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Center on Human Development and Disability

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Collaborative Research Area on Disorders of Hindbrain Development

Coordinator: Daniel A. Doherty, M.D., Ph.D.

This CRA is focuses on hindbrain malformation disorders such as Joubert syndrome, Dandy-Walker Malformation, rhombencephalosynapsis, pontine tegmental cap dysplasia, and Chudley-McCullough syndrome, as well as disorders affecting hindbrain functions such as respiratory control, occulomotor control, motor learning and balance. The hindbrain is comprised of the brainstem (pons and medulla) and the cerebellum, important structures that are responsible for sensory and motor function of head and neck structures, regulate heart rate, breathing and level of consciousness, and coordinate movements. More recently, the hindbrain has been found to play a role in cognition, behavior and emotional regulation, and studying hindbrain malformation disorders provides an opportunity to understand the role of the hindbrain in cognition, since most patients with hindbrain malformations have cognitive impairment.

For example, Joubert syndrome is a recessive neurodevelopmental disorder characterized by hypotonia, cognitive impairment, and a distinctive brain malformation visualized as the "molar tooth sign" on axial brain imaging. Patients also display abnormal eye movements, respiratory control, and other functions governed by the hindbrain. Over the past several years, investigators in this CRA have involved in identifying 8 of the 16 genes known to be responsible for Joubert syndrome. All of these genes have been shown to play a role in the primary cilium/basal body, making Joubert syndrome one of the expanding group of disorders called ciliopathies.

The Disorders of Hindbrain Development CRA represents a multidisciplinary collaboration by investigators with the shared purpose to understand hindbrain malformation conditions and their impact on functional capabilities, intellectual development, and long-term morbidity and mortality. The group interacts in a coordinated fashion to achieve several specific goals.

  • Phenotyping: The first goal is to define more specific clinical categories for patients with hindbrain malformations through detailed clinical evaluation, neuroimaging, eye movement testing and neuropathology. Understanding the natural history of each disorder improves treatment strategies and provides prognostic information for families.
  • Gene identification: Using cohorts of well characterized patients, the next goal is to identify the genetic causes of these disorders using cutting edge genome wide techniques such as array CGH and exome sequencing.
  • Functional work: Once a gene(s) is identified for a disorder, we use cultured cells, animal models and a variety of biochemical and cell biological techniques to understand the mechanisms underlying the disorder. Functional studies advance the understanding of human hindbrain development, as well as identify the most promising targets for disease-specific therapies.
  • Treatment: The ultimate goal of the CRA is to develop treatments for hindbrain malformation disorders. The current studies directly impact patient care by improving the quality of diagnostic, prognostic and recurrence risk information. Specific genetic diagnosis guides medical monitoring for complications and in some patients alters treatment. While it is unlikely that we will be able to correct abnormal brain development, it may be possible to improve ongoing function of the brain and other organs, once we understand the molecular mechanisms involved. In addition, cerebellar dysfunction has been implicated in a variety of common developmental and mental health disorders such as autism, intellectual disability and schizophrenia. Understanding the mechanisms underlying hindbrain malformations is likely to improve our ability to diagnose and treat these more common disorders associated with hindbrain dysfunction.

Faculty Investigators

  • Daniel Doherty, M.D., Ph.D., Associate Professor, Pediatrics, Coordinator
  • Ruxandra Bachmann-Gagescu, M.D., Acting Assistant Professor, Pediatrics
  • Teresa Chapman, M.D., Assistant Professor, Radiology
  • Maida Chen, M.D., Assistant Professor, Pediatrics
  • William Dobyns, M.D. Professor, Pediatrics
  • Ian Glass, M.D., Professor, Pediatrics
  • Robert Hevner, M.D., Ph.D. Professor, Pathology
  • Gisele Ishak, M.D., Assistant Professor, Radiology
  • Raj Kapur, M.D., Ph.D., Professor, Pathology
  • Kathleen Millen, Ph.D., Associate Professor, Pediatrics
  • Cecilia Moens, Ph.D., Affiliate Professor, Biology and Biological Structure
  • Kelly Owens, Ph.D., Lecturer, Otolaryngology/Head and Neck Surgery
  • James Phillips, Ph.D., Research Associate Professor, Otolaryngology/Head and Neck Surgery
  • David W. Raible, Ph.D., Professor, Biological Structure
  • Jan (Nino) Ramirez, Ph.D., Professor, Neurological Surgery
  • Wendy Raskind, M.D., Ph.D., Professor, Medicine
  • Edwin Rubel, Ph.D., Professor, Otolaryngology/Head and Neck Surgery and Physiology & Biophysics
  • Dennis Shaw, M.D., Professor, Radiology
  • Joseph Seibert, M.D., Professor, Pathology
  • Colin Studholme, Ph.D., Professor,f Pediatrics and Bioengineering
  • Avery Weiss, M.D., Professor, Ophthalmology

University of Washington Disorders of Hindbrain Development Program

University of Washington • Center on Human Development and Disability Box 357920 • Seattle WA 98195-7920 USA • 206-543-7701 •