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RETT SYNDROME

RETT SYNDROME. UNDERSTANDING RETT SYNDROME AND THE ROLE OF MECP2 NEUROSCIENCE JANUARY 2009. OUTLINE. CLINICAL BACKGROUND MOLECULAR IMPLICATIONS PHENOTYPE-GENOTYPE RELATION ANIMAL MODELS THERAPY.

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RETT SYNDROME

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  1. RETT SYNDROME UNDERSTANDING RETT SYNDROME AND THE ROLE OF MECP2 NEUROSCIENCE JANUARY 2009

  2. OUTLINE • CLINICAL BACKGROUND • MOLECULAR IMPLICATIONS • PHENOTYPE-GENOTYPE RELATION • ANIMAL MODELS • THERAPY

  3. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Ruthie E. Amir, Ignatia B. van den Veyver, Mimi Wan, Charles Q. Tran, Uta Francke & Huda Y. Zoghbi Nature Genet 1999;23:185

  4. RETT SYNDROMEA NEURODEVELOPMENTAL DISORDER OF YOUNG FEMALES CHARACTERIZED BY • PROFOUND COGNITIVE IMPAIRMENT • COMMUNICATION DYSFUNCTION • STEREOTYPIC MOVEMENTS • PERVASIVE GROWTH FAILURE

  5. RETT SYNDROME CONSENSUS CRITERIA - 2001 • Normal at birth • Apparently normal early development (may be delayed from birth) • Postnatal deceleration of head growth in most • Lack of achieved purposeful hand skills • Psychomotor regression: Emerging social withdrawal, communication dysfunction, loss of learned words, and cognitive impairment • Stereotypic movements: Hand washing/wringing/squeezing; Hand clapping/tapping/rubbing; Hand mouthing • Gait dysfunction: Impaired (dyspraxic) or failing locomotion

  6. RETT SYNDROME TEMPORAL PROFILE • APPARENTLY NORMAL DEVELOPMENT • ARREST OF DEVELOPMENTAL PROGRESS • FRANK REGRESSION WITH POOR SOCIAL CONTACT AND FINGER SKILLS • STABILIZATION: BETTER SOCIAL CONTACT AND EYE GAZE, BUT GRADUAL SLOWING OF MOTOR FUNCTIONS

  7. RETT SYNDROMEWhat do we know? • Genetic disorder - mainly in females • Diagnosis based on meeting clinical criteria • Variable clinical expression • Significant longevity • Consistent neuropathology

  8. RETT SYNDROMEBRAIN MORPHOLOGY • REDUCED BRAIN WEIGHT • REDUCED VOLUME OF SPECIFIC REGIONS • REDUCED MELANIN PIGMENTATION • SMALL NEURONS; SIMPLIFIED DENDRITES WITH REDUCED SPINES • ABSENCE OF RECOGNIZABLE DISEASE

  9. Spine Dysgenesis in Mental Retardation Normal DS MR FraX FMR1 KO mice wt Rett Syndrome • Down’s Syndrome (Huttenlocher ‘70, ‘74; Marin-Padilla ‘72, ‘76; Purpura ‘74, ‘75); Fragile X Syndrome - and FMR1 KO mice (Wisniewski ‘85; Greenough ‘97); Rett Syndrome (Balichenko ‘94)

  10. OTHER NEURODEVELOPMENTAL DISORDERS • DOWN SYNDROME • REDUCED DENDRITIC BRANCHES AND SPINES AFTER EARLY INFANCY • AUTISM • INCREASED PACKING DENSITY • DECREASED CELL SIZE • ANGELMAN AND FRAGILE X SYNDROMES: • REDUCED DENDRITIC ARBORIZATIONS AND SPINES

  11. RETT SYNDROME AND MECP2 • RETT SYNDROME IS A CLINICAL DIAGNOSIS • RETT SYNDROME IS NOT SYNONYMOUS WITH MECP2 MUTATIONS • RETT SYNDROME MAY BE SEEN WITHMECP2 MUTATIONS • RETT SYNDROME MAY BE SEEN WITHOUTMECP2 MUTATIONS • MECP2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME

  12. MECP2 AND RETT SYNDROME • 90-95% of classic RTT due to mutations in MECP2 • 4 missense and 4 nonsense mutations account for ~ 65%; c-terminal truncations and large deletions account for another 15-18% • Sporadic RTT: majority of paternal origin • Familial RTT (<<1% of total): majority due to large deletions • Phenotypes extend beyond classic RTT

  13. Continuum of MECP2 Associated Phenotypes Females Males Normal* Learning Disabilities* Behavioral Phenotype* Autistic; OCD Hyperactive/aggressive Moderate cognitive delay Forme fruste Preserved speech variant Rett syndrome 95% with MECP2 mutation; 80-85% of RTT and variants Early onset seizure variant Congenital variant MECP2 Duplication syndrome* +/- recurrent infections X-linked cognitive impairment* +/- progressive spasticity; other NDD features/OCD; aggression Rett syndrome XXY; somatic mosaicism Severe encephalopathy* * *Likely under-represented

  14. Medical Issues • Longevity • Growth • Epilepsy • GI dysfunction • Scoliosis • Osteopenia • Breathing irregularities • Sleep • Cardiac conduction • Sexual Maturation

  15. LONGEVITY IN RETT SYNDROME • Unpublished study from Baylor College of Medicine: survival follows that of all females until age 10; 70% survival to age 35 versus 98% in all females • Recent study from Australia: 78% survival to age 25 versus 99.9% in all females - Laurvick et al. J Pediatr 2006;148:347

