Research
Through the generous support of the Rett Syndrome Research Foundation and NINDS, the following research projects are currently under way:
Clinical Projects
Autonomic Dysfunction and Seizures in Rett Syndrome
Solomon L. Moshé, MD, and Alexis D. Boro, MD, are interested in studying the relationship of autonomic dysfunction and seizures in children with Rett syndrome (RTT).
RTT results in abnormal regulation of vital functions such as breathing, heart rate and blood pressure. RTT is also often associated with seizures and epilepsy. Even in the absence of RTT, seizures can impact the control of vital functions. Vital functions are regulated automatically by specialized circuits and brain regions in the nervous system known collectively as the autonomic nervous system. Seizures can disrupt normal function in the autonomic nervous system. In fact, sudden unexpected death in epileptic patients (SUDEP) is strongly suspected to result from seizure-induced disruption of vital functions by disrupting activity of the autonomic nervous system.
Drs. Moshé and Boro are investigating whether the underlying abnormality of autonomic function associated with RTT results in an increased susceptibility to seizure-induced disruptions of vital functions and increased risk of death or impairment in children with RTT.
Children with RTT (positive MECP2 testing is not necessary) who have seizures or suspected seizures will be studied in the epilepsy monitoring unit of the Children's Hospital at Montefiore in the Bronx, NY.
The usual set of scalp electrodes used in video-EEG monitoring is applied. In addition, patients will wear a vest with respiration sensors woven into it, additional EKG leads and a pulse oximeter.
If you wish to participate and your child is 12 years of age or under, please call Dr. Moshé at 718-405-8140 for an appointment to assess the child for inclusion in the study.
Children 13 years of age and older will be evaluated by Dr. Boro. He can be contacted at 718-920-5370.
Basic Science Projects
MECP2-dependent mechanisms that disrupt normal brain development in Rett syndrome as targets for therapeutic interventions
Recent studies in mouse models of RTT have indicated that functional restoration of MeCP2 expression, after the onset of symptoms, can reverse certain symptoms of the disease.
A primary goal in the laboratory of Aristea S. Galanopoulou, MD, PhD, is to identify signaling pathways that are important for normal brain development, but are disrupted by pathogenic MeCP2 mutations. The GABAA receptor signaling pathway has been recognized as a vital mediator of developmentally appropriate differentiating signals in neurons. Using a combination of molecular, electrophysiological, histological and behavioral techniques, the team has been studying the mechanisms through which MeCP2 mutations disrupt the developmental programs regulated by GABAA signaling. A region of interest in these studies is the substantia nigra, given its importance in controlling motoric functions and seizures. The ultimate goal is to test whether interventions that functionally restore the disrupted developmental programs may reverse certain symptoms, including stereotypies and seizures, after the onset of the disease.
Pathophysiology, impact and treatment of seizures associated with Rett syndrome
Epilepsy is a prominent feature of RTT that can significantly impact on the quality of life and contribute to the associated neurodevelopmental regression. A key point of interest in the laboratories of Drs. Galanopoulou and Moshé is to understand the impact of early life seizures on normal brain development as well as identify more efficient ways of curing difficult-to-treat seizures seen in RTT.
Previous work in their laboratory has shown that early life seizures may disrupt normal brain development, through targeting signaling pathways also affected in RTT. Ongoing studies are aiming to identify interventions that may functionally restore these disrupted pathways after they have occurred.
Among the difficult-to-treat seizures seen in a subset of patients with RTT are infantile spasms (IS). Although classically affecting patients with West syndrome, IS can also be seen in RTT patients, including those affected by CDKL5 mutations. They have a grave clinical outcome, often being associated with mental retardation. Using the only available rodent model of symptomatic infantile spasms, recently developed in their laboratory, Drs. Galanopoulou and Moshé are aiming to identify strategies to develop more effective ways of treating IS.