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Recent Advances in Rett Syndrome
Mario Petersen, MD Associate Professor of Pediatrics Institute on Developmental Disabilities Child Development and rehabilitation Center Oregon Health Science University
Bibliography:
Clinical Care:
1. The Rett Syndrome Handbook, available in the website of the International Rett
Syndrome Foundation:
http://www.rettsyndrome.org/family-support/newly-diagnosed/the-rett-syndrome-handbook
2. Rett Syndrome, Therapeutic Interventions. By Meier Lotan and Joav Merrick, Nova
Biomedical , NY, 2011
Clinical Outcome and medical Issues
Baikie, G., M. Ravikumara, J. Downs, N. Naseem, K. Wong, A. Percy, J. Lane, B. Weiss, C.
Ellaway, K.
Briggs, A. (2013). "Primary care of a child with Rett syndrome." J Am Assoc Nurse Pract.
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on hand function in girls and women with Rett syndrome." Dev Neurorehabil 17(3): 210-217.
Dolce, A., B. Ben-Zeev, S. Naidu and E. H. Kossoff (2013). "Rett syndrome and epilepsy: an
update for child neurologists." Pediatr Neurol 48(5): 337-345.
Bathgate and H. Leonard (2014). "Gastrointestinal dysmotility in rett syndrome." J Pediatr
Gastroenterol Nutr 58(2): 244-251.
Freilinger, M., M. Bohm, I. Lanator, K. Vergesslich-Rothschild, W. D. Huber, A. Anderson, K.
Wong, G. Baikie, M. Ravikumara, J. Downs and H. Leonard (2014). "Prevalence, clinical
investigation, and management of gallbladder disease in Rett syndrome." Dev Med Child Neurol
56(8): 756-762.
Motil, K. J., M. Morrissey, E. Caeg, J. O. Barrish and D. G. Glaze (2009). "Gastrostomy
placement improves height and weight gain in girls with Rett syndrome." J Pediatr Gastroenterol
Nutr 49(2): 237-242.
Halbach, N. S., E. E. Smeets, C. Steinbusch, M. A. Maaskant, D. van Waardenburg and L. M.
Curfs (2013). "Aging in Rett syndrome: a longitudinal study." Clin Genet 84(3): 223-229.
Kaufmann, W. E., E. Tierney, C. A. Rohde, M. C. Suarez-Pedraza, M. A. Clarke, C. F. Salorio,
G. Bibat, I. Bukelis, D. Naram, D. C. Lanham and S. Naidu (2012). "Social impairments in Rett
syndrome: characteristics and relationship with clinical severity." J Intellect Disabil Res 56(3):
233-247.
Leonard, H., S. Fyfe, S. Leonard and M. Msall (2001). "Functional status, medical impairments,
and rehabilitation resources in 84 females with Rett syndrome: a snapshot across the world
from the parental perspective." Disabil Rehabil 23(3-4): 107-117.
Motil, K. J., R. J. Schultz, K. Browning, L. Trautwein and D. G. Glaze (1999). "Oropharyngeal
dysfunction and gastroesophageal dysmotility are present in girls and women with Rett
syndrome." J Pediatr Gastroenterol Nutr 29(1): 31-37.
Naidu, S., G. Bibat, L. Kratz, R. I. Kelley, J. Pevsner, E. Hoffman, C. Cuffari, C. Rohde, M. E.
Blue and M. V. Johnston (2003). "Clinical variability in Rett syndrome." J Child Neurol 18(10):
662-668.
Neul, J. L., W. E. Kaufmann, D. G. Glaze, J. Christodoulou, A. J. Clarke, N. Bahi-Buisson, H.
Leonard, M. E. Bailey, N. C. Schanen, M. Zappella, A. Renieri, P. Huppke, A. K. Percy and C.
RettSearch (2010). "Rett syndrome: revised diagnostic criteria and nomenclature." Ann Neurol
68(6): 944-950.
Motil, K. J., E. Caeg, J. O. Barrish, S. Geerts, J. B. Lane, A. K. Percy, F. Annese, L. McNair, S.
