*5.1.2.4 MEF2C-related disorder*

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

genes with and their relation to seizures and ASDs are not clarified.

*5.1.2.1 MECP2-related disorder (Rett syndrome)*

severity appears to decline after adolescence.

networks in the MeCP2-deficient brain [60].

*5.1.2.2 CDKL5-related disorder*

forms of ASD.

membrane [61].

*5.1.2.3 FOXG1-related disorders*

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

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

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

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

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

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

**16**

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 systems.

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.

## *5.1.2.5 CASK-related disorders*

CASK-related disorders are genetically defined neurodevelopmental syndromes that includes ASD, ID, ADHD as well as epilepsies. CASK encodes for calcium/ calmodulin-dependent serine protein kinase (CASK), located on chromosome Xp11.4, in which pathogenic variants underlie a range of NDDs.

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 impairment and ID.

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 the NDDs of different genetic origin.

### *5.1.2.6 Other conditions with genetic abnormalities*

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 SCN1A, SCN2.

### *5.1.3 Genomic copy number variants*

### *5.1.3.1 15q11-q13 duplication syndrome*

15q11-q13 duplication syndrome is characterized by developmental delay (DD), epilepsy, and autism.

Individuals with this syndrome have features of both PWS and AS which are caused by deletions spanning this region. Muscle hypotonia is observed in almost all individuals with Dup15q syndrome, and can be severe. ID and feeding difficulties are common. Joint hyperextensibility and drooling accompanies the hypotonia in most individual.

Seizures affect approximately 60% of children with Dup15q syndrome, with the typical onset occurring before age 5 years. A high incidence of infantile spasm with later progression to Lennox–Gastaut syndrome (LGS) has also been reported [64]. However, multiple seizure types including tonic, atonic, tonic–clonic, myoclonic, complex partial, and atypical absence have also been reported. These seizures can be intractable.

A majority of individuals with Dup15q syndrome meet the diagnostic criteria for autism. Expressive language is typically severely impacted, and may even be absent. Behavioral difficulties like ADHD, anxiety, and frustration leading to tantrums are sometimes associated in some affected individuals.

Dup15q syndrome is caused by presence of at least one extra maternally derived copy of the Prader-Willi/Angelman critical region (PWACR) within chromosome 15q11.2-q13.1. Duplications may vary in size but must contain the PWACR to be causative of dup15q syndrome. This duplicated region encodes for GABRA5, GABRB3, and GABRG3 of the GABA receptor subunit allow one to hypothesize the inhibitory-synapses mediated dysregulation as the pathogenesis of the epilepsy and ASD phenotypes found in this disorder [65].

#### *5.1.3.2 Trisomy 21 (Down syndrome)*

Trisomy 21 or Down syndrome (DS) is a genetic condition in which a child is born with an extra copy of their 21st chromosome. It is usually associated with characteristic facial features, mild to moderate ID, and few associated congenital anomalies. Previous thinking held that autism is rare in DS. But the fact is that, it is estimated that autism in individuals with Down syndrome is 10–25 times more common than in the typical population [66]. However, this diagnosis often comes much later than it would for an otherwise typical child. This might be due to the presence of associated ID. The prevalence of epilepsy in patients with DS is approximately 1–13%. Infantile spasm (IS) is most frequently found seizure and represents 4.5–47% of these children [67]. Lennox–Gastaut syndrome (LGS), reflex seizures and others such as partial and generalized tonic clonic seizures have also been described in children with DS. A high rate of EEG abnormalities has been reported in DS, even among children without epilepsy [67].

Important mechanisms of epileptogenesis in DS are due to alteration of neuronal or synaptic anatomy resulting from fewer inhibitory inter-neurons, decreased neuronal density and membrane channel dysfunction due to altered membrane potassium permeability, decreased voltage threshold for spike generation.

#### *5.1.3.3 Other copy number variants (CNVs)*

Certain pathogenic copy number variants are highly associated with ASD and epilepsy. Deletions of 15q11.2, 16p11.2, and duplication of 16p13.11 have been detected with high frequency in individuals with ASD [68].

#### *5.1.3.4 Phelan–McDermid syndrome (22q13 deletion syndrome)*

Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by deletion of 22q13.3 containing the SHANK3 gene. The genetic changes that cause PMS

**19**

rity as well as parental age at conception.

