An investigational study of autism features, seizure characteristics and SCN1A gene in Dravet syndrome

Dravet syndrome (DS) is a rare epileptic encephalopathy characterized by prolonged febrile and afebrile generalized or unilateral clonic epileptic seizures with infantile onset in a previously normal child. Subsequently, multiple seizure types including myoclonic, focal, and atypical absence seizures emerge between one and four years of age, with slowing of development and cognitive skills, and often with the appearance of behavioural disorders. Individual characteristics (seizure types, progression of epilepsy, developmental skills, genetic mutation, comorbidities and long-term outcome) are variable across DS patients. Autism Spectrum Disorder (ASD) is a group of complex neurodevelopmental disorders affecting individuals along a continuum of severity of communication, social interaction and repetitive behaviours. Currently, there is a lack of research on the possible comorbidity of ASD in the majority of epileptic syndromes, and limited data concerning the prevalence and relationship of ASD with DS. The aim of this thesis is to analyze the seizure presentation and clinical characteristics of DS patients in relationship to the clinical phenotype, autism features, and genetic etiology. We examined the presentation, clinical characteristics, demographics, epilepsy phenotype, the use of anti-epileptic drugs, diagnostic investigations and genetic etiology in DS. The studies in this thesis analyzed the relationship of ASD, the role of SCN1A mutation, dysmorphology, physical measurements, early recognition and diagnosis, disease-related predictors for Health-related quality of life (HRQoL) and the association of vaccination with the onset of febrile seizure or epileptic encephalopathy in patients with DS. Fifty-four DS patients, 31 (57.4%) males, with mean age of 9.8 years (range= 1.5-35.4) were recruited into the study. Twenty-eight (51.9%) DS patients met diagnostic criteria for ASD as outlined by the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5) and the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2). We report that DS patients with ASD were significantly associated with intellectual disability (ID) and global developmental delay (GDD) (p=0.000 and p=0.021, respectively). The genetic etiology identified by DNA sequencing revealed mutations in the sodium channel, voltagegated, type I, alpha subunit (SCN1A) gene in 45 (83.3%) DS patients (24 missense and 21 truncated mutations), of which 38 (84.4%) were de novo. DS patients with positive SCN1A mutations were associated with an earlier age of seizure onset, experienced a higher frequency of generalized tonic-clonic (p=0.041) and prolonged seizures (p=0.023) in the first year of life as compared to DS patients without SCN1A mutations. In our study cohort, the early age of seizure onset (M=6.8 months, SD=4.5) and long duration of first seizure (M=11.7 minutes, SD=14.7) were two important characteristics for early recognition for DS. Disease-related predictors for HRQoL in DS included ID, GDD, ASD, developmental regression, status epilepticus, and SCN1A mutation. No association with vaccination was found in our DS patients for the clinical and seizure characteristics. This thesis extends the knowledge of seizure presentation, clinical characteristics, autism features, SCN1A phenotype-genotype relationship and HRQoL in DS. DS is lifelong and devastating disorder. Early recognition and diagnosis of DS combined with appropriate clinical management may help to improve the quality of life for DS patients and their families.published_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph