Clinical and Genetic Profile of Autism Spectrum Disorder–Epilepsy (ASD-E) Phenotype: Two Sides of the Same Coin!

Abstract

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 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.

The epilepsy–autism spectrum disorder phenotype in the era of molecular genetics and precision therapy

“…The concept of developmental and epileptic encephalopathy (DEE) 18 is now a crucial topic for current research in order to represent the common genetic etiologies for both early onset epilepsy and associated cognitive and or behavioral disturbances, including ASD 19 . Molecular products involved in synaptic function and plasticity (eg, genes encoding for neuroligins and neurexins), neuronal activity (eg, methyl CpG binding protein 2 [ MECP2 ] and Ubiquitin‐protein ligase E3A [ UBE3A ]), brain development (eg, ARX and FOXP2 ), ion channel function—especially sodium and calcium channels—and neurotransmission (eg, γ‐aminobutyric acid [GABA] receptor subunits 20 ) can be the common pathological process of childhood epilepsy and comorbid ASD 21 …”

“…16,17 The concept of developmental and epileptic encephalopathy (DEE) 18 is now a crucial topic for current research in order to represent the common genetic etiologies for both early onset epilepsy and associated cognitive and or behavioral disturbances, including ASD. 19 Molecular products involved in synaptic function and plasticity (eg, genes encoding for neuroligins and neurexins), neuronal activity (eg, methyl CpG binding protein 2 [MECP2] and Ubiquitin-protein ligase E3A [UBE3A]), brain development (eg, ARX and FOXP2), ion channel function-especially sodium and calcium channels-and neurotransmission (eg, γaminobutyric acid [GABA] receptor subunits 20 ) can be the common pathological process of childhood epilepsy and comorbid ASD. 21 The aim of this review is to summarize our current understanding of the causal mechanisms of the association between epilepsy and ASD, dissecting the genetic basis in patients with both conditions, and to evaluate the therapeutic approach in terms of targeted or precision medicine in infants and children with early onset epilepsy and comorbid ASD.…”

Electroclinical Phenotype-Genotype Homogeneity in Drug-Resistant “Generalized” Tonic-Clonic Seizures of Early Childhood

“…This was conducted using a clinical exome–based gene panel, wherein only nonsynonymous and splice site variants found were used for clinical interpretation as detailed previously. 7,8 Pathogenicity of the variants was determined by the American College of Medical Genetics criteria for classification. 9 This retrospective study was conducted with the approval of the Institute Ethics Committee.…”

Ketogenic and Low FODMAP Diet in Therapeutic Management of a Young Autistic Patient with Epilepsy and Dysmetabolism Poorly Responsive to Therapies: Clinical Response and Effects of Intestinal Microbiota

“…Autism spectrum disorder (ASD) is a condition that can be associated with other neurological manifestations such as epilepsy, defining a phenotypic manifestation common to various genetic disorders: ASD-epilepsy (ASD-E) [ 1 ]. This clinical manifestation can be considerably worsened by associated metabolic disorders, which can make patient management a decidedly complex task, especially when a known clinical–syndromic scenario is not readily recognizable.…”