ASD

(Steffenburg, Steffenburg et al. 2003, Gabis, Pomeroy et al. 2005, Canitano 2007, Levisohn 2007,
Amiet, Gourfinkel-An et al. 2008, Combi, Redaelli et al. 2010, Amiet, Gourfinkel-An et al. 2013,
Mannion, Leader et al. 2013, Nicholl, Waters et al. 2013, van Harssel, Weckhuysen et al. 2013, Lo-
Castro and Curatolo 2014, Marchese, Conti et al. 2014, Lee, Smith et al. 2015, Besag, Aldenkamp et
al. 2016, Blackmon, Bluvstein et al. 2016, Finucane and Myers 2016, Keller, Basta et al. 2017, Bozzi,
Provenzano et al. 2018, Jay, Mitra et al. 2019, Long, Zhou et al. 2019, Pacheva, Ivanov et al. 2019, von
Stülpnagel, Hartlieb et al. 2019, Karunakaran, Menon et al. 2020, Tang, Addis et al. 2020, Eisenberg,
Subramanian et al. 2021, Peng, Zhou et al. 2021, Shillington and Capal 2021, Trivisano, De Dominicis
et al. 2022)

Amiet, C., et al. (2008). "Epilepsy in autism is associated with intellectual disability and gender:
evidence from a meta-analysis." Biol Psychiatry 64(7): 577-582.
BACKGROUND: The association between epilepsy and autism is consistently reported, with a
wide range of prevalence rates. This may be attributed to the heterogeneity of the samples with
respect to age, comorbidity, sex, and intellectual disability (ID). We aimed to compare the prevalence
of epilepsy 1) among autistic patients with ID versus autistic patients without ID and 2) among male
versus female autistic patients. METHODS: We reviewed all data available from published reports
(1963-2006) on autism and epilepsy and conducted a meta-analysis of 10 and 14 studies,
respectively, to assess the relative risk (RR) of epilepsy in autism according to ID and gender. The
pooled groups included 2112 (627 with IQ > or = 70, 1485 with IQ < 70) and 1530 (1191 male, 339
female) patients, respectively. RESULTS: There was a strong discrepancy in relative risk (RR) according
to IQ, with more autistic patients with ID having epilepsy (RR = .555; 95% confidence interval
[CI]: .42-.73; p < .001). The pooled prevalence of epilepsy was 21.5% in autistic subjects with ID
versus 8% in autistic subjects without ID. There was a strong discrepancy in RR according to sex,
favoring comorbidity of epilepsy in autistic girls (RR = .549; 95% CI: .45-.66; p < .001). The
male:female ratio of autism comorbid with epilepsy was close to 2:1 whereas the male:female ratio
of autism without epilepsy was 3.5:1. CONCLUSIONS: The results of this meta-analysis indicate that
risk for epilepsy in autism is a function of ID severity and distinguishes autism associated with
epilepsy as a subgroup of autism by its male-female ratio.

Amiet, C., et al. (2013). "Does epilepsy in multiplex autism pedigrees define a different subgroup in
terms of clinical characteristics and genetic risk?" Mol Autism 4(1): 47.
BACKGROUND: Autism spectrum disorders (ASD) and epilepsy frequently occur together.
Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of
pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate
clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to
assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-
genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and
epilepsy cosegregate within multiplex autism families. METHODS: We extracted from the Autism
Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with
relevant medical data (n = 664 children from 290 families). The sample included 478 children with
ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-
genetic risk factors, gender, and cognitive functioning as assessed by Raven's Colored Progressive
Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS). RESULTS: The prevalence of epilepsy
was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS

1
measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual
disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be
significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal
insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children
with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation
test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-
4). CONCLUSIONS: Epilepsy in multiplex autism may define a different subgroup in terms of clinical
characteristics and genetic risk.

Besag, F., et al. (2016). "Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task
Force Report): Epilepsy and Autism." 18(s1): S16-S23.
ABSTRACT A high proportion of children with epilepsy have autism spectrum disorder.
Although estimates vary, depending both on the population studied and the definitions used, a figure
of around 20% has typically been reported. Autism can have a major impact on the life of the child
and family. Despite the importance of this comorbidity and although many studies have been
performed, a full understanding of the possible links between epilepsy and autism remains elusive. In
a minority of cases, for example in the Landau-Kleffner syndrome, the autistic features can be the
result of the epilepsy itself. However, there has been a failure to demonstrate that the epilepsy itself
plays a major role in most cases. The current evidence seems to point to a common underlying
predisposing factor. The discovery of a growing number of genetic defects leading to both conditions
would support this explanation of the link.