A. Skinner, H. S. Lee, J. L. Neul and D. G. Glaze (2012). "Gastrointestinal and nutritional
problems occur frequently throughout life in girls and women with Rett syndrome." J Pediatr
Gastroenterol Nutr 55(3): 292-298.
Neul, J. L., J. B. Lane, H. S. Lee, S. Geerts, J. O. Barrish, F. Annese, L. M. Baggett, K. Barnes,
S. A. Skinner, K. J. Motil, D. G. Glaze, W. E. Kaufmann and A. K. Percy (2014). "Developmental
delay in Rett syndrome: data from the natural history study." J Neurodev Disord 6(1): 20.
Percy, A. (2014). "The American history of Rett syndrome." Pediatr Neurol 50(1): 1-3.
Marschik, P. B., W. E. Kaufmann, J. Sigafoos, T. Wolin, D. Zhang, K. D. Bartl-Pokorny, G. Pini,
M. Zappella, H. Tager-Flusberg, C. Einspieler and M. V. Johnston (2013). "Changing the
perspective on early development of Rett syndrome." Res Dev Disabil 34(4): 1236-1239.
Marschik, P. B., R. Vollmann, K. D. Bartl-Pokorny, V. A. Green, L. van der Meer, T. Wolin and
C. Einspieler (2014). "Developmental profile of speech-language and communicative functions
in an individual with the preserved speech variant of Rett syndrome." Dev Neurorehabil 17(4):
284-290.
Lee, J. Y., H. Leonard, J. P. Piek and J. Downs (2013). "Early development and regression in
Rett syndrome." Clin Genet 84(6): 572-576.
Leonard, H., M. Ravikumara, G. Baikie, N. Naseem, C. Ellaway, A. Percy, S. Abraham, S.
Geerts, J. Lane, M. Jones, K. Bathgate, J. Downs and R. Telethon Institute for Child Health
(2013). "Assessment and management of nutrition and growth in Rett syndrome." J Pediatr
Gastroenterol Nutr 57(4): 451-460.
Tarquinio, D. C., K. J. Motil, W. Hou, H. S. Lee, D. G. Glaze, S. A. Skinner, J. L. Neul, F.
Annese, L. McNair, J. O. Barrish, S. P. Geerts, J. B. Lane and A. K. Percy (2012). "Growth
failure and outcome in Rett syndrome: specific growth references." Neurology 79(16): 1653-
1661.
Rose, S. A., A. Djukic, J. J. Jankowski, J. F. Feldman, I. Fishman and M. Valicenti-McDermott
(2013). "Rett syndrome: an eye-tracking study of attention and recognition memory." Dev Med
Child Neurol 55(4): 364-371.
Genetic
Amir, R. E., I. B. Van den Veyver, M. Wan, C. Q. Tran, U. Francke and H. Y. Zoghbi (1999).
"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding
protein 2." Nat Genet 23(2): 185-188.
Guy, J., J. Gan, J. Selfridge, S. Cobb and A. Bird (2007). "Reversal of neurological defects in a
mouse model of Rett syndrome." Science 315(5815): 1143-1147.
Guy, J., H. Cheval, J. Selfridge and A. Bird (2011). "The role of MeCP2 in the brain." Annu Rev
Cell Dev Biol 27: 631-652.
Therapy research
Chapleau, C. A., J. Lane, L. Pozzo-Miller and A. K. Percy (2013). "Evaluation of current
pharmacological treatment options in the management of Rett syndrome: from the present to
future therapeutic alternatives." Curr Clin Pharmacol 8(4): 358-369.
BDNF- IGF-1
Katz, D. M. (2014). "Brain-derived neurotrophic factor and Rett syndrome." Handb Exp
Pharmacol 220: 481-495.
Khwaja, O. S., E. Ho, K. V. Barnes, H. M. O'Leary, L. M. Pereira, Y. Finkelstein, C. A. Nelson,
3rd, V. Vogel-Farley, G. DeGregorio, I. A. Holm, U. Khatwa, K. Kapur, M. E. Alexander, D. M.
Finnegan, N. G. Cantwell, A. C. Walco, L. Rappaport, M. Gregas, R. N. Fichorova, M. W.
