**5. Etiology and pathogenesis**

The high co-occurrence of autism and epilepsy has led to the speculation that there are some common mechanisms linking these two types of disorders. But a singular *pathophysiological* mechanism responsible for the seizures and autistic phenotype is unlikely. Scientists have stressed mainly upon the genetic factors as the most common contribution for this co-occurrence followed by environmental and metabolic conditions.

Buckley and Holmes have conceptualized ASD and epilepsy both as disorders of aberrant connectivity caused by multiple genetic and environmental factors [36]. Chromosomal abnormalities [37], metabolic conditions [38, 39], environmental factors, e.g., maternal rubella during pregnancy [40], and brain damage via neonatal jaundice are examples that have been recognized as predisposing to both epilepsy and autism [41].

## **5.1 Genetic factors and syndromes**

ASD and epilepsy are both described in various genetic syndromes, which includes single and common gene mutations as well as undiscovered rare mutations and copy number variations [36, 42]. Both ASD and epilepsy can be understood as disorders of synaptic plasticity, where the same pathological mechanisms result in developmental imbalances of excitation and inhibition in the developing brain.

This genetically-derived abnormal plasticity can result in both ASD and epilepsy. Examples are fragile X, Rett syndrome, tuberous sclerosis complex (TSC), CDKL5 mutations, neuroligin mutations, "interneuronopathies" that results from X-linked aristaless-related homeobox (ARX) and Neuropilin 2 (NRP2) gene mutations. Moreover, the process of epileptogenesis and/or spontaneous seizures may result in maladaptive synaptic plasticity and produce imbalances of excitation and inhibition. All these processes might contribute to behavioral and learning difficulties. Alterations in receptors, signaling molecules or neurotropins may also result in synaptic abnormalities. Early-life seizures due to genetic conditions may be associated with both ASD and epilepsy (**Figure 1**).

Synaptic plasticity is the process whereby, the connections between 2 neurons of the synapses, get strengthened by experiencing or practicing. When these connections (i.e., synapses) are activated, AMPA receptors mediated by depolarization blocks release of magnesium and helps in entry of calcium through the NMDA receptors. This stimulates calcium dependent activation of kinases and other signaling pathways and enhances gene transcription and trafficking of receptors. This results in faster and stronger synaptic connections. This is known as long-term

#### **Figure 1.**

*Abnormal excitability and disrupted synaptic plasticity in the developing brain result in both ASD and Epilepsy. This abnormal plasticity can result from different genetic conditions. Early life seizures during early post-natal development may also alter synaptic plasticity and results in ASD. Mechanisms lie in alterations in receptors, signaling molecules or neurotrophins.*

**13**

shown in **Figure 2**.

**Figure 2.**

*SHANK3).*

*5.1.1 Single gene disorders*

*5.1.1.1 Fragile X syndrome*

*Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

potentiation and, is believed be the cellular basis of learning. In some of the genetic conditions associated with autism and epilepsy, variety of genes are disrupted upon which synaptic plasticity depends. These include cyclin-dependent kinase-like 5 (CDKL5) in West syndrome, MeCP2 in Rett syndrome, FMRP in fragile X mental retardation syndrome, mTOR in tuberous sclerosis, and reelin in lissencephaly. Knowledge of copy number variation and single gene disorders that are disturbed in these two developmental disorders include gene transcriptional regulation; cellular growth and proliferation; and synapse development, stability, and function. An overview of biological common pathway of ASD and epilepsy are

*Four important biological pathways for neuronal development and function common to autism spectrum disorder and epilepsy, that includes transcriptional regulation (FOXG1, MECP2 and MEF2C), cellular growth (PTEN, TSC1, and TSC2), synaptic channels (SCN2A), and synaptic structure (CASK, CDKL5, FMR1, and* 