Blackmon, K., et al. (2016). "Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased
Risk for Females." Autism Res 9(2): 311-320.
The male:female ratio in autism spectrum disorder (ASD) averages greater than 4:1 while the
male:female ratio of ASD with epilepsy averages less than 3:1. This indicates an elevated risk of
epilepsy in females with ASD; yet, it is unknown whether phenotypic features of epilepsy and ASD
differ between males and females with this comorbidity. The goal of this study is to investigate sex
differences in phenotypic features of epilepsy and ASD in a prospective sample of 130 children and
young adults with an initial ASD diagnosis and subsequent epilepsy diagnosis. All participants were
characterized by standardized diagnostic inventories, parent/caregiver completed questionnaires,
and medical/academic record review. Diagnostic classifications of epilepsy, ASD, and intellectual
disability were performed by board certified neurologists and a pediatric neuropsychologist. Results
demonstrated a lower male:female ratio (1.8:1) in individuals with ASD and treatment-resistant
epilepsy relative to those with ASD and treatment-responsive epilepsy (4.9:1), indicating a higher risk
of treatment-resistant epilepsy in females. Mild neuroimaging abnormalities were more common in
females than males and this was associated with increased risk of treatment-resistance. In contrast,
ASD symptom severity was lower in females compared with males. Findings distinguish females with
ASD and epilepsy as a distinct subgroup at higher risk for a more severe epilepsy phenotype in the
context of a less severe ASD phenotype. Increased risk of anti-epileptic treatment resistance in
females with ASD and epilepsy suggests that comprehensive genetic, imaging, and neurologic
screening and enhanced treatment monitoring may be indicated for this subgroup. Autism Res 2016,
9: 311-320. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Bozzi, Y., et al. (2018). "Neurobiological bases of autism-epilepsy comorbidity: a focus on

excitation/inhibition imbalance." Eur J Neurosci 47(6): 534-548.

2
 Autism spectrum disorders (ASD) and epilepsy are common neurological diseases of
childhood, with an estimated incidence of approximately 0.5-1% of the worldwide population.
Several genetic, neuroimaging and neuropathological studies clearly showed that both ASD and
epilepsy have developmental origins and a substantial degree of heritability. Most importantly, ASD
and epilepsy frequently coexist in the same individual, suggesting a common neurodevelopmental
basis for these disorders. Genome-wide association studies recently allowed for the identification of
a substantial number of genes involved in ASD and epilepsy, some of which are mutated in
syndromes presenting both ASD and epilepsy clinical features. At the cellular level, both preclinical
and clinical studies indicate that the different genetic causes of ASD and epilepsy may converge to
perturb the excitation/inhibition (E/I) balance, due to the dysfunction of excitatory and inhibitory
circuits in various brain regions. Metabolic and immune dysfunctions, as well as environmental
causes also contribute to ASD pathogenesis. Thus, an E/I imbalance resulting from
neurodevelopmental deficits of multiple origins might represent a common pathogenic mechanism
for both diseases. Here, we will review the most significant studies supporting these hypotheses. A
deeper understanding of the molecular and cellular determinants of autism-epilepsy comorbidity will
pave the way to the development of novel therapeutic strategies.

Canitano, R. (2007). "Epilepsy in autism spectrum disorders." Eur Child Adolesc Psychiatry 16(1): 61-
66.
Epilepsy is quite common in autism spectrum disorders, and it is increasingly recognized as an
additional clinical problem that must be dealt with. The rate of comorbidity varies, depending upon
the age and type of disorder, and currently the conservative estimate of comorbidity cases is 20-25%
of the whole spectrum. Major risk factors for seizure occurrence are mental retardation and
additional neurological disorders, as well as some specific associated medical conditions. Autism with
regression has been reported in one-third of children with previously normal or nearly normal
development. In an unknown proportion of these subjects, epileptic disorders are concomitant,
leading to so-called autistic epileptiform regression. Furthermore, epileptiform abnormalities without
seizures are frequent in this population and their role in the development of the nuclear disturbances
of autism is controversial. The therapeutic approaches to epilepsy in autism are conventional
treatments, yet when seizures are not evident, there is still controversy. Anticonvulsant medications
could also potentially interfere with mood and behavioral disturbances frequently observed in ASD.
The current understanding of the association between epilepsy and autism is still limited, but from a
clinical point of view this association should not be overlooked, and it should be routinely
investigated.