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

features.

chromosome 22 [69].

*5.2.1 Environmental fctors*

epilepsy as well.

**5.2 Environmental and epigenetic**

vary from person to person and so do the clinical features. PMS can appear de novo or be inherited from a parent (20%) who carries a related genetic defect. A broad spectrum of medical, intellectual and behavioral challenges can arise from the symptoms of PMS; however, ID at varying stages, delayed or absent speech, motor delays, low muscle tone, symptoms of ASD and epilepsy have been found to be some of the most regularly observed traits of people with PMS. Some have reported a benign course of generalized tonic–clonic or myoclonic seizures with typical EEG

Current research specifies the inability of the single functioning copy of *SHANK3* to produce sufficient Shank3 protein for normal functioning. This may be responsible for most of the neurologic symptoms associated with this disorder. A larger series found seizures to be three times more common when the de novo deletion occurred on the maternally rather than paternally inherited

Although genetic factors are clearly involved in ASD risk, they cannot fully account for all the cases. It is likely that a combination of autism-related genes and specific environmental factors might act as risk factors that triggers the development of autism. A population-based case–control study done in India found several environmental factors for example, the living conditions of family members, infection during pregnancy and preeclampsia, that could trigger development of the autism disorder [70]. Schmidt 2014 reviewed the environmental factors associated with autism, some of which may also be associated with epilepsy [71]. They reported consistent results for an association of higher maternal intake of certain supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements [71, 72]. If a mother is exposed to a relevant environmental toxin and her offspring has a genetic predisposition, the combined effect might result in development of ASD, and carries a risk of

Intrauterine infection, e.g., maternal rubella during pregnancy has long been associated with a high risk of ID, autism and epilepsy in the offspring [40]. Use of antiepileptic drug sodium valproate during pregnancy can also affect brain development of the fetus, leading to ID and autism [71]. Rybakowski et al., emphasized that factors occurring already before conception like age of the parents, family autoimmune factors and maternal metabolic factors like obesity, diabetes, hypertension play important roles [72]. Many authors reported of factors occurring during pregnancy, such as bleeding throughout the pregnancy, multiple pregnancy, intrauterine infections (TORCH, bacterial, other) and maternal hypothyroidism. Arterial hypertension during pregnancy seems important, along with pre-eclampsia and eclampsia, severe anemia, smoking during the pregnancy [71, 73], maternal stress during pregnancy etc. Among other factors preterm delivery, low birth weight, intrauterine growth retardation and hypoxic ischaemic encephalopathy are mentioned. Among neonatal factors, the most commonly mentioned are: intraventricular bleeding, hyperbilirubinemia and congenital defects. While all these are responsible for development of ASD, more research is needed to know the association of epilepsy in these cases. However, environmental risk factors do not solely cover the exposure to toxins but include all changes other than those on a DNA–level, such as maternal nutrition, infection during pregnancy, and prematu-

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

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

sometimes associated in some affected individuals.

ASD phenotypes found in this disorder [65].

in DS, even among children without epilepsy [67].

detected with high frequency in individuals with ASD [68].

*5.1.3.4 Phelan–McDermid syndrome (22q13 deletion syndrome)*

*5.1.3.3 Other copy number variants (CNVs)*

*5.1.3.2 Trisomy 21 (Down syndrome)*

most individual.

be intractable.

Individuals with this syndrome have features of both PWS and AS which are caused by deletions spanning this region. Muscle hypotonia is observed in almost all individuals with Dup15q syndrome, and can be severe. ID and feeding difficulties are common. Joint hyperextensibility and drooling accompanies the hypotonia in

Seizures affect approximately 60% of children with Dup15q syndrome, with the typical onset occurring before age 5 years. A high incidence of infantile spasm with later progression to Lennox–Gastaut syndrome (LGS) has also been reported [64]. However, multiple seizure types including tonic, atonic, tonic–clonic, myoclonic, complex partial, and atypical absence have also been reported. These seizures can

A majority of individuals with Dup15q syndrome meet the diagnostic criteria for autism. Expressive language is typically severely impacted, and may even be absent. Behavioral difficulties like ADHD, anxiety, and frustration leading to tantrums are

Dup15q syndrome is caused by presence of at least one extra maternally derived

Trisomy 21 or Down syndrome (DS) is a genetic condition in which a child is born with an extra copy of their 21st chromosome. It is usually associated with characteristic facial features, mild to moderate ID, and few associated congenital anomalies. Previous thinking held that autism is rare in DS. But the fact is that, it is estimated that autism in individuals with Down syndrome is 10–25 times more common than in the typical population [66]. However, this diagnosis often comes much later than it would for an otherwise typical child. This might be due to the presence of associated ID. The prevalence of epilepsy in patients with DS is approximately 1–13%. Infantile spasm (IS) is most frequently found seizure and represents 4.5–47% of these children [67]. Lennox–Gastaut syndrome (LGS), reflex seizures and others such as partial and generalized tonic clonic seizures have also been described in children with DS. A high rate of EEG abnormalities has been reported

Important mechanisms of epileptogenesis in DS are due to alteration of neuronal

Certain pathogenic copy number variants are highly associated with ASD and epilepsy. Deletions of 15q11.2, 16p11.2, and duplication of 16p13.11 have been

Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by deletion of 22q13.3 containing the SHANK3 gene. The genetic changes that cause PMS

or synaptic anatomy resulting from fewer inhibitory inter-neurons, decreased neuronal density and membrane channel dysfunction due to altered membrane potassium permeability, decreased voltage threshold for spike generation.

copy of the Prader-Willi/Angelman critical region (PWACR) within chromosome 15q11.2-q13.1. Duplications may vary in size but must contain the PWACR to be causative of dup15q syndrome. This duplicated region encodes for GABRA5, GABRB3, and GABRG3 of the GABA receptor subunit allow one to hypothesize the inhibitory-synapses mediated dysregulation as the pathogenesis of the epilepsy and

**18**

vary from person to person and so do the clinical features. PMS can appear de novo or be inherited from a parent (20%) who carries a related genetic defect. A broad spectrum of medical, intellectual and behavioral challenges can arise from the symptoms of PMS; however, ID at varying stages, delayed or absent speech, motor delays, low muscle tone, symptoms of ASD and epilepsy have been found to be some of the most regularly observed traits of people with PMS. Some have reported a benign course of generalized tonic–clonic or myoclonic seizures with typical EEG features.

Current research specifies the inability of the single functioning copy of *SHANK3* to produce sufficient Shank3 protein for normal functioning. This may be responsible for most of the neurologic symptoms associated with this disorder. A larger series found seizures to be three times more common when the de novo deletion occurred on the maternally rather than paternally inherited chromosome 22 [69].

## **5.2 Environmental and epigenetic**

#### *5.2.1 Environmental fctors*

Although genetic factors are clearly involved in ASD risk, they cannot fully account for all the cases. It is likely that a combination of autism-related genes and specific environmental factors might act as risk factors that triggers the development of autism. A population-based case–control study done in India found several environmental factors for example, the living conditions of family members, infection during pregnancy and preeclampsia, that could trigger development of the autism disorder [70]. Schmidt 2014 reviewed the environmental factors associated with autism, some of which may also be associated with epilepsy [71]. They reported consistent results for an association of higher maternal intake of certain supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements [71, 72]. If a mother is exposed to a relevant environmental toxin and her offspring has a genetic predisposition, the combined effect might result in development of ASD, and carries a risk of epilepsy as well.

Intrauterine infection, e.g., maternal rubella during pregnancy has long been associated with a high risk of ID, autism and epilepsy in the offspring [40]. Use of antiepileptic drug sodium valproate during pregnancy can also affect brain development of the fetus, leading to ID and autism [71]. Rybakowski et al., emphasized that factors occurring already before conception like age of the parents, family autoimmune factors and maternal metabolic factors like obesity, diabetes, hypertension play important roles [72]. Many authors reported of factors occurring during pregnancy, such as bleeding throughout the pregnancy, multiple pregnancy, intrauterine infections (TORCH, bacterial, other) and maternal hypothyroidism. Arterial hypertension during pregnancy seems important, along with pre-eclampsia and eclampsia, severe anemia, smoking during the pregnancy [71, 73], maternal stress during pregnancy etc. Among other factors preterm delivery, low birth weight, intrauterine growth retardation and hypoxic ischaemic encephalopathy are mentioned. Among neonatal factors, the most commonly mentioned are: intraventricular bleeding, hyperbilirubinemia and congenital defects. While all these are responsible for development of ASD, more research is needed to know the association of epilepsy in these cases. However, environmental risk factors do not solely cover the exposure to toxins but include all changes other than those on a DNA–level, such as maternal nutrition, infection during pregnancy, and prematurity as well as parental age at conception.

#### **5.3 Metabolic disorders associated with epilepsy in ASD**

Many metabolic disorders may be associated with ASD and epilepsy. Among them, conditions like mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism are the common associations. Many of these conditions can lead to brain damage if inadequately treated. Frye provided a strong argument for treating any underlying metabolic disorders, both for ameliorating autism and epilepsy [74]. He also added the importance of understanding metabolic and genetic biomarkers. If these disorders can be detected early in life or even prenatally, treatment can be started at the earliest possible time. Identifying metabolic defects might help using standard known or novel treatments in children with epilepsy.

These metabolic disorders have diverse classic presentations, so basing a diagnostic strategy on the search for one or two specific key symptoms is inappropriate.

However, mitochondrial disease is of particular interest in children with ASD since it is being increasingly recognized as a cause of epilepsy in individuals with ASD [74, 75].

#### *5.3.1 Disorders of energy metabolism*

Several disorders affecting energy metabolism have been documented in ASD, including mitochondrial disorders and creatine deficiency syndromes. The prevalence of mitochondrial abnormalities appears to be very high in ASD [75].

Disorders of creatine metabolism have also been reported in children with ASD and epilepsy [76].

The general presentation of children with disorders of creatine metabolism includes developmental delay, regression, ASD features, ID, receptive and expressive language disorders, and seizures.

#### *5.3.2 Disorders of cholesterol metabolism*

Smith–Lemli–Opitz syndrome (SLOS) is a congenital disorder of cholesterol metabolism caused by mutations in both DHCR7 genes. Metabolically, children with SLOS demonstrate elevated concentrations of 7-dehydrocholesterol and reduced cholesterol concentrations in the blood. Interestingly, 50%–75% of children with this disorder meet the criteria for ASD [77]. This disorder is may be associated with seizures along with their other clinical presentations [78].

#### *5.3.3 Disorders of vitamin metabolism*

These include disorders of folate, pyridoxine, biotin, and carnitine metabolism. Children with cerebral folate deficiency (CFD) are commonly diagnosed with epilepsy and/or ASD [78].

Since the folate transport system is energy-dependent, a wide variety of mitochondrial diseases and novel forms of mitochondrial dysfunction related to ASD [79] have been associated with CFD.

Pyridoxine and its active form pyridoxal-5-phosphate play major roles in metabolism of glutamic acid to GABA acting as a cofactor. Pyridoxal-5-phosphate depletion reduces glutamic acid decarboxylase activity, resulting in a reduction in GABA synthesis. In children with ASD, several studies have reported significant improvement in behavior and cognition attributable to combined therapy with magnesium and pyridoxine [80].

**21**

epilepsy in ASD.

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

*5.3.4 Disorders of* γ*-aminobutyric acid metabolism*

*5.3.5 Disorders of pyrimidine and purine metabolism*

*5.3.6 Disorders of amino acid metabolism*

manifest mitochondrial dysfunction.

children with ASD is exceedingly high.

mitochondrial disease are reported to have seizures.

with epilepsy, regardless of the underlying cause**.**

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of GABA metabolism that results from a mutation in both ALDH5A1 genes. Neurological

Children with ASD and comorbid seizures have been described to have disorders

Disorders in the metabolism of phenylalanine, have been described in children with ASD and comorbid epilepsy. Phenylketonuria is an autosomal recessive inborn error of phenylalanine metabolism resulting from deficiency of phenylalanine hydroxylase secondary to a mutation in the PAH gene on chromosome 12q23.2. Children with PKU who go untreated or who do not adhere to the diet adequately may demonstrate poor growth, poor skin pigmentation, microcephaly, seizures, spasticity, ataxia, aggressive behavior, hyperactivity, ASD features, global developmental delay, and/or severe intellectual impairment. Recently an inactivating mutation in the branched-chain ketoacid dehydrogenase kinase was described to be associated with autism, epilepsy, and intellectual disability in three families with

A recent meta-analysis found that 5% of children with ASD met the criteria for classic mitochondrial disease, while as many as 30% of children with ASD may

Prevalence of abnormal mitochondrial function in immune cells derived from

A meta-analysis found that, overall, 41% of children with ASD and documented

Mitochondrial dysfunction has also been reported in many genetic syndromes

Abnormalities in mitochondrial function can lead to abnormal development in brain circuits, resulting in both neurodevelopmental disorders and epilepsy through several mechanisms. Abnormalities in mitochondrial biomarkers have also been found in the brains of individuals with ASD. Thus, it is very likely that changes in mitochondrial function in the brain affect neural transmission and function in children with ASD. Neural synapses that are areas of high energy consumption and are especially dependent on mitochondrial function may be one of the mechanisms for developing these developmental disorders. Recent studies have suggested that

Studies have found connection between reactive oxygen species and mitochondrial dysfunction in brain tissue from individuals with ASD. This may be another mechanism where mitochondrial dysfunction can lead to the development of

associated with ASD and epilepsy. For example, in Rett syndrome, Phelan– McDermid syndrome, 15q11-q13 duplication syndrome, Angelman syndrome and Down syndrome, mitochondrial dysfunction may underlie the phenotype of ASD

oxidative stress may be involved in the development of epilepsy.

of purine and pyrimidine metabolism. Patients show a variable combination of mental retardation, epilepsy, ASD features, and cerebellar vermis hypoplasia.

manifestations may include seizures, and ASD features among others.

two children each who were products of first-cousin consanguinity.

*5.3.7 Mitochondrial dysfunction associated with epilepsy in ASD*

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

Many metabolic disorders may be associated with ASD and epilepsy. Among them, conditions like mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism are the common associations. Many of these conditions can lead to brain damage if inadequately treated. Frye provided a strong argument for treating any underlying metabolic disorders, both for ameliorating autism and epilepsy [74]. He also added the importance of understanding metabolic and genetic biomarkers. If these disorders can be detected early in life or even prenatally, treatment can be started at the earliest possible time. Identifying metabolic defects might help using standard known or novel treatments in children with

These metabolic disorders have diverse classic presentations, so basing a diagnostic strategy on the search for one or two specific key symptoms is

However, mitochondrial disease is of particular interest in children with ASD since it is being increasingly recognized as a cause of epilepsy in individuals with

Several disorders affecting energy metabolism have been documented in ASD, including mitochondrial disorders and creatine deficiency syndromes. The preva-

Disorders of creatine metabolism have also been reported in children with ASD

The general presentation of children with disorders of creatine metabolism includes developmental delay, regression, ASD features, ID, receptive and expres-

Smith–Lemli–Opitz syndrome (SLOS) is a congenital disorder of cholesterol metabolism caused by mutations in both DHCR7 genes. Metabolically, children with SLOS demonstrate elevated concentrations of 7-dehydrocholesterol and reduced cholesterol concentrations in the blood. Interestingly, 50%–75% of children with this disorder meet the criteria for ASD [77]. This disorder is may be associated with

These include disorders of folate, pyridoxine, biotin, and carnitine metabolism.

Since the folate transport system is energy-dependent, a wide variety of mitochondrial diseases and novel forms of mitochondrial dysfunction related to ASD

Children with cerebral folate deficiency (CFD) are commonly diagnosed with

Pyridoxine and its active form pyridoxal-5-phosphate play major roles in metabolism of glutamic acid to GABA acting as a cofactor. Pyridoxal-5-phosphate depletion reduces glutamic acid decarboxylase activity, resulting in a reduction in GABA synthesis. In children with ASD, several studies have reported significant improvement in behavior and cognition attributable to combined therapy with

lence of mitochondrial abnormalities appears to be very high in ASD [75].

**5.3 Metabolic disorders associated with epilepsy in ASD**

**20**

epilepsy.

inappropriate.

ASD [74, 75].

and epilepsy [76].

*5.3.1 Disorders of energy metabolism*

sive language disorders, and seizures.

*5.3.2 Disorders of cholesterol metabolism*

*5.3.3 Disorders of vitamin metabolism*

[79] have been associated with CFD.

magnesium and pyridoxine [80].

epilepsy and/or ASD [78].

seizures along with their other clinical presentations [78].