Fragile X syndrome (FXS) is the most frequent form of genetic disorder causing ID and often presents with ASD and epilepsy. It occurs when a triplet repeat (CGG) expansion leads to inactivation of the FMR1 gene which is responsible for coding of FMRP- fragile X mental retardation protein. FMRP is associated with and regulates various mRNA related to development and functions of dendritic spines, axons and synapses, formation and wiring of neuronal circuits and plasticity of brain. It also regulates metabotropic glutamate receptor (mGluR)-induced long-term depression (LTD). As the "mGluR theory of fragile X" postulates that FMRP and group I metabotropic glutamate receptors (mGluRs) play oppositional roles at the level of synaptic function, loss of FMRP function and activation of mGluRs lead to excessive AMPA receptor internalization, exaggerated LTD and therefore, disrupted synaptic activity. Bianchi et al. provided compelling evidence that a voltage-gated

**Figure 2.**

*Autism Spectrum Disorder - Profile, Heterogeneity, Neurobiology and Intervention*

ated with both ASD and epilepsy (**Figure 1**).

and copy number variations [36, 42]. Both ASD and epilepsy can be understood as disorders of synaptic plasticity, where the same pathological mechanisms result in developmental imbalances of excitation and inhibition in the developing brain. This genetically-derived abnormal plasticity can result in both ASD and epilepsy. Examples are fragile X, Rett syndrome, tuberous sclerosis complex (TSC), CDKL5 mutations, neuroligin mutations, "interneuronopathies" that results from X-linked aristaless-related homeobox (ARX) and Neuropilin 2 (NRP2) gene mutations. Moreover, the process of epileptogenesis and/or spontaneous seizures may result in maladaptive synaptic plasticity and produce imbalances of excitation and inhibition. All these processes might contribute to behavioral and learning difficulties. Alterations in receptors, signaling molecules or neurotropins may also result in synaptic abnormalities. Early-life seizures due to genetic conditions may be associ-

Synaptic plasticity is the process whereby, the connections between 2 neurons of the synapses, get strengthened by experiencing or practicing. When these connections (i.e., synapses) are activated, AMPA receptors mediated by depolarization blocks release of magnesium and helps in entry of calcium through the NMDA receptors. This stimulates calcium dependent activation of kinases and other signaling pathways and enhances gene transcription and trafficking of receptors. This results in faster and stronger synaptic connections. This is known as long-term

*Abnormal excitability and disrupted synaptic plasticity in the developing brain result in both ASD and Epilepsy. This abnormal plasticity can result from different genetic conditions. Early life seizures during early post-natal development may also alter synaptic plasticity and results in ASD. Mechanisms lie in alterations in* 

**12**

**Figure 1.**

*receptors, signaling molecules or neurotrophins.*

*Four important biological pathways for neuronal development and function common to autism spectrum disorder and epilepsy, that includes transcriptional regulation (FOXG1, MECP2 and MEF2C), cellular growth (PTEN, TSC1, and TSC2), synaptic channels (SCN2A), and synaptic structure (CASK, CDKL5, FMR1, and SHANK3).*

potentiation and, is believed be the cellular basis of learning. In some of the genetic conditions associated with autism and epilepsy, variety of genes are disrupted upon which synaptic plasticity depends. These include cyclin-dependent kinase-like 5 (CDKL5) in West syndrome, MeCP2 in Rett syndrome, FMRP in fragile X mental retardation syndrome, mTOR in tuberous sclerosis, and reelin in lissencephaly.

Knowledge of copy number variation and single gene disorders that are disturbed in these two developmental disorders include gene transcriptional regulation; cellular growth and proliferation; and synapse development, stability, and function. An overview of biological common pathway of ASD and epilepsy are shown in **Figure 2**.

