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

Now we’re talking snow

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

ADVENTURES IN SCIENCE

Kidney sulfatides

Metachromatic Leukodystrophy Leucocyte Arylsulfatase A Activity in nmoles/mg protein/hr Controls N = 16 100.9 ± 6.5 MLD N = 6 11.7 ± 2.4 Percy & Brady Science, 1968

Roscoe O. Brady

Percy, Kaback, Herndon Neurology, 1977

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

Bengt Hagberg Andreas Rett

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

CSF Monoamine Metabolites MHPG 5-HIAA (in nanomoles/ml CSF) Control 63 - 70 126 - 209 N = 6 Participants 32 - 52 78 - 162 p < 0.01 < 0.15 Zoghbi, Percy, Glaze, Butler, Riccardi NEJM 1985

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

Natural History Studies 1-2 Office of Rare Diseases established RDCRN NHS 1: 2003-2009 – Angelman, Prader-Willi, and Rett syndromes NHS 2: 2009-2014 – refunded RTT study enrolled >1200 individuals Produced series of critical cross-sectional and longitudinal reports Data mining on-going

Natural History Team

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

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;315:1143-1147

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

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

Bengt and Gudrun Hagberg and Jean Aicardi

Bengt Hagberg

My First Friend with Rett Syndrome

That’s all folks!!!