The NIH Funded Natural History Study

November 5, 2014

Last week a co-operative agreement was announced to fund research for the Natural History Study, a Research Consortium, to be led by Dr. Alan Percy University of Alabama at Birmingham.

“The potential for developing effective clinical trials is now tangible with other disease-modifying agents rapidly coming to the clinics.”  Alan K. Percy, MD, University of Alabama at Birmingham.  This video explains results from the last Natural History Study, some aims of the new round, and the overall research strategy.


This project will investigate

  • longitudinal natural history
  • neuro-behavioral assessments
  • biomarkers
  • outcome measures
  • neurophysiological
  • neuroimaging - in relation to disease severity
  • and the effects on Rett syndrome, MECP2 Duplication disorder, CDKL5 disorder, and FOXG1 syndrome.

“Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.”  Janet Woodcock, M.D., Director of FDA’s Center for Drug Evaluation and Research (CDER)

11 of our existing specialty Rett centers will form the basis of this study

  1. University of Alabama at Birmingham – Alan K. Percy, MD
  2. Baylor College of Medicine, Texas Children’s Hospital – Daniel G. Glaze, MD
  3. Harvard Medical School, Boston Children’s Hospital - Walter E. Kaufmann, MD
  4. Greenwood Genetic Center – Steven A. Skinner, MD
  5. Children’s Hospital of Philadelphia - Eric D. Marsh, MD PhD
  6. University of Rochester Medical Center – Alex R. Paciorkowski, MD, FACMG
  7. University of Colorado Medical School, Denver – Timothy A. Benke, MD PhD
  8. University of California, San Diego, Rady Children’s Hospital – Jeffrey L. Neul, MD PhD
  9. Vanderbilt University Medical Center – Sarika U. Peters, PhD
  10. Rush University Medical Center – Peter T. Heydemann, MD
  11. University of California San Francisco Benioff Oakland Children’s Hospital – Mary Jones, MD

“Through this Natural History Study (NHS) we will transform Rett syndrome and the Rett-related disorders care initiatives by stimulating more clinical research that will help draft guidance on how to standardize and optimize the best care for the children and adults with these four disorders as soon as possible through building a collaborative clinical network.” says Steven Kaminsky, PhD, Chief Science Officer,

Investigators realized the importance of delving even deeper into clinical research around four disorders, and the NIH saw the logic of studying this cluster of disorders and approved the new U54 award.

The new NHS research work has 3 major goals over the next 5 years:

  • Identify and understand the core clinical features of each disorder;
  • Identify factors that can modify the severity of the disorders; and
  • Understand the relationship between patients’ symptoms, their brain imaging and electroencephalography alterations.

The Primary Investigators (PIs), ORDR-NCATS, RDCRN and other NIH sponsoring departments met in Bethesda Oct 1-2 to learn that the awards were secured, and to be assigned our NICHD program manager (Melissa Parisi) and science manager (Danuta Krotoski). 

(Steve Kaminsky, PhD,CSO,; Jeffrey Neul, MD PhD, UCSD; Alan Percy, MD, lead PI, UAB; Paige Nues, Director, and representative of Patient Advocacy Group)

Dr. Alan Percy and Jane Lane (Consortium Project Manager) are hard at work making sure this wonderful new initiative not only builds effective protocols and processes but also meets the requirements of Institutional Review Board. This is a mammoth task and we thank all of those involved in building a baseline for success.

Ms. Lane comments, "The Rett syndrome, MECP2 Duplication disorder, and Rett-related disorders Consortium recognizes how appropriate and exciting it is for all of the disorders associated with Rett syndrome to now be together under one roof.  It's validation of the hard work on the part of researchers, by families who participated and by Rettsyndrome.organd its volunteers through the funding and support of the travel clinics that made the Rett Syndrome Natural History Study such a success.  This success most certainly influenced the decision by NIH to fund this new Consortium.  We look forward to another 5 years!" will take a central role in this endeavor as a member of the Coalition of Patient Advocacy Groups (CPAGs) within the RDCRN, and as administrative partner of this 5-year cooperative agreement. 

Details for enrolling in this version of the Natural History Study will be forthcoming. We hope the community will become as engaged and enthusiastic as last time, when our researchers were able to follow over 1,170 girls and women with typical and atypical Rett syndrome.  This resulted in the publication of over 14 papers illuminating new information about the course of Rett syndrome, and quite significantly, this organized study drew the attention of a pharmaceutical company which resulted in a significant clinical trial:  NNZ-2566. Watch this video to learn more of that story.

We are grateful for the commitment of our physician research community, and the NIH, to helping us. This tremendous outcome was the result of a lot of hard work from so many people, and we are eternally grateful for their energy and support.

Please contact Paige Nues at for enrollment questions.

Read more in the official press release from October, 2014. 

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