Combi, R., et al. (2010). "Clinical and genetic evaluation of a family showing both autism and
epilepsy." Brain Res Bull 82(1-2): 25-28.
Autism is a strong genetic disorder, with an estimated heritability greater than 90%.
Nonetheless, its specific genetic aetiology remains largely unknown. Autism is associated with
epilepsy in early childhood and epilepsy occurs in 10-30% of individuals with autism. Here we report
the case of a woman affected by a severe epileptic disorder with an onset at 14 years old. She is
affected by a cryptogenetic focal epilepsy with complex partial (psychomotor) and secondarily
generalized tonic-clonic seizures, which are drug resistant. The woman is married to a healthy man
and has six children: two girls are healthy, a girl and two boys are affected by autism while one boy
shows partial seizures. The three children with autism show moderate mental retardation and an EEG
with no epileptiform alterations. The child with epileptic seizures shows an asymmetric EEG that is

3
not necessarily pathological. In this family, no chromosomal rearrangements were detected by
means of classical cytogenetic analyses. The presence of FRAXA alterations and of microdeletions of
the 15q11-q13 chromosome region were also excluded. A genome-wide linkage analysis using
microsatellite markers revealed several chromosome regions as possible susceptibility loci.

Eisenberg, C., et al. (2021). "Reduced hippocampal inhibition and enhanced autism-epilepsy
comorbidity in mice lacking neuropilin 2." Translational Psychiatry 11(1): 537.
The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit
development by regulating numerous crucial neuronal processes, including the maturation of
synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the
neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD).
Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order
to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of
interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice
lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/−
mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1.
Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane
potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-
type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and
amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient
mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with
significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+
animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility
demonstrated by reward-based reversal learning, a task associated with hippocampal circuit
function. Together these data demonstrate a broad reduction in interneuron subtypes and
compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure
susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

Finucane, B. and S. M. Myers (2016). "Genetic Counseling for Autism Spectrum Disorder in an
Evolving Theoretical Landscape." Curr Genet Med Rep 4: 147-153.
PURPOSE OF REVIEW: Psychiatry is steadily moving toward a new conceptualization of brain
disorders that blurs long-held diagnostic distinctions among neurodevelopmental and psychiatric
conditions, including autism. Genomic discoveries are driving these changing perceptions, yet there
has so far been minimal impact on traditional genetic counseling practices that continue to view
autism through the lens of a dichotomous, all-or-none risk model. RECENT FINDINGS: High rates of
comorbidity exist across autism spectrum disorder, schizophrenia, intellectual disability, and other
brain-based disorders. Recent epidemiological studies have shown that co-occurrence of
neurodevelopmental and psychiatric disorders is the rule, rather than the exception, in affected
individuals and within families. Moreover, studies of chromosomal microarray analysis and whole
exome sequencing have now detected many of the same pathogenic copy number and sequence-
level variants across cohorts with different clinical presentations. SUMMARY: Going forward, the
genetic counseling field will need to significantly adapt its approaches to pedigree interpretation,
variant analysis, and patient education to more precisely describe both the chance and the nature of
autism recurrence in terms of a continuum of brain dysfunction. These efforts will have implications
for multiple practice areas and require philosophical changes for experienced practitioners and for
the training of new genetic counselors. Resetting entrenched dichotomous notions about autism and

4
other brain-based manifestations of genetic conditions will require a strategic educational effort on
the part of the genetic counseling profession.

Gabis, L., et al. (2005). "Autism and epilepsy: cause, consequence, comorbidity, or coincidence?"
Epilepsy Behav 7(4): 652-656.
Autism is associated with epilepsy in early childhood, with evidence suggesting that
individuals with both autism and more severe cognitive impairment are at higher risk. However, the
incidence of an abnormal electroencephalogram and/or epilepsy in the full range of pervasive
developmental disorders (PDDs) is not well defined. This naturalistic study addresses the incidence of
epilepsy and electroencephalographic abnormalities in children with PDDs. The clinical history and
electroencephalograms of 56 children diagnosed with PDD-not otherwise specified, autism, or
Asperger syndrome were retrospectively reviewed. Forty percent of children with autism were
diagnosed with epilepsy. Abnormal electroencephalograms and epilepsy occurred at significantly
higher rates in children in the more impaired range of the autism spectrum (P<0.05). These findings
suggest that the use of neurological investigative techniques such as electroencephalography should
be a consequence of careful clinical evaluation and should be considered routinely during evaluation
of more impaired individuals.

Jay, K., et al. (2019). "Identification of a de novo FOXP1 mutation and incidental discovery of
inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy." Mol
Genet Genomic Med 7(7): e00751.
BACKGROUND: Autism spectrum disorder is commonly co-diagnosed intellectual disability,
language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the
complex genetic nature of ASD. METHODS: We present a next-generation sequencing-based case
study with both de novo and inherited genetic variants and highlight the impact of structural variants
on post-translational regulation of protein expression. Since management of symptoms has
classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to
determine possible drug/gene interactions. RESULTS: A de novo variant was identified within the
FOXP1 3' untranslated regulatory region using exome sequencing. Additionally, inherited variants
that likely contribute to the current and potential future traits were identified within the COMT,
SLC6A4, CYP2C19, and CYP2D6 genes. CONCLUSION: This study aims to elucidate how a collection of
variant genotypes could potentially impact neural development resulting in a unique phenotype
including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the
interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in
conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic
treatments for ASD-related symptoms.

Karunakaran, S., et al. (2020). "Clinical and Genetic Profile of Autism Spectrum Disorder-Epilepsy
(ASD-E) Phenotype: Two Sides of the Same Coin!" Clin EEG Neurosci 51(6): 390-398.
The clinical phenotype of autism spectrum disorder and epilepsy (ASD-E) is a common
neurological presentation in various genetic disorders, irrespective of the underlying
pathophysiological mechanisms. Here we describe the demographic and clinical profiles, coexistent
neurological conditions, type of seizures, epilepsy syndrome, and EEG findings in 11 patients with
ASD-E phenotype with proven genetic etiology. The commonest genetic abnormality noted was
CDKL5 mutation (3), MECP2 mutation (2), and 1p36 deletion (2). The median age of onset of clinical
seizures was 6 months (range, 10 days to 11 years). The most common seizure type was focal onset

5
seizures with impaired awareness, observed in 7 (63.6%) patients followed by epileptic spasms in 4
(30.8%), generalized tonic-clonic and atonic seizures in 3 (27.3%) patients each and tonic seizures in 2
(18.2%) patients and myoclonic seizures in 1 (9.1%) patient. Focal and multifocal interictal
epileptiform abnormalities were seen in 6 (54.6%) and 5 (45.5%) patients, respectively. Epileptic
encephalopathy and focal epilepsy were seen in 7 (63.6%) and 4 (36.4%) patients, respectively. The
diagnostic yield of genetic testing was 44% (11 of 25 patients) and when variants of unknown
significance and metabolic defects were included, the yield increased to 60% (15 of 25 patients). We
conclude that in patients with ASD-E phenotype with an underlying genetic basis, the clinical seizure
type, epilepsy syndrome, and EEG patterns are variable. Next-generation exome sequencing and
chromosomal microarray need to be considered in clinical practice as part of evaluation of children
with ASD-E phenotype.

Keller, R., et al. (2017). "Autism, epilepsy, and synaptopathies: a not rare association." Neurological
Sciences 38(8): 1353-1361.
Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in
childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted
interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and
environmental factors have been considered as potential risk factors for their onset. ASD are often
associated with neurological conditions: the co-occurrence of epilepsy is well documented and there
is also evidence of a higher prevalence of EEG abnormalities with 4–86% of individuals with ASD
presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people
with ASD may be determined by several structural alterations, genetic conditions, or metabolic
dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this
article is to discuss precisely such latter cause of the autism–epilepsy association, focusing specifically
on those “synaptic genes,” whose mutation predisposes to both the diseases.

Lee, B. H., et al. (2015). "Autism spectrum disorder and epilepsy: Disorders with a shared biology."
Epilepsy Behav 47: 191-201.
There is an increasing recognition of clinical overlap in patients presenting with epilepsy and
autism spectrum disorder (ASD), and a great deal of new information regarding the genetic causes of
both disorders is available. Several biological pathways appear to be involved in both disease
processes, including gene transcription regulation, cellular growth, synaptic channel function, and
maintenance of synaptic structure. We review several genetic disorders where ASD and epilepsy
frequently co-occur, and we discuss the screening tools available for practicing neurologists and
epileptologists to help determine which patients should be referred for formal ASD diagnostic
evaluation. Finally, we make recommendations regarding the workflow of genetic diagnostic testing
available for children with both ASD and epilepsy. This article is part of a Special Issue entitled
"Autism and Epilepsy".

