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RETT SYNDROME

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					   RETT SYNDROME
  UNDERSTANDING RETT
SYNDROME AND THE ROLE OF
        MECP2

      NEUROSCIENCE
      JANUARY 2009
          OUTLINE
CLINICAL BACKGROUND

MOLECULAR IMPLICATIONS

PHENOTYPE-GENOTYPE RELATION

ANIMAL MODELS

THERAPY
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
     RETT SYNDROME
 A NEURODEVELOPMENTAL DISORDER OF
  YOUNG FEMALES CHARACTERIZED BY


 PROFOUND COGNITIVE
  IMPAIRMENT

 COMMUNICATION DYSFUNCTION

 STEREOTYPIC MOVEMENTS

 PERVASIVE GROWTH FAILURE
             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
      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
        RETT SYNDROME
        What do we know?
 Genetic disorder - mainly in females

 Diagnosis based on meeting clinical
  criteria

 Variable clinical expression

 Significant longevity

 Consistent neuropathology
     RETT SYNDROME
    BRAIN MORPHOLOGY

 REDUCED BRAIN WEIGHT
 REDUCED VOLUME OF SPECIFIC REGIONS
 REDUCED MELANIN PIGMENTATION
 SMALL NEURONS; SIMPLIFIED DENDRITES
 WITH REDUCED SPINES
 ABSENCE OF RECOGNIZABLE DISEASE
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)
    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
     RETT SYNDROME AND MECP2
 RETT SYNDROME IS A CLINICAL DIAGNOSIS
 RETT SYNDROME IS NOT SYNONYMOUS
    WITH MECP2 MUTATIONS
   RETT SYNDROME MAY BE SEEN WITH MECP2
    MUTATIONS
   RETT SYNDROME MAY BE SEEN WITHOUT
    MECP2 MUTATIONS
   MECP2 MUTATIONS MAY BE SEEN WITHOUT
    RETT SYNDROME
    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
                         Continuum of MECP2
   Females               Associated Phenotypes     Males
Normal*

Learning Disabilities*
                                          MECP2 Duplication syndrome*
Behavioral Phenotype*                     +/- recurrent infections
 Autistic; OCD
 Hyperactive/aggressive
 Moderate cognitive delay
                                          X-linked cognitive impairment*
Forme fruste                               +/- progressive spasticity;
                                           other NDD features/OCD;
Preserved speech variant                   aggression

Rett syndrome                             Rett syndrome
 95% with MECP2                            XXY; somatic mosaicism
 mutation; 80-85% of RTT
 and variants

Early onset seizure variant               Severe encephalopathy*

Congenital variant                        *
                                  *Likely under-represented
         Medical Issues
Longevity
Growth
Epilepsy
GI dysfunction
Scoliosis
Osteopenia
Breathing irregularities
Sleep
Cardiac conduction
Sexual Maturation
       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
   RETT SYNDROME – SURVIVAL BY DATE OF
                 BIRTH
            Figure 1
1. 00




0. 75




0. 50




0. 25




0. 00

        0     10         20               30              40        50               60   70

                                                 E R
                                                Y A S

             TR TA
            S A :       Y A =1935- 1959
                       B E R                    Y A =1960- 1969
                                               B E R               Y A =1970- 1979
                                                                  B E R
                        Y A =1980- 1989
                       B E R                    Y A =1990- 1999
                                               B E R               Y A =2000- 2009
                                                                  B E R
MOLECULAR IMPLICATIONS
  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
    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
Mecp2 plays complex role in the nucleus
with differential effects on transcription




                Yasui et al. PNAS 2007




               Chahrour et al. Science 2008
    Mutated MeCP2

                     HDAC
             Sin3A

  MeCP2


Methylated
   CpG
             Chromatin
PHENOTYPE-GENOTYPE
     RELATION
   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
          Medical Issues
   Frequency (%) by Mutation Type
Mutation (n)     Seizures   Scoliosis   Sc Surgery
R106W (20)         78          45          15
R133C    (28)      50          25           0
T158M    (64)      74          50          16
R168X    (55)      54          35          11
R255X    (60)      49          42           7
R270X    (34)      53          50          12
R294X    (37)      69          43           3
R306C    (45)      49          31           4
Lrg del (49)       57          55          12
c-ter del (53)     69          51           9
          Medical Issues
   Frequency (%) by Mutation Type
Mutation (n)     Constipation   GERD   Fractures
R106W (20)           75          50       20
R133C (28)           75          43        7
T158M (64)           78          56       16
R168X (55)           73          55       16
R255X (60)           75          52       17
R270X (34)           74          62       27
R294X (37)           81          49       19
R306C (45)           62          47       13
Lrg del (49)         69          55       20
c-ter del (53)       75          38       13
      MOUSE MODELS

Knock-out mouse: Mecp2 deleted

Knock-in mouse: Insertion of
mutation in Mecp2
  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
      KNOCK-IN MUTANT
Note
humped
back and
forelimb
clasping
Young and
Zoghbi, Am J
Hum Genet
2004;74:511-
520
      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
    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
    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
But overexpression is
     detrimental




              Collins et al., HMG 2004
THERAPY
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/
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?
 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…..
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
Gene therapy
    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
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
Therapies for Rett Syndrome
Nutrition
Physical Therapy
Occupational Therapy
Communication Therapy
Hippotherapy
Music Therapy
Aquatherapy
TOE WALKING
ANKLE-FOOT DYSTONIA
A successful
intervention
           Conclusions
Current investigations into neurobiological
underpinnings of CNS dysfunction opening
doors to new therapies in immediate future.
– Repurposing existing drugs
– Development of new agents
Gene based therapies are potential avenues
of treatment in the future.
Role of environmental enrichment (supports
early intervention programs)
Need to examine treatments in female mice
Cogent planning needed for clinical trials for
selected agents
                   The Team
Baylor College of       UAB
Medicine                –   Alan Percy
–   Daniel Glaze        –   Jane Lane
–   Kay Motil           –   Suzie Geerts
–   Jeff Neul           –   Jerry Childers
–   Judy Barrish        –   Russell Kirby
–   Carmel Lusk
Greenwood Genetic       NIH/NCRR/NICHD
Center
–   Steve Skinner       DTCC – Hye-Seung Lee
–   Fran Annese
–   Joy Graham          Girls and women with
                        RS and their families
–   Lauren McNair
…Rollin’ with Curly

				
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posted:10/28/2011
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