contains the SHANK3 gene. Phenotypic manifestations of this syndrome include: hypotonia, developmental and speech retardation, ASD, lymphedema, and various dysmorphic signs [11].

The prevalence of epilepsy in patients with 22q13.3 region deletion is unknown. Some reported a benign evolution of generalized tonic-clonic or myoclonic seizures [14]. The SHANK3 gene encodes a post-synaptic scaffold structure that regulates the expression of mGluR5 (Glutamate metabotropic receptor 5). The deletion of the SHANK1 gene and the presence of mutations in the SHANK2 gene were detected in ASD patients [13]. The CDKL5 gene encodes the synthesis of a Ser/ Thr protein kinase. The disorders associated with mutations in the CDKL5 gene are characterized by the early onset of epilepsy, infantile spasms, microcephaly, lack of verbal language and stereotypical movements of hands [8]. It has been observed that patients with mutations in the CDKL5 gene have many common features with ASD patients (abnormal social interactions, presence of repetitive movements and language impairments). However, in children with both ASD and epilepsy, the disease has more severe evolution [19]. Archer et al investigated the presence of mutations in the CDKL5 gene in a group of 73 patients and they found that 49 (67.1%) of them experienced epileptic seizures in the first 6 months of life. In 7 female patients out of 49, the presence of mutations in the CDKL5 gene were identified, which is 9.58% of the initial group.

All patients with mutations had retard in development. Additional clinical information revealed in 6 patients the presence of ASD, and a patient had suggestive clinical signs for Rett syndrome [1]. Mutations in the CASK gene located on the Xp11.4 chromosome were described in patients with severe microcephaly and pontocerebellar hypoplasia (predominantly in girls) and intellectual disabilities and oculomotor disorders (predominantly in boys). The absence of spoken language and ASD were observed predominantly in girls with microcephaly. Almost all female patients with mutations in the CASK gene have disorders in intellectual development. Patients showed stereotypical behavior and were biting themselves. There is no data on the prevalence of ASD in people with such disorders. It is difficult to diagnose ASD because of the vague clinical picture. The presence of epilepsy was observed at more than half of female patients. It is considered that the phenotype of male patients is usually less affected [5, 8]. In an 8-year-old US girl diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia, Moog et al. identified a 1639C>T transition in the CASK gene, exon 17, which resulted in the synthesis of a STOP codon (Q547X, Q-glutamine, X-STOP codon). The patient had microcephaly, seizures, severe retardation in development, hypotonia, strabismus and scoliosis [12].

The CASK gene encodes the synthesis of a dependent calcium/calmodulin serum protein kinase expressed in the brain. These proteins are scaffold associated and are located in the synapses of the brain tissue. It binds to other cell surface proteins, including the amyloid precursor protein, neurexin and sindecans, which is a bridge between the extracellular matrix and the cytoskeleton. Thus, the protein product of the CASK gene plays an important role in the normal formation and functioning of synapses, in cortical development, in the migration of neural crests, and in the formation of postsynaptic structures [8]. Thus, ASD and epilepsy often emerge concurrently, but the pathogenetic mechanisms underlying this association are still unclear. Due to the vague clinical picture, it is difficult to diagnose the presence of both disorders at time, and the small number of patients does not allow establishing definite conclusions. It has been found that low IQ is a major risk factor for ASD in children with epilepsy. ASD and epilepsy often overlap and present different degrees of psychomotor retardation, learning disabilities, intellectual and behavioral problems, all of these factors create confusion in establishing the diagnosis, which is most often a real challenge for clinicians. The presence of family history of ASD and/ or epilepsy, disembriogenetic stigma, micro-/ macrocephaly, intellectual disabilities from the start warns the doctor about the probability of a genetic disorder that may associate ASD and/or epilepsy.

The presence of characteristic phenotype and family history will require genetic testing to establish the correct diagnosis. Genetic testing strategies for both epilepsy and ASD are similar and involve karyotyping – in order to assess chromosomal aberrations, FISH test – to highlight microdeletional syndromes, ASD/ epilepsy specific gene panel testing, and when all of these are negative, will be performed whole genome sequencing. The significant cost of these tests drastically reduces the accuracy of diagnosis and treatment, which leads to a low quality of life for the patients. In this article some genes involved in transcription regulation, cell growth, function and structure of synaptic channels have been elucidated. These are just a few elements of the ASD pathogenesis associated with epilepsy. Thus, we can suggest that suspected FXS patients should be genetically tested for the presence of mutations in the FMR1 gene. In all ASD girls, the MECP2 gene need to be tested, and at all children with macrocephaly are recommended to be tested the PTEN gene. Subsequent research of the most specific ASD/epilepsy genes will allow the development of the panel of genes necessary for investigation in such patients. However, the presence of de novo mutations will always create difficulties in practice of geneticists, so continuous research and teamwork with the neurologists is the key to success in establishing of a correct diagnosis and treatment.

CONCLUSIONS

ASD and epilepsy overlap frequently, but the mechanisms underlying this interaction are vast and still unclear. The geneticist and neurologist need to work in a team and recognize the main features of ASD (deficits in social behaviors, restricted interests, repetitive behavior patterns) and epilepsy. Data from the literature suggest that polygenic and monogenic disorders, as well as de novo mutations, can cause ASD and epilepsy. Due to advances in this field, it will soon be more feasible to perform the panel gene sequencing, as well as whole genome sequencing to prevent these pathologies. Continuing research into this field will help to better understand these genetic disorders, establish an early diagnosis, introduce new therapies, and prevent the onset of ASD and epilepsy.

BIBLIOGRAPHY

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9. Le Meur N, Holder-Espinasse M, Jaillard S, et al. MEF2C haploinsuffi ciency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 2010; 47: 22-29.
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13. Peca J, Feliciano C., Ting J.T., Wang W., Wells M.F., Venkatraman T.N., Feng G., Shank3 mutant mice display autistic-like behaviours and striatal dysfunction, Nature, 472:437-442, 2011.
14. Shcheglovitov A, Shcheglovitova O, Yazawa M, et al. SHANK3 and IGF1 restore synaptic defi cits in neurons from 22q13 deletion syndrome patients. Nature. 2013; 503:267-271.
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17. Tavassoli T, Kolevzon A, Wang AT, et al. De novo SCN2A splice site mutation in a boy with autism spectrum disorder. BMC Med. Genet. 2014; 15:35.
18. Viscidi EW, Johnson AL, Spence SJ, et al. Th e association between epilepsy and autism symptoms and maladaptive behaviors in children with Autism Spectrum Disorder. Autism. 2014; 8(8): 996–1006.
19. Zweier M, Gregor A, Zweier C, et al. Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum. Mutat. 2010; 31:722-733.
20. Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J. Med. Genet. 2006; 43:729-734.
21. Brunetti-Pierri N, Paciorkowski AR, Ciccone R, Della, et al. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Europ. J. of Hum. Gen. 2011; 102–107.
22. Budimirovic DB, Kaufmann WE, What Can We Learn about Autism from Studying Fragile X Syndrome. Dev. Neurosci. 2011; 33:379–394.
23. Hernandez C, Luis EG, GABR genes, Autism Spectrum Disorder and Epilepsy. Autism Open Access, 2015; 5:2.
24. Jokiranta E, Sourander A, Suominen A, et al. Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. J. Autism. Dev. Disord. 2013; 44(10):2547–57.
25. Kamiya K, Kaneda M, Sugawara T, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J. Neurosci. 2004; 24:2690-2698.
26. Kim OH, Cho HJ, Han E, et al. Zebrafi sh knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. Molecular Autism Brain, Cognition and Behavior. 2017; 8:50.
27. Lee BH, Smith T, Paciorkowski AR, Autism Spectrum Disorder and Epilepsy: disorders with a shared biology. Epilepsy Behav. 2015; 47:191–201.
28. Le Meur N, Holder-Espinasse M, Jaillard S, et al. MEF2C haploinsuffi ciency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 2010; 47: 22-29.
29. McLennan Y, Polussa J, Tassone F, et al. Fragile X Syndrome. Current Genomics. 2011; 216-224.
30. Mei Y, Monteiro P, ZhouY, Kim JA, et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature. 2016; 530:481-484.
31. Moog U, Kutsche K, Kortum F, et al. Phenotypic spectrum associated with CASK loss-of-function mutations, J. Med. Genet., 2011; 48:741-751.
32. Peca J, Feliciano C., Ting J.T., Wang W., Wells M.F., Venkatraman T.N., Feng G., Shank3 mutant mice display autistic-like behaviours and striatal dysfunction, Nature, 472:437-442, 2011.
33. Shcheglovitov A, Shcheglovitova O, Yazawa M, et al. SHANK3 and IGF1 restore synaptic defi cits in neurons from 22q13 deletion syndrome patients. Nature. 2013; 503:267-271.
34. Spurling Jeste S, Tuchman R, Autism Spectrum Disorder and Epilepsy: Two Sides of the Same Coin, J.Child. Neurol., 2015; 30(14):1963–1971.
35. Szczałuba K, Jaszczuk I, Lejman M, et al. Paternally Inherited GABRB3 Intragenic Deletion in a Boy with Autistic Featuresand Angelman Syndrome Phenotype – Case Report and Literature Review. Autism Open Access. 2016; 6:3.
36. Tavassoli T, Kolevzon A, Wang AT, et al. De novo SCN2A splice site mutation in a boy with autism spectrum disorder. BMC Med. Genet. 2014; 15:35.
37. Viscidi EW, Johnson AL, Spence SJ, et al. Th e association between epilepsy and autism symptoms and maladaptive behaviors in children with Autism Spectrum Disorder. Autism. 2014; 8(8): 996–1006.
38. Zweier M, Gregor A, Zweier C, et al. Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum. Mutat. 2010; 31:722-733.