#### *5.1.1 Single gene disorders*

### *5.1.1.1 Fragile X syndrome*

Fragile X syndrome (FXS) is the most frequent form of genetic disorder causing ID and often presents with ASD and epilepsy. It occurs when a triplet repeat (CGG) expansion leads to inactivation of the FMR1 gene which is responsible for coding of FMRP- fragile X mental retardation protein. FMRP is associated with and regulates various mRNA related to development and functions of dendritic spines, axons and synapses, formation and wiring of neuronal circuits and plasticity of brain. It also regulates metabotropic glutamate receptor (mGluR)-induced long-term depression (LTD). As the "mGluR theory of fragile X" postulates that FMRP and group I metabotropic glutamate receptors (mGluRs) play oppositional roles at the level of synaptic function, loss of FMRP function and activation of mGluRs lead to excessive AMPA receptor internalization, exaggerated LTD and therefore, disrupted synaptic activity. Bianchi et al. provided compelling evidence that a voltage-gated

inward current, ImGluR (V), is the cellular basis for the epileptogenic behavior induced by activation of the mGluR5 receptor [43, 44]. In addition, dysregulation of glutamergic neurons in FXS can disrupt the normal actions of inhibitory GABAergic neurons, and downregulation of GABA receptor subunits and altered expression of a number of enzymes involved in the metabolism of GABA. Identification of this mechanism could contribute to hyperexcitability and epilepsy in the fragile X syndrome [45].

Physical features include prominent ears, long face, macrocephaly, and macroorchidism. The cognitive profile includes hyperactivity, anxiety, tactile defensiveness, gaze avoidance, and socialization difficulties. Epilepsy is reported in approximately 10–20% of individuals with FXS [46]. Seizure patterns in FXS typically resemble benign focal epilepsy of childhood (BFEC). Moreover, 23% of individuals with FXS without clinical seizures demonstrated centrotemporal spikes on EEG.

#### *5.1.1.2 Tuberous sclerosis complex*

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the *TSC1* or *TSC2* genes [47]. Although skin, kidney, heart, eye, and lung can be affected, involvement of the brain is associated with most significant morbidity. Central nervous system is consistently involved, with 90% of individuals affected showing structural abnormalities, and almost all having some degree of CNS clinical manifestations [48].

*TSC1* and *TSC2* genes, found in chromosomes 9 and 16, are responsible for encoding two proteins namely hamartin and tuberin respectively. They bind together to form a protein complex which in turn regulates the mammalian target of rapamycin (mTOR). The loss of function mutation in either of the two genes results in overactivity in mTOR signaling cascade with consequent disinhibition of protein synthesis and cell growth. A simplified diagram in **Figure 3** shows the activation of mTOR cascade [48]. This shows the underlying brain dysfunction resulting in susceptibility to epilepsy, autism and cognitive impairment.

Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral TSC. The number and localization of cortical tubers may account for the variability of the neurological phenotype observed in TSC patients [49]. Autism appears to be more common in infants with frontal and temporal tubers, and it has been suggested that an early dysfunction in the associative areas owing to the location of cortical tuber may be responsible for the autistic features [49]. Tuberin, the product of TSC2 gene is expressed to a large extent in frontal and temporal regions of brain- the areas that are responsible for the behavioral phenotypes of the autistic disorder [50].

Epilepsy is the most common presenting symptom in tuberous sclerosis complex. In up to 80% to 90% of persons with TSC, seizures will develop during their lifetime, with the onset most frequently in childhood. Approximately one-third develop infantile spasms. Almost all seizure types can be seen in persons with tuberous sclerosis complex, including tonic, clonic, tonic–clonic, atonic, myoclonic, atypical absence, partial, and complex partial. Only "pure" absence seizures are not observed [51].

Epilepsy in TSC is often medically intractable. The treatment of seizures in TSC is often difficult but efficacy of Vigabatrin in children has proved to have best results.

