Mechanism-based biomarkers are needed to guide clinical trials for neurodevelopmental disorders by indexing disease pathology or a treatment response. In this dissertation, I describe electroencephalogram (EEG) biomarkers in two neurodevelopmental disorders, Dup15q syndrome and Angelman syndrome. Dup15q syndrome is caused by duplications of 15q11.2-q13.1, including UBE3A—a paternally imprinted gene involved in synapse development—and several gamma-aminobutyric acid type-A (GABA-A) receptor subunit genes. In Angelman syndrome, the majority of cases are caused by deletions of 15q11.2-q13.1, though some cases are caused by UBE3A dysfunction alone. Both disorders are characterized by epilepsy, intellectual disability, and phenotypic overlap with autism spectrum disorder (ASD).
In Chapter 1, I introduce biomarkers and neurodevelopmental disorders. In Chapter 2, I infer the emergence of stable oscillations from neural noise in typically developing (TD) preschool age children. In Chapter 3, I describe a beta EEG phenotype of Dup15q syndrome, which distinguishes children with this disorder from TD and nonsyndromic ASD controls. In Chapter 4, I compare this phenotype with beta oscillations induced with midazolam, a GABA-A modulator, in healthy adult participants. Furthermore, two cases of paternal Dup15q syndrome (i.e., duplications of the UBE3A-silenced allele) also show this EEG phenotype, suggesting that it is a marker of GABAergic pathology. In Chapter 5, I describe a delta EEG phenotype of Angelman syndrome (previously described by Sidorov and colleagues in 2017) that is stronger in children with a deletion genotype than those with a non-deletion genotype. Furthermore, I find lower beta power and higher theta power in the deletion genotype. Thus, beta power and theta power appear to reflect GABAergic dysfunction, whereas delta power appears to reflect UBE3A dysfunction but is modulated by GABA-A receptor gene deletion. Chapter 6 summarizes this work and provides a discussion about implications and next steps.
In conclusion, neurophysiological oscillations are likely markers of gene-specific disease pathology in Dup15q syndrome and Angelman syndrome. Clinical trials targeting specific gene products (e.g., GABA-A receptors) may utilize these EEG measures as biomarkers of target engagement or surrogate endpoints.