30 research outputs found
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Electrophysiological biomarkers of neurodevelopmental disorders: Discoveries from Dup15q syndrome
Neurodevelopmental disorders (NDDs) show considerable heterogeneity, both in terms of genetic underpinnings and clinical presentation. Certain NDDs arise due to rare genetic etiologies, providing a valuable opportunity to explore possible mechanisms of cognitive and behavioral dysfunction. For instance, duplications of 15q11.2-13.1 cause Dup15q syndrome, an NDD characterized by intellectual disability, autism spectrum disorder (ASD), epilepsy, motor delays, sleep impairment and abnormal brain activity. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased oscillatory activity within the beta range (12-30 Hz) that likely reflects aberrant GABAergic neurotransmission. By rigorously investigating the properties of this EEG biomarker, this dissertation expands our understanding of Dup15q syndrome pathophysiology and uses an innovative methodological pipeline to gather and process remote clinical EEG recordings from patients across the country, thus facilitating large scale studies across NDDs. Chapter 1 introduces NDDs, Dup15q syndrome and EEG biomarkers. Chapter 2 investigates the properties of beta oscillations in Dup15q syndrome, including their relationship to clinical symptomatology, stability over time, and reproducibility, both across analytic pipelines and across research and clinical EEG. Chapter 3 evaluates the presence of beta oscillations across brain states such as wakefulness and sleep and describes novel quantitative biomarkers of sleep disruption in children with Dup15q syndrome, including elevated beta oscillations in sleep and abnormal NREM sleep physiology. Chapter 4 explores the relationship between abnormal sleep physiology and the neurobehavioral phenotype in Dup15q syndrome. Chapter 5 discusses key next steps in further understanding the implications of genetic and brain circuit level changes that occur in Dup15q syndrome and considers whether pharmacological manipulation of the neural dysfunction can change outcomes. Both beta oscillations and healthy sleep rhythms necessary for healthy cognitive development rely on GABAergic modulation. As such, elevated beta oscillations and the sleep disruptions reported in this dissertation both point towards GABAergic dysfunction in Dup15q syndrome. Therapeutic advances in Dup15q syndrome can include disease-modifying therapies that target GABA signaling. The EEG biomarkers described in this dissertation have the potential to serve as measures of drug target engagement or as a proximal outcome measures that precede behavioral responses to treatment. Ultimately, these biomarkers will help monitor treatment progress and change in clinical outcomes in individuals with NDDs
Recommended from our members
Electrophysiological biomarkers of neurodevelopmental disorders: Discoveries from Dup15q syndrome
Neurodevelopmental disorders (NDDs) show considerable heterogeneity, both in terms of genetic underpinnings and clinical presentation. Certain NDDs arise due to rare genetic etiologies, providing a valuable opportunity to explore possible mechanisms of cognitive and behavioral dysfunction. For instance, duplications of 15q11.2-13.1 cause Dup15q syndrome, an NDD characterized by intellectual disability, autism spectrum disorder (ASD), epilepsy, motor delays, sleep impairment and abnormal brain activity. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased oscillatory activity within the beta range (12-30 Hz) that likely reflects aberrant GABAergic neurotransmission. By rigorously investigating the properties of this EEG biomarker, this dissertation expands our understanding of Dup15q syndrome pathophysiology and uses an innovative methodological pipeline to gather and process remote clinical EEG recordings from patients across the country, thus facilitating large scale studies across NDDs. Chapter 1 introduces NDDs, Dup15q syndrome and EEG biomarkers. Chapter 2 investigates the properties of beta oscillations in Dup15q syndrome, including their relationship to clinical symptomatology, stability over time, and reproducibility, both across analytic pipelines and across research and clinical EEG. Chapter 3 evaluates the presence of beta oscillations across brain states such as wakefulness and sleep and describes novel quantitative biomarkers of sleep disruption in children with Dup15q syndrome, including elevated beta oscillations in sleep and abnormal NREM sleep physiology. Chapter 4 explores the relationship between abnormal sleep physiology and the neurobehavioral phenotype in Dup15q syndrome. Chapter 5 discusses key next steps in further understanding the implications of genetic and brain circuit level changes that occur in Dup15q syndrome and considers whether pharmacological manipulation of the neural dysfunction can change outcomes. Both beta oscillations and healthy sleep rhythms necessary for healthy cognitive development rely on GABAergic modulation. As such, elevated beta oscillations and the sleep disruptions reported in this dissertation both point towards GABAergic dysfunction in Dup15q syndrome. Therapeutic advances in Dup15q syndrome can include disease-modifying therapies that target GABA signaling. The EEG biomarkers described in this dissertation have the potential to serve as measures of drug target engagement or as a proximal outcome measures that precede behavioral responses to treatment. Ultimately, these biomarkers will help monitor treatment progress and change in clinical outcomes in individuals with NDDs
The diagnostic journey of genetically defined neurodevelopmental disorders
BackgroundThe development of advanced genetic technologies has resulted in rapid identification of genetic etiologies of neurodevelopmental disorders (NDDs) and has transformed the classification and diagnosis of various NDDs. However, diagnostic genetics has far outpaced our ability to provide timely medical counseling, guidance, and care for patients with genetically defined NDDs. These patients and their caregivers present with an unmet need for care coordination across multiple domains including medical, developmental, and psychiatric care and for educational resources and guidance from care professionals. After a genetic diagnosis is made, families also face several barriers in access to informed diagnostic evaluations and medical support.MethodsAs part of Care and Research in Neurogenetics (CARING), a multidisciplinary clinical program for children and adults with neurogenetic disorders, we conducted qualitative clinical interviews about the diagnostic journey of families. This included the overall timeline to receiving diagnoses, experiences before and after diagnosis, barriers to care, and resources that helped them to navigate the diagnostic process.ResultsA total of 37 interviews were conducted with parents of children ages 16 months to 33 years. Several key themes were identified: (1) delays between initial caregiver observations and formal developmental or genetic diagnoses; (2) practical barriers to clinical evaluation and care, including long wait times for an appointment, lack of insurance coverage, availability of local evaluations, transportation difficulties, and native language differences; (3) the importance of being part of a patient advocacy group to help navigate the diagnostic journey; and (4) unique challenges faced by adults (18 years or older).ConclusionsFamilies of children with complex neurodevelopmental and genetic disabilities face numerous challenges in finding adequate medical care and services for their child. They experience considerable delays in receiving timely diagnoses and face significant barriers that further delay the process of receiving access to services needed for the child's continued care. The gaps indicated in this study speak to the need for more comprehensive coordination of care for patients with intellectual and developmental disabilities, as well as the development of systematic, disorder-specific resources both for providers and families in order to improve patient outcomes