Although mutations in both TSC1 and TSC2 are associated with development of autism, TSC2 mutation has greater likelihood of developing ASD [52]. Again, early-onset and difficult to control infantile spasms, especially if there is an epileptic focus in a temporal lobe, carry an increased likelihood of getting ASD in a

**15**

*5.1.2 PTEN*

**Figure 3.**

*Lancet Neurol 2015; 14: 733–45.*

*Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

child. Because early onset of infantile spasms and associated hypsarrhythmia may have a malignant effect on brain development in infants with TSC, the importance to search for ways to anticipate the onset of infantile spasms before they become

*Schematic representation of the potential roles of mTOR overactivation in determining the neurological and neuropsychiatric manifestations of tuberous sclerosis. (A) mTOR overactivation can dysregulate the balance between neuronal excitation and inhibition, leading to epileptogenesis. (B) mTOR overactivation can alter synaptogenesis and synaptic pruning, connectivity, and long-term potentiation, leading to an increased susceptibility to autism or intellectual disability, or both. mTOR=mammalian target of rapamycin. Courtesy of: Curatolo P, Moavero Vries P J. Neurological and neuropsychiatric aspects of tuberous sclerosis complex.* 

Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease.

PTEN is a tumor suppressor gene that encodes a phosphatase affecting G1 cell cycle arrest and inhibiting the PI3K–AKT–mTOR pathway, which has roles in controlling cell growth, survival and proliferation [54, 55]. ASD and macrocephaly and have been reported in children with germline PTEN mutations. PTEN-related

apparent as seizures is very important [53].

*Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

*Autism Spectrum Disorder - Profile, Heterogeneity, Neurobiology and Intervention*

without clinical seizures demonstrated centrotemporal spikes on EEG.

in the fragile X syndrome [45].

*5.1.1.2 Tuberous sclerosis complex*

degree of CNS clinical manifestations [48].

susceptibility to epilepsy, autism and cognitive impairment.

inward current, ImGluR (V), is the cellular basis for the epileptogenic behavior induced by activation of the mGluR5 receptor [43, 44]. In addition, dysregulation of glutamergic neurons in FXS can disrupt the normal actions of inhibitory GABAergic neurons, and downregulation of GABA receptor subunits and altered expression of a number of enzymes involved in the metabolism of GABA. Identification of this mechanism could contribute to hyperexcitability and epilepsy

Physical features include prominent ears, long face, macrocephaly, and macroorchidism. The cognitive profile includes hyperactivity, anxiety, tactile defensiveness, gaze avoidance, and socialization difficulties. Epilepsy is reported in approximately 10–20% of individuals with FXS [46]. Seizure patterns in FXS typically resemble benign focal epilepsy of childhood (BFEC). Moreover, 23% of individuals with FXS

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results

from mutations in the *TSC1* or *TSC2* genes [47]. Although skin, kidney, heart, eye, and lung can be affected, involvement of the brain is associated with most significant morbidity. Central nervous system is consistently involved, with 90% of individuals affected showing structural abnormalities, and almost all having some

*TSC1* and *TSC2* genes, found in chromosomes 9 and 16, are responsible for encoding two proteins namely hamartin and tuberin respectively. They bind

together to form a protein complex which in turn regulates the mammalian target of rapamycin (mTOR). The loss of function mutation in either of the two genes results in overactivity in mTOR signaling cascade with consequent disinhibition of protein synthesis and cell growth. A simplified diagram in **Figure 3** shows the activation of mTOR cascade [48]. This shows the underlying brain dysfunction resulting in

Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral TSC. The number and localization of cortical tubers may account for the variability of the neurological phenotype observed in TSC patients [49]. Autism appears to be more common in infants with frontal and temporal tubers, and it has been suggested that an early dysfunction in the associative areas owing to the location of cortical tuber may be responsible for the autistic features [49]. Tuberin, the product of TSC2 gene is expressed to a large extent in frontal and temporal regions of brain- the areas that are responsible for the behavioral phenotypes of the autistic

Epilepsy is the most common presenting symptom in tuberous sclerosis complex. In up to 80% to 90% of persons with TSC, seizures will develop during their lifetime, with the onset most frequently in childhood. Approximately one-third develop infantile spasms. Almost all seizure types can be seen in persons with tuberous sclerosis complex, including tonic, clonic, tonic–clonic, atonic, myoclonic, atypical absence, partial, and complex partial. Only "pure" absence seizures

Epilepsy in TSC is often medically intractable. The treatment of seizures in TSC is often difficult but efficacy of Vigabatrin in children has proved to have best

Although mutations in both TSC1 and TSC2 are associated with development of autism, TSC2 mutation has greater likelihood of developing ASD [52]. Again, early-onset and difficult to control infantile spasms, especially if there is an epileptic focus in a temporal lobe, carry an increased likelihood of getting ASD in a

**14**

results.

disorder [50].

are not observed [51].

#### **Figure 3.**

*Schematic representation of the potential roles of mTOR overactivation in determining the neurological and neuropsychiatric manifestations of tuberous sclerosis. (A) mTOR overactivation can dysregulate the balance between neuronal excitation and inhibition, leading to epileptogenesis. (B) mTOR overactivation can alter synaptogenesis and synaptic pruning, connectivity, and long-term potentiation, leading to an increased susceptibility to autism or intellectual disability, or both. mTOR=mammalian target of rapamycin. Courtesy of: Curatolo P, Moavero Vries P J. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015; 14: 733–45.*

child. Because early onset of infantile spasms and associated hypsarrhythmia may have a malignant effect on brain development in infants with TSC, the importance to search for ways to anticipate the onset of infantile spasms before they become apparent as seizures is very important [53].

Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease.

#### *5.1.2 PTEN*

PTEN is a tumor suppressor gene that encodes a phosphatase affecting G1 cell cycle arrest and inhibiting the PI3K–AKT–mTOR pathway, which has roles in controlling cell growth, survival and proliferation [54, 55]. ASD and macrocephaly and have been reported in children with germline PTEN mutations. PTEN-related

ASD is, therefore, emerging as one of a group of megalencephaly disorders associated with dysregulation of the PI3K–AKT–mTOR pathway [56]. In patients with PTEN mutations, seizures have been reported, in whom focal cortical dysplasia has also been reported [57]. Epilepsy seems to be a part of the phenotype for many of the megalencephaly disorders that are associated with impaired regulation of the PI3K–AKT–mTOR pathway [56] but the exact roles of mutations in these specific genes with and their relation to seizures and ASDs are not clarified.

### *5.1.2.1 MECP2-related disorder (Rett syndrome)*

MECP2-related disorder, result of an X- linked loss- of- function mutation of MECP2, starts presenting with regression typically at 6 to 18 months of age after a period of apparently normal development. Females are predominantly affected with this disorder which is manifested with ID, postnatal microcephaly, loss of spoken language, and stereotypic hand movements. Besides autistic symptoms individuals with MECP2-related disorder may present other symptoms like respiratory rhythm abnormalities, gait impairment, and cardiac complications as well. Approximately 50–90% of children are reported to have seizures, the type of which is variable [58]. The age of onset of seizure is rarely before 2 years of age, and the severity appears to decline after adolescence.

MeCP2 acts, at least in part, as a transcriptional repressor during brain development. And it may be required to reduce aberrant transcriptional events, thus allowing the transcriptional machinery to function efficiently. In addition, it has been suggested to have a function in synaptogenesis or maintenance of neuronal function. The onset of Rett syndrome at 6 to 18 months, coincides with a period of widespread synaptogenesis in the human brain [59], which is compatible with the view that RTT could be caused by failure to form synapses appropriately. Evidence supporting a role for MeCP2 in synapse formation includes altered glutamatergic synapse numbers in vitro and in vivo and changes to neuronal morphology in some brain regions. These findings suggest that long-term changes occur in neuronal networks in the MeCP2-deficient brain [60].

#### *5.1.2.2 CDKL5-related disorder*

CDKL5-related disorders are X-linked condition, manifest early in life with epilepsy, usually infantile spasms, postnatal microcephaly and severe neurodevelopmental problems. Girls with mutations in CDKL5 display various ASD features including abnormal social interactions, repetitive movements, and absent speech. However, the developmental disability and the epilepsy phenotype associated with this condition are much greater than those typically seen in children with classical forms of ASD.