Levisohn, P. M. (2007). "The autism-epilepsy connection." Epilepsia 48 Suppl 9: 33-35.

The high prevalence of epilepsy in children with autism supports a neurobiologic etiology for
autism. It remains unclear whether seizures and epileptiform activity on the EEG are causative or
comorbid. It is also uncertain if focal epileptiform EEG abnormalities may be associated with stable
cognitive impairment. Even less clear is whether these EEG abnormalities can result in the
combination of language and social dysfunction seen in autistic spectrum disorders.

6
Lo-Castro, A. and P. Curatolo (2014). "Epilepsy associated with autism and attention deficit
hyperactivity disorder: is there a genetic link?" Brain Dev 36(3): 185-193.
Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD)
are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of
an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous
pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain
development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare
clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an
increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are
involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32,
ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA
methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and
Fragile X syndrome may serve as models for understanding the common pathogenic pathways
leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new
biologically focused treatment options.

Long, S., et al. (2019). "The Clinical and Genetic Features of Co-occurring Epilepsy and Autism
Spectrum Disorder in Chinese Children." Front Neurol 10: 505.
There is still no comprehensive description of the general population regarding clinical
features and genetic etiology for co-occurring epilepsy and autism spectrum disorder (ASD) in
Chinese children. This study was a retrospective study of children diagnosed with epilepsy and ASD
from January 1st, 2015, to May 1st, 2018, at the Children's Hospital of Fudan University. A total of
117 patients met the inclusion criteria, and 103 subjects were eligible. Among them, 88 underwent
genetic testing, and 47 children (53.4%) were identified as having pathogenic or likely pathogenic
variants: 39 had single gene mutations (83.0%, 39/47), and eight had copy number variants (17.0%,
8/47), with SCN1A (14.9%, 7/47) and MECP2 (10.6%, 5/47) gene mutations being the most common.
Mutations in other genes encoding voltage-gated ion channels including SCN2A, CACNA1A,
CACNA1H, CACNA1D, and KCNQ2 were also common, but the number of individual cases for each
gene was small. Epilepsy syndrome and epilepsy-associated syndrome were more common (P =
0.014), and higher rates of poly-therapy (P = 0.01) were used in the positive genetic test group than
in the negative group. There were no statistically significant differences in drug-refractory epilepsy,
ASD severity, or intellectual disability between the positive genetic test group and the negative
genetic group. These data strongly indicate the need for ASD screening in children with epilepsy with
voltage-gated ion channel gene variants for better diagnosis and early intervention.

Mannion, A., et al. (2013). "An investigation of comorbid psychological disorders, sleep problems,
gastrointestinal symptoms and epilepsy in children and adolescents with Autism Spectrum Disorder."
Research in Autism Spectrum Disorders 7(1): 35-42.
The current study investigated comorbidity in eighty-nine children and adolescents with
Autism Spectrum Disorder in Ireland. Comorbidity is the presence of one or more disorders in
addition to a primary disorder. The prevalence of comorbid psychological disorders, behaviours
associated with comorbid psychopathology, epilepsy, gastrointestinal symptoms and sleep problems
were examined. Age, gender, level of intellectual disability, presence of epilepsy, attention
deficit/hyperactivity disorder (AD/HD) and an anxiety disorder were determined using a self-
constructed demographic questionnaire. The Autism Spectrum Disorder-Comorbidity-Child (ASD-CC)
was administered to informants to assess symptoms of psychopathology and emotional difficulties.

7
The Children's Sleep Habits Questionnaire (CSHQ) and Gastrointestinal Symptom Inventory were
administered to assess sleep problems and gastrointestinal symptoms respectively. Forty-six percent
of participants had a comorbid disorder, with this number increasing to 78.7% if intellectual disability
was included. The prevalence of epilepsy was 10.1%, AD/HD was 18% and an anxiety disorder was
15.7%. Prevalence rates of gastrointestinal symptoms and sleep problems are discussed in the study.

Marchese, M., et al. (2014). "Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not
GLIALCAM, genetic screening." BMC Med Genet 15: 26.
BACKGROUND: With a complex and extremely high clinical and genetic heterogeneity, autism
spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes.
Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have
strong genetic background. Macrocephaly also represents a well-known endophenotype in
subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in
early development and predisposing to the disorder. We attempted to estimate the association of
gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP)
and cranial overgrowth, analyzing two genes previously reported to be associated with autism and
macrocephaly. METHODS: We analyzed the coding sequences and exon-intron boundaries of
GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum
Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the
PTEN gene in the subsample with macrocephaly. RESULTS: Among 81 individuals with ASD, 31 had
concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile ("extreme"
macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide
variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation
in one case with "extreme" macrocephaly, autism, intellectual disability and seizures. CONCLUSIONS:
We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly
comorbidity. The identification of a novel frameshift variant of PTEN in a patient with "extreme"
macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in
the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also
suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in
autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address
genetic studies and establish actual causative correlations in autism-epilepsy.

Nicholl, J., et al. (2013). "Epilepsy with cognitive deficit and autism spectrum disorders: prospective
diagnosis by array CGH." Am J Med Genet B Neuropsychiatr Genet 162b(1): 24-35.
The clinical significance of chromosomal microdeletions and microduplications was predicted
based on their gene content, de novo or familial inheritance and accumulated knowledge recorded
on public databases. A patient group comprised of 247 cases with epilepsy and its common co-
morbidities of developmental delay, intellectual disability, autism spectrum disorders, and congenital
abnormalities was reviewed prospectively in a diagnostic setting using a standardized oligo-array CGH
platform. Seventy-three (29.6%) had copy number variations (CNVs) and of these 73 cases, 27
(37.0%) had CNVs that were likely causative. These 27 cases comprised 10.9% of the 247 cases
reviewed. The range of pathogenic CNVs associated with seizures was consistent with the existence
of many genetic determinants for epilepsy.

Pacheva, I., et al. (2019). "Epilepsy in Children with Autistic Spectrum Disorder." Children (Basel) 6(2).

8
 The comorbidity of autistic spectrum disorder (ASD) and epilepsy has been widely discussed
but many questions still remain unanswered. The aim of this study was to establish the occurrence of
epilepsy among children with ASD to define the type of epileptic seizures and syndromes, the age of
onset of epilepsy, EEG abnormalities, the used antiepileptic drugs and the therapeutic responses for
seizures and autistic behavior, as well as to find some correlations between epilepsy and gender,
etiology and intellectual disability (ID). A retrospective study of medical files of 59 patients (aged
1⁻18 years) with ASD during a 5-year period was performed. ASD diagnosis was based on the DSM-5
diagnostic criteria. The patients were examined with a detailed medical history, physical and
neurological examination, as well as some additional functional, imaging, laboratory and genetic
investigations ASD etiology was syndromic in 9, probable syndromic in 9, and idiopathic in 41
children. ID was established in 90% of ASD children, and epilepsy in 44.4%. The onset of epilepsy
prevailed before 7 years of age. The most common seizure types were focal with or without
secondary generalization (53.4%). Focal epileptiform EEG abnormalities prevailed. Therapeutic
response to seizures was good: 58% were seizure-free, while 27% had >50% seizure reduction but no
improvement in autistic behavior. There was no correlation between epilepsy and either occurrence
or degree of ID. There was a correlation between the frequency of epileptic seizures and the degree
of ID. There was no significant difference among epilepsy rates in different etiologic, gender, and ID
groups, probably because of the high percentage of ID and because this was a hospital-based study.
Our study showed a significant percentage of epilepsy in ASD population and more than 1/4 were of
symptomatic etiology. Those could be managed with specific treatments based on the
pathophysiology of the gene defect.

Peng, J., et al. (2021). "Multiplex gene and phenotype network to characterize shared genetic
pathways of epilepsy and autism." Sci Rep 11(1): 952.
It is well established that epilepsy and autism spectrum disorder (ASD) commonly co-occur;
however, the underlying biological mechanisms of the co-occurence from their genetic susceptibility
are not well understood. Our aim in this study is to characterize genetic modules of subgroups of
epilepsy and autism genes that have similar phenotypic manifestations and biological functions. We
first integrate a large number of expert-compiled and well-established epilepsy- and ASD-associated
genes in a multiplex network, where one layer is connected through protein-protein interaction (PPI)
and the other layer through gene-phenotype associations. We identify two modules in the multiplex
network, which are significantly enriched in genes associated with both epilepsy and autism as well
as genes highly expressed in brain tissues. We find that the first module, which represents the Gene
Ontology category of ion transmembrane transport, is more epilepsy-focused, while the second
module, representing synaptic signaling, is more ASD-focused. However, because of their enrichment
in common genes and association with both epilepsy and ASD phenotypes, these modules point to
genetic etiologies and biological processes shared between specific subtypes of epilepsy and ASD.
Finally, we use our analysis to prioritize new candidate genes for epilepsy (i.e. ANK2, CACNA1E,
CACNA2D3, GRIA2, DLG4) for further validation. The analytical approaches in our study can be
applied to similar studies in the future to investigate the genetic connections between different
human diseases.

Shillington, A. and J. K. Capal (2021). "Genetic testing in patients with nonsyndromic autism spectrum
disorder and EEG abnormalities with or without epilepsy: Is exome trio-based testing the best clinical
approach?" Epilepsy Behav 114(Pt A): 107564.

9
 OBJECTIVES: The association between autism spectrum disorder (ASD) and epilepsy is well-
known. Abnormalities on electroencephalography (EEG) studies have been reported in patients with
ASD without a history of seizures, and these patients have lower functional scores on adaptive
measures than patients with ASD with normal EEG studies. The purpose of the study was to evaluate
the genetic test approach in children with ASD and abnormal EEGs. METHODS: Data were collected
from medical records at Cincinnati Children's Hospital Medical Center (CCHMC) of a previously
published cohort of patients with well-characterized ASD based on evaluation by Developmental
Pediatrics. Patients were subdivided into two groups: ASD without epilepsy, but with abnormal EEG
results, and ASD with epilepsy. EEG data were abstracted from reports. In this follow-up study, we
analyzed genetic testing data, namely the proportion of this cohort that received genetic testing, and
the specific type of genetic testing that was ordered to analyze if there were any differences between
groups. RESULTS: Analysis was performed on 173 patients with ASD. Ninety-five patients had a
diagnosis of epilepsy. Seventy-eight patients did not have a diagnosis of epilepsy but did have
abnormal EEGs. In both groups, approximately three quarters of all subjects received routine
neurodevelopmental genetic testing (77% versus 72% p = 0.15) without significant differences
between groups. The ASD + epilepsy group was more likely to receive additional second-tier genetic
testing outside of a routine neurodevelopmental workup (35% versus 15% p = 0.007). The
ASD + epilepsy group was more likely to receive phenotype specific panels, most often an epilepsy
gene panel of less than 250 genes (15% versus 3% p = 0.008). However, the ASD + epilepsy group was
less likely to receive a genetic diagnosis from testing than the ASD + abnormal EEG group (9% versus
33%, p = 0.047). CONCLUSIONS: Patients with ASD along with a formal epilepsy diagnosis received
more genetic testing; but had an overall lower diagnostic rate than patients with ASD with abnormal
EEGs but without a formal epilepsy diagnosis. Patients in this cohort without a diagnosis of epilepsy
were more likely to get broad trio-based exome testing instead of targeted epilepsy gene panel
testing. A higher diagnostic rate was found in patients when a broad genetic test strategy was
implemented.

Steffenburg, S., et al. (2003). "Autism spectrum disorders in children with active epilepsy and learning
disability: comorbidity, pre- and perinatal background, and seizure characteristics." Dev Med Child
Neurol 45(11): 724-730.
The aim of this study was to examine the comorbidity pattern, seizure characteristics, and
aetiology in a representative group of children with a combination of autism spectrum disorder
(ASD), active epilepsy, and learning disability. Ninety children (47 males, 43 females; mean age 11
years 2 months, range 8 to 16 years at the time of psychiatric examination) with active epilepsy and
learning disability, identified in a population-based study in Göteborg, Sweden, were subdivided into
those with and those without ASD and compared with respect to aetiology, additional
neuroimpairments, and seizure characteristics. In addition, the cohorts were examined for trends of
prevalence over a period of time. Results indicated that established aetiology was much more often
present in the prenatal period than in the peri- or postnatal periods in the ASD group. Cerebral palsy
and visual impairment were under-represented in the ASD group. Partial seizures tended to be more
common and generalized seizures less common in the ASD group compared with the non-ASD group.
Seizure onset was later in the ASD group. Many of the significant differences were accounted for by a
large group of psychiatrically unclassifiable participants in the non-ASD group. There was no trend
towards an increase of affected children over the 12-year period. There was no increase in the
prevalence of active epilepsy and learning disability nor in the rate of autism with active epilepsy and
learning disability in children born between 1981 and 1986 compared with those born from 1976 to

10
1980, indicating no statistical association with the general measles-mumps-rubella vaccination
introduced in the early 1980s.