  16. RETT SYNDROME – SURVIVAL BY DATE OF BIRTH Figure 1

  17. MOLECULAR IMPLICATIONS

  18. METHYL-CpG-BINDING PROTEIN 2 • ONE OF FAMILY OF METHYL-BINDING PROTEINS • CAPABLE OF TRANSCRIPTIONAL SILENCING OR REGULATION • UBIQUITOUS IN MAMMALIAN TISSUES • HIGHLY EXPRESSED IN MAMMALIAN BRAIN • SPECIFIC TARGET GENES UNDEFINED • MAY FUNCTION IN MAINTENANCE OF DEVELOPING AND MATURE NEURONS

  19. MeCP2 DISTRIBUTION IN HUMAN BRAIN DURING DEVELOPMENT • CAUDAL-ROSTRAL GRADIENT OF MeCP2 IN HUMAN BRAIN • CORTICAL NEURONS LAST TO EXPRESS Shahbazian et al. Hum Mol Genet 2002;11:115

  20. Mecp2 plays complex role in the nucleus with differential effects on transcription Yasui et al. PNAS 2007 Chahrour et al. Science 2008

  21. HDAC Sin3A Mutated MeCP2 MeCP2 Methylated CpG Chromatin

  22. PHENOTYPE-GENOTYPE RELATION

  23. Does mutation predict outcome • R133C, R294X, and R306C mutations and c-term truncations are associated with lower severity scores, slower progression, preserved speech • Classic RTT: missense and nonsense • Variant RTT: nonsense • Non-RTT: missense and frameshift

  24. Medical IssuesFrequency (%) by Mutation Type

  25. Medical IssuesFrequency (%) by Mutation Type

  26. MOUSE MODELS • Knock-out mouse: Mecp2 deleted • Knock-in mouse: Insertion of mutation in Mecp2

  27. KNOCK-OUT MUTANT • Is Mecp2 knock-out reversible? • Using estrogen receptor controlled Mecp2 promoter: • Mecp2 knock-out phenotype reversed in both immature male and mature male and female mice with estrogen analog, tamoxifen • Rapid re-expression in immature males resulted in death in 50% • Guy et al. Science 2007;315:1143-1147

  28. KNOCK-IN MUTANT • Note humped back and forelimb clasping Young and Zoghbi, Am J Hum Genet 2004;74:511-520

  29. KNOCK-IN MUTANT • Impaired hippocampus-dependent social, spatial, and contextual fear memory • Impaired long-term potentiation and depression • Reduced post-synaptic densities • No change in BDNF expression Moretti et al. J Neurosci 2006;26:319-327

  30. KNOCK-IN MUTANT • Enhanced anxiety and fear based on: • Elevated blood corticosterone levels • Elevated corticotropin-releasing hormone in hypothalamus, central nucleus of amygdala, and bed nucleus of stria terminalis • MeCP2 binds to Crh promoter methylated region • McGill et al. PNAS 2006;103:18267-18272

  31. KNOCK-IN MUTANT • Implications of Crh over-expression: • Anxiety plays central role in clinical RS • Amygdala has direct input into hypothalamus and brainstem autonomic nuclei correlating with clinical problems of respiration, GI function, and peripheral sympathetic NS • Suggests strategies for therapeutic intervention

  32. But overexpression is detrimental Collins et al., HMG 2004

  33. THERAPY

  34. Therapeutic interventions in Rett syndrome • Genetic • Gene therapy • Post-transcriptional repair • Protein • Reintroduce protein • Modifiers of mutant MECP2 function http://fajerpc.magnet.fsu.edu/Education/2010/

  35. New treatments on the horizon? • Gene repair, replacement strategies • Gene therapy • Reintroduction of protein • Can we modulate expression of the gene/protein? • Up-regulation in “normal” cells in heterozygotes • Reactivate normal gene • Post transcriptional repair • Treatment being tested in CF and Duchenne muscular dystrophy of a drug that allows the cell to “read through” a nonsense mutation • Targeted treatments based on what Mecp2 does in neurons • Can we improve protein function? • Can we make another protein take over? • Can we intercede on specific downstream targets? • Can we modulate neurophysiology?

  36. Challenges across the board for therapies in Rett syndrome • No clear-cut reliable outcome measure for all the girls. • Natural history study may be key. • ?EEG or other objective physiologic measure. • Girls will be heterogeneous in genetic background and XCI. • Even in cultured cells, outcome measures are tricky. • But the mice can help us here…..

  37. What about gene therapy for Rett syndrome? Disorders due to mutations in one or more genes • Single-gene disorders are more easily treated The responsible gene is known • +/- The role of the protein encoded by the gene is known • + Adding a normal gene will fix the problem The affected tissues are known and accessible

  38. Gene therapy

  39. Post-transcriptional repair: aminoglycosides • Aminoglycoside antibiotics allow “read-through” of premature stop signals • Nonsense mutations • Problems with toxicity • Need to be given IV • Introduce a missense mutation at the “stop” site http://www.ptcbio.com/3.1.1_genetic_disorders.aspx

  40. Post-transcriptional repair? • PTC124: New Agent developed by PTC Therapeutics with similar action • Orally available • Less toxic • Being tested in cystic fibrosis and Duchenne Muscular Dystrophy with very promising results • Phase 2 trials- increased walking duration in DMD, improved chloride conductance in CF http://www.ptcbio.com/3.1.1_genetic_disorders.aspx

  41. Therapies for Rett Syndrome • Nutrition • Physical Therapy • Occupational Therapy • Communication Therapy • Hippotherapy • Music Therapy • Aquatherapy

  42. TOE WALKING

  43. ANKLE-FOOT DYSTONIA

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