• autism
• endophenotypes
• epilepsy

Epilepsy and EEG abnormalities are frequently associated with Autism Spectrum Disorders (ASD), defining a condition termed “Autism-Epilepsy Phenotype” (AEP). The lack of clear conclusions about this relationship reflects the complexity and heterogeneity of the disorder and its presumed multifactorial pathophysiology. This strong comorbidity also suggests that ASD, epilepsy and EEG abnormalities may share common genetic or pathophysiologic underpinnings which deserve to be further investigated. The first aim of this PhD was therefore to perform a full clinical and EEG characterization of a large sample of idiopathic ASD individuals, in order to pinpoint distinctive endophenotypic subgroups within the autism-epilepsy comorbidity. We found that seizures are associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature seems to be a phenotypic ‘‘biomarker’’ of susceptibility to EEG abnormalities or late onset epilepsy in ASD and, when concurring with macrocephaly, predisposes to early onset seizures. The EEG characterization, conducted by reviewing the awake and sleep interictal recordings of 220 individuals in our sample, either with or without history of seizures, showed a significant association between EEG abnormalities, type of onset of ASD (regressive versus non regressive) and somatic features. The second aim of this PhD was to carry out genetic studies on specific endophenotypic subgroups, through a candidate gene approach. In particular, we focused on the association of macrocephaly, ASD and epilepsy (or EEG abnormalities) and screened for mutations of two genes previously reported to be associated with autism and macrocephaly (GLIALCAM and PTEN). Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one patient with “extreme” macrocephaly, autism, intellectual disability and seizures, confirming PTEN as a major candidate gene in the ASD-macrocephaly endophenotype and suggesting that the PTEN/AKT/mTOR pathway should deserve to be investigated in autism-epilepsy comorbidity. Finally, following the report of gain-of-function mutations of KCNJ10 (Kir4.1) in epilepsy and ASD by our research group, we aimed at further defining whether defects of genes encoding astrocytic Kir channels, KCNJ10 (Kir4.1), KCNJ2 (Kir2.1), KCNJ16 (Kir5.1), underlie the disorder, and performing genotype-phenotype correlation.