CDKL5 is a key-limiting factor in regulating synapse formation. To exert its role CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95 (key candidates in ASD pathogenesis) in glutamatergic post synapses during dendrite spine development and generates significant role in stabilizing the postsynaptic membrane [61].

#### *5.1.2.3 FOXG1-related disorders*

FOXG1-related disorders are associated with epilepsy, severe ID, absent speech with autistic features. Children may present with duplications on chromosome 14q12 or mutations of FOXG1. Children with duplication of 14q12 often present

**17**

*Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

*5.1.2.4 MEF2C-related disorder*

*5.1.2.5 CASK-related disorders*

the NDDs of different genetic origin.

*5.1.3 Genomic copy number variants*

*5.1.3.1 15q11-q13 duplication syndrome*

*5.1.2.6 Other conditions with genetic abnormalities*

systems.

ment and ID.

SCN1A, SCN2.

epilepsy, and autism.

with infantile spasm followed by ID with autistic features [62]. These patients may also present postnatal microcephaly, morphologic abnormalities of corpus callosum and choreiform movements. The mean age at epilepsy onset for children with deletions/loss-of function mutations of FOXG1 is 22 months. FOXG1 is a brain-specific

These are extremely rare genetic disorder caused by a in the *MEF2C* gene. This mutation, often a deletion, leads to the dysfunction of MEF2C protein which is essential to the proper functioning of the neurological system in addition to other

Patients with mutations and deletions of MEF2C on chromosome 5q14.3 may present with severe ID, epilepsy, and stereotypic movements. Autistic features have been recognized with some overlap with features found in MECP2-related disorder with a very small deletion encompassing the MEF2C gene [63]. This The epilepsy found in individuals with MEF2C-related disorder can be variable, with 20% presenting with infantile spasms, 33% presenting with infant-onset myoclonic epilepsy, 24% presenting with childhood onset generalized epilepsy. *MEF2C* is essential for early neurogenesis, neuronal migration and differentiation.

CASK-related disorders are genetically defined neurodevelopmental syndromes

CASK is expressed with high expression in the developing human brain and has a role in synapse formation and cortical development. Reduced CASK protein levels affect presynaptic development and decrease inhibitory pre-synapse size, which might have consequences to E/I balance in developing neural circuitries. Aberrant E/I balance, and synaptogenesis are two common biological pathways that underlies

There are few syndromes which are not always present with autism and epilepsy both. But where, genetic mutation in combination with environmental risk factors can result in the appearance of autism and epilepsy. The responsible genes are CNTNAP2, RELN, SYNGAP1, SYN1, NRXN1, BCKDK, RBFOX1 and

15q11-q13 duplication syndrome is characterized by developmental delay (DD),

that includes ASD, ID, ADHD as well as epilepsies. CASK encodes for calcium/ calmodulin-dependent serine protein kinase (CASK), located on chromosome

Mutations affecting CASK were first described in cases with microcephaly with pontine and cerebellar hypoplasia (MICPCH), followed by the identification in cases with X-linked ID (XL-ID), developmental delay (DD), and ASD. But ASD diagnosis here is difficult because of the presence of the severity of impair-

Xp11.4, in which pathogenic variants underlie a range of NDDs.

transcriptional repressor protein that regulates neurogenesis.

#### *Epilepsy: A Common Co-Morbidity in ASD DOI: http://dx.doi.org/10.5772/intechopen.96484*

with infantile spasm followed by ID with autistic features [62]. These patients may also present postnatal microcephaly, morphologic abnormalities of corpus callosum and choreiform movements. The mean age at epilepsy onset for children with deletions/loss-of function mutations of FOXG1 is 22 months. FOXG1 is a brain-specific transcriptional repressor protein that regulates neurogenesis.