Shannon, M. Sur and W. E. Kaufmann (2014). "Safety, pharmacokinetics, and preliminary
assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett
syndrome." Proc Natl Acad Sci U S A 111(12): 4596-4601.
Li, W. and L. Pozzo-Miller (2014). "BDNF deregulation in Rett syndrome." Neuropharmacology
76 Pt C: 737-746.
Pini, G., M. F. Scusa, A. Benincasa, I. Bottiglioni, L. Congiu, C. Vadhatpour, A. M. Romanelli, I.
Gemo, C. Puccetti, R. McNamara, S. O'Leary, A. Corvin, M. Gill and D. Tropea (2014).
"Repeated insulin-like growth factor 1 treatment in a patient with rett syndrome: a single case
study." Front Pediatr 2: 52.
Pini, G., M. F. Scusa, L. Congiu, A. Benincasa, P. Morescalchi, I. Bottiglioni, P. Di Marco, P.
Borelli, U. Bonuccelli, A. Della-Chiesa, A. Prina-Mello and D. Tropea (2012). "IGF1 as a
Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients." Autism Res
Treat 2012: 679801.
Other MeCP2
Leonard, H., J. Silberstein, R. Falk, I. Houwink-Manville, C. Ellaway, L. S. Raffaele, I. W.
Engerstrom and C. Schanen (2001). "Occurrence of Rett syndrome in boys." J Child Neurol
16(5): 333-338.
Shimada, S., N. Okamoto, M. Ito, Y. Arai, K. Momosaki, M. Togawa, Y. Maegaki, M. Sugawara,
K. Shimojima, M. Osawa and T. Yamamoto (2013). "MECP2 duplication syndrome in both
genders." Brain Dev 35(5): 411-419.
Van Esch, H. (2012). "MECP2 Duplication Syndrome." Mol Syndromol 2(3-5): 128-136.
Slide 1
RETT SYNDROME UPDATE
Mario C. Petersen. M.D
Associate Professor of Pediatrics
Child Development and Rehabilitation Center
Oregon Health Science University
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Slide 2 Learning Objectives
Brief Review Of Diagnosis and last diagnostic
criteria 2010
Key Research Studies on Rett
Brief description MeCP2 function
Promising Research Advances on Treatment
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Slide 3 History of Rett SyndromeDr. Andreas Rett, identified females who had a unique pattern of
Neurodevelopment in 1966
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Slide 4 History of Rett Syndrome
Dr. Andreas Rett, first description 1966
Dr. Bengt Hagberg, neurologist in Göteborg, Sweden,
Publishes 35 cases in English in 1983. (Hagberg B et al
Ann Neurol 1983; 14:471–479.
Diagnosis Criteria
1985 (Hagberg B, et al. 1985. Brain Dev 7:372–373)
1994 Rett Syndrome is included in DSM IV as a PDD
2001 (Hagberg B et al. Eur J Paediatr Neurol 2002; 6:293–297)
2010 (Neul J L et al. Ann Neurol 2010; 68:944–950)
Rett Syndrome was removed from DSM V
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Slide 5 Diagnostic Criteria 2010-Main criteria
1. Partial or complete loss of acquired purposeful hand skills
2. Partial or complete loss of acquired spoken language
3. Gait abnormalities: Impaired (dyspraxic) or absence of ability.
4. Stereotypic hand movements such as hand wringing/squeezing,
clapping/tapping, mouthing and washing/rubbing automatisms
Consider diagnosis when postnatal deceleration of head growth observed
Neul J L et al, Ann Neurol 2010; 68:944–950.
