1. A Look Back at Rett Syndrome with a View to the Future
Alan Percy
June 23, 2016

4. Now we’re talking snow

5. When you are the hammer, Strike.
PREPAREDNESS
For all your days prepare,
And meet them ever alike:
When you are the anvil, bear - -
When you are the hammer, Strike.
-- Edwin Markham

6. ADVENTURES IN SCIENCE

8. Kidney sulfatides

9. Metachromatic Leukodystrophy
Leucocyte Arylsulfatase A Activity
in nmoles/mg protein/hr
Controls N = ± 6.5
MLD N = ± 2.4
Percy & Brady Science, 1968

10. Roscoe O. Brady

11. Percy, Kaback, Herndon Neurology, 1977

12. Brain Phospholipid Synthesis
Properties of particulate and detergent-solubilized phospholipid N-methyl-transferase activity from calf brain.
Percy, Moore, Waechter J Neurochem 1982
Characterization of brain phosphatidyl-serine decarboxylase: localization in the mitochondrial inner membrane.
Percy, Moore, Carson, Waechter Arch Biochem Biophys 1983

13. Bengt Hagberg
Andreas Rett

15. The Baylor Years First girl with RTT seen in 1983
Developed research group including Dan Glaze, Huda Zoghbi, and Vic Riccardi
Hugo Moser and Sakku Naidu at Kennedy Krieger (Johns Hopkins) in 1985
International Rett Syndrome Association: Kathy Hunter, Gail Smith, and Jane Brubaker
Initial studies: diagnostic features, biogenic amines, neurophysiology, genetics

16. CSF Monoamine Metabolites
MHPG 5-HIAA
(in nanomoles/ml CSF)
Control
N = 6
Participants
p < < 0.15
Zoghbi, Percy, Glaze, Butler, Riccardi NEJM 1985

17. Genetic probing Probing the X-chromosome X-linked dominant disorder
Refining area of interest to Xq28
Definitive report: Amir R,…,Zoghbi H. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Nature Genet 1999;23:185
Gene well-known in tumor biology

18. Natural History Studies 1-2
Office of Rare Diseases established RDCRN
NHS 1: – Angelman, Prader-Willi, and Rett syndromes
NHS 2: – refunded
RTT study enrolled >1200 individuals
Produced series of critical cross-sectional and longitudinal reports
Data mining on-going

19. Natural History Team

20. Natural History Study 3
RTT, MECP2 Duplication, CDKL5, FOXG1, MECP2 positive-Non-RTT
Enrollment in new NHS proceeding
5211: Longitudinal study of core features
5212: Advanced neurophysiologic correlates
5213: Biomarker outcome measures
Pilot studies
5214: Behavioral outcome measure
Metabolomics approach

21. Implication for effective therapy
Is Mecp2 knock-out reversible?
Estrogen receptor Mecp2 promoter:
Mecp2 knock-out phenotype reversed in both immature male and mature male and female mice
Rapid re-expression in immature males resulted in death in 50%
Guy et al. Science 2007;315:

22. Clinical Trials Critical pre-clinical and translational studies
Pre-mutation: Lamotrigine, Bromocriptine, Naltrexone – important lessons learned
Post-mutation: Folate-betaine, Dextromethorphan, Desipramine, Epitra, IGF-1, Trofinetide, Sarizotan, Ketamine
Under planning: Anavex, Neurolixis
Long term: Gene replacement; XCI reversal

23. The Future Great progress over past 30 years
Future depends on efforts of basic and clinical scientists; but insufficient alone….
Requires energies of the international community
Funding agencies, pharmaceutical firms, patient advocacy groups, and families
Above all, this demands patience and courage, focus and understanding, and the collective will to succeed

24. Bengt and Gudrun Hagberg and Jean Aicardi

25. Bengt Hagberg

27. My First Friend with Rett Syndrome

28. That’s all folks!!!