Tang, S., et al. (2020). "Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures."
Epilepsia 61(5): 995-1007.
OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and
identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic
seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual
disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized
neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered
on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101
patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-
72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic
in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed
intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In
addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity
symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously
published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and
SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified
three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is
associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and
we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings
suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Trivisano, M., et al. (2022). "MED13 mutation: A novel cause of developmental and epileptic
encephalopathy with infantile spasms." Seizure 101: 211-217.
PURPOSE: Mutations in the MED13 gene are reported in the literature in association with
clinically variable, neurodevelopmental disorders, which are characterized by mild-to-severe
intellectual disability, autism spectrum disorder, attention deficit/hyperactivity disorder, epilepsy,
ocular or skeletal abnormalities, congenital cardiac defects, and facial dysmorphisms. Here, we
report a patient with an epileptic phenotype carrying a novel missense mutation characterized by
developmental and epileptic encephalopathy with infantile spasms. METHODS: Through trio-based
WES, we identified a novel de novo heterozygous missense variant c.2501A>G in the MED13 gene.
We reviewed all medical charts of the present patient and reviewed all previously reported cases
with pathogenic variants of MED13. RESULTS: This study involves a 24-month-old boy with epilepsy
onset at the age of 3 months with drug-resistant focal seizures followed by infantile spasms at the
age of 10 months. He had a severe, developmental delay along with microcephaly and dysmorphic
features. From a literature review, it emerged that epilepsy is described in only one out of nineteen
of previously reported patients with a phenotype of generalized, drug-resistant epilepsy with
myoclonic-atonic seizures. Microcephaly, developmental delay, hypotonia, corpus callosum
abnormalities, deafness, and retinal atrophy were common features in the previously described
cases. CONCLUSION: This case expands the genetic landscape of infantile spasms as well as the
phenotype of MED13-related disorders adding the electroclinical features of early-onset
developmental and epileptic encephalopathy with infantile spasms to the previously described,
generalized epilepsy with myoclonic-atonic seizures.

11
van Harssel, J. J., et al. (2013). "Clinical and genetic aspects of PCDH19-related epilepsy syndromes
and the possible role of PCDH19 mutations in males with autism spectrum disorders." Neurogenetics
14(1): 23-34.
Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has
a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by
fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are
reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore,
this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in
Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering
from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and
genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR
reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of
clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but
epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features.
Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural
disturbances are common. Fifty percent of all mutations are missense mutations, located in the
extracellular domains only. Truncating mutations have been identified in all protein domains. One
ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that
ASD in males can be associated with PCDH19 mutations.

von Stülpnagel, C., et al. (2019). "Chewing induced reflex seizures (“eating epilepsy”) and eye closure
sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature
and report of 8 cases." Seizure 65: 131-137.
Purpose Heterozygous SYNGAP1 gene mutations have been associated with several forms of
idiopathic generalized epilepsy, autism spectrum disorders and delay of psychomotor development.
We report eight patients with a SYNGAP1 mutation and chewing/eating induced reflex seizures as
new phenotype and compare them to other patients with eating epilepsy and genetic mutations.
Methods Presentation of clinical and anamnestic features and retrospective analysis of Video-EEG
data of a 4 year old index patient with SYNGAP1 mutation and chewing /eating induced seizures.
Clinical and anamnestic features and home videos of seven additional patients (4 female; age: 4–14 
years) with SYNGAP1 mutation and eating induced reflex seizures were compared. Results All reflex
seizures of the index patient showed similar focal EEG pattern with 1–5 seconds high amplitude,
irregular 3/sec spike-wave complexes with initiation from left temporo-occipital, right temporo-
occipital or bi- occipital / temporo-occipital regions. Eyelid myoclonia, the most common seizure type
in all 8 patients, were typically initiated by eating or other simple orofacial stimuli. In the index
patient eye closure preceded eating induced-eyelid myoclonia in 30/38 seizures. Conclusion The
main clinical features of our patient (i.e. intellectual disability, epilepsy, autistic features) are
compatible with previous reports on patients with SYNGAP1 mutations. This is the first complete
description of eating induced seizures in association with SYNGAP1 mutations. Whether eye closure
sensitivity (ECS) represents an independent reflex epileptic trait, as seen in other patients with
idiopathic “generalized” epilepsies (IGE), or eye closure is part of a complex trigger mechanism in
SYNGAP1 patients’ remains to be elucidated.

12