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Slide 6 Diagnostic Criteria 2010
Required for typical or classic RTT
1. A period of regression followed by recovery or stabilization
2. All main criteria and all exclusion criteria
3. Supportive criteria are not required, although often present in typical RTT
Required for atypical or variant RTT
1. A period of regression followed by recovery or stabilization
2. At least 2 of the 4 main criteria
3. 5 out of 11 supportive criteria
ANN NEUROL 2010;68:944–950, Jeffrey L. Neul, MD, PhD et al
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Slide 7 Diagnostic Criteria 2010
Supportive criteria for atypical RTT
1. Breathing disturbances when awake
2. Bruxism when awake
3. Impaired sleep pattern
4. Abnormal muscle tone
5. Peripheral vasomotor disturbances
6. Scoliosis/kyphosis
7. Growth retardation
8. Small cold hands and feet
9. Inappropriate laughing/screaming spells
10. Diminished response to pain
11. Intense eye communication - ‘‘eye pointing’’
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Slide 8 Diagnostic Criteria 2010
Exclusion criteria for typical RTT
1. Brain injury secondary to trauma (peri- or
postnatally), neurometabolic disease, or severe
infection that causes neurological problems
2. Grossly abnormal psychomotor development in
first 6 months of life
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Slide 9
ANN NEUROL 2010;68:944–950, Jeffrey L. Neul, MD, PhD et al
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Slide 10 Staging system for classical Rett syndrome.
Weaving L S et al. J Med Genet 2005;42:1-7
©2005 by BMJ Publishing Group Ltd
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Slide 11 History of Rett Syndrome
MeCP2 identified in 1999 in Huda Zoghbi ‘s lab
Amir et al, Nat Genet 1999;23:185–188
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Slide 12 MeCP2 mutations
MeCP2 contains three functional domains:
1. a methyl-binding domain (MBD) on the N-terminus allowing binding to DNA
2. a nuclear localization sequence allowing trafficking of MeCP2 to the nucleus
3. a transcriptional repression domain (TRD), which modulates gene transcription.
80 % have MeCP2 mutation Missense mutations 39% Nonsense mutations 28%
Frame shift mutations 17%
Large deletions 14.5%
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Slide 13 2001 - KO mice (MeCP2 -)
at Huda Zoghbi lab
Develops progressive symptoms
Paws wringing movements
Poor motor coordination
Smaller brain
Abnormal breathing
Early death
Shahbazian MD, et al
Neuron, Vol. 35, 243–254, July 18, 2002,
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Slide 14 Brain changes in Rett Syndrome
Decreased size of the neurones
Immature Neurones
Smaller Nucleus
Reduced Dendrites
Reduced synapsis
Reduced spines.
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Slide 15 2007. Dr. Adrian Bird’s Mice model
Mecp2 gene is silenced by insertion of a lox-Stop cassette
Mice develops Rett
Abnormal gait, hind-limb clasping, tremor, irregular breathing, and poor general condition
Early death
MECP2 is activated with Tamoxifen
When MECP2 is activated with Tamoxifen
Increase MeCP2 in the brain
Decreased symptoms, long survival
Guy, J et al. Science Vol313, 1143-1147
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Slide 16 MeCP2 Reversal of deficitGuy, J et al. Science Vol313, 1143-1147
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Slide 17 Male
Female
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Slide 18 MeCP2 Reversal of deficit Guy, J et al. Science Vol313, 1143-1147
Developmental absence of MeCP2
does not irreversibly damage neurons.
Guy, J et al. Science Vol313, 1143-1147
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Slide 19
MeCP2 function
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Slide 20 MeCP2
• Binds to DNA
• activates or inhibits transcription
• Increased MeCP2increased DNA Methylation
• Methylation is associated with gene inactivation
• Binds to BDNF exon IV
Binding is methylation dependent
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Slide 21 Fig. 1. Significant gene expression changes in hypothalami of MeCP2 mouse models.
Chahrour M et al. Science 2008;320:1224-1229
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Slide 22
Chahrour M et al. Science 2008;320:1224-1229
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Slide 23 MeCP2
MeCP2 is a vertebrate invention
MeCP2 is involved in brain plasticity
In MeCP2- development is OK when experience is not
important
MeCP2 is more critical in older mice
Tam-Cre model at different ages
Other proteins are MeCP2 partners (N-Cor, Sind3A,
GPS2 and others)
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Slide 24 Developmental Stages Balance
Early Stages in Rett results from Glutamate-mediated excitotoxicity during synaptogenesis
Late phase hypo-connectivity of excitatory circuit
Therapies may need to be different at different stages of the disease
Colleen Niswender, PHD Vanderbilt Uni. Medical Center, 2014 IRSA Research Symposium
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Slide 25 Balancing the Excitatory/Inhibitory Balance
In MeCP2 mice model
BDNF Inhibits excitatory in Brain Stem
Enhances Excitatory activity in Cortex
Prefrontal Cortex= NMDA, activity, dendrites
Brainstem = Activity
David Katz, Case Western Reserve University, Colleen Niswender, PHD Vanderbilt Uni. Medical Center, 2014 IRSA Research Symposium
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Slide 26 MeCP2
Type of Mutation is associated with severity
More Severe:
p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions
Less Sever and Atypical Rett:
p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT.
Cuddapah VA, et al. J Med Genet. 2014 Mar;51(3):152-8.
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Slide 27 Other MeCP2 Clinical presentations
X-linked MR
Fatal encephalopathy
Autistic spectrum disorders
Mild learning disability
Normal carrier
Angelman phenotype
Somatic mosaicism
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Slide 28 Males with Rett/MECP2
Few cases described
Early presentation
Severe mental retardation
Some Rett like symptoms:
Hand stereotypies
Breathing abnormalities
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Slide 29 MeCP2 duplication
Duplications in Xq28 : severe mental disability, delayed milestones, absence of language, hypotonia replaced by spasticity and retractions, and recurrent and often severe infections.
Echenne, B., A. Roubertie, et al. (2009). "Neurologic aspects of MECP2 gene duplication in male patients." Pediatr Neurol
2% of Males with MR Campos, M., Jr., S. M. Churchman, et al. "High frequency of nonrecurrent MECP2 duplications among Brazilian males with mental retardation." J Mol Neurosci 41(1): 105-9. 2009
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Slide 30 Cyclin-Dependent Kinase-Like 5
(CDKL5) in Xp22.13
Early-onset, often intractable epileptic seizures (17% of infantile spasm)
Severe mental retardation Most patients also show impaired social interaction
with avoidance of eye-to-eye contact Some clinical features of Rett syndrome (RTT)
Stereotypic hand movements Lack of purposeful hand use Acquired microcephaly Hypotonia One case with classic Rett
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Slide 31 Atypical Rett
(Forkhead box G1 -FOXG1 Deletion)
The Forkhead box G1 (FOXG1) is a transcription
factor that promotes progenitor proliferation and
suppresses premature neurogenesis. Typical stereotypic hand movements with hand-
washing and hand-mouthing activities
Early Symptoms Microcephaly at birth
Hypotonia
2-4 % of Atypical Rett Sx
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Slide 32
Current Research
on
Treatment of Rett
Syndrome
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Slide 33 Treatments Proposals: genetics
• Gene Therapy: replacement
• Challenges in Rett
– Excess of MeCP2 can have severe adverse effects
– Patients do have 50% of the chromosomes with normal MeCP2 gene
– How to deliver only to the cells that need it?
• Aminoglycoside
– Gentamicin, Amikacina
– Shown to read through Missense Mutations( 30 - 40% of girls with Rett Syndrome have missense mutation).
– So far not helpful
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Slide 34 Gene Therapy
Adeno-associated virus serotype 9 (AAV9) vector)
Used AAV9 with MeCP2 cDNA under control of a
fragment of its own promoter (scAAV9/MeCP2)
3 % of cells expressed hMeCP2, these cells 65% more
GABA.
Increased survival (50% more),
Increase MeCP2 in brain
(Cortex, hippocampus)
Increased in heart,
liver, kidney
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Slide 35 Gene Therapy - AAV9 with MeCP2 cDNA
Garg, S et al J. Neurosci., August 21, 2013 • 33(34):13612–13620
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Slide 36
IGF-1 and BDNF
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Slide 37 Insuline like growth factor-1 (IGF-1)
MeCP2 controls BDNF (Brain derived Neuro-trophic Factor)
RTT mice have decreased BDNF
BDNF deficient mice have RTT like symptoms (hand clasp, loss
weight)
Over-expression of BDNF in KO mice (Rett) improves motor and
respiratory abnormalities. BDNF over-expression in hippocampal neurons prevents dendritic
atrophy caused by Rett-associated MECP2 mutations.
Synapsis remains immature but can be “activated”
Molecules that increased BDNF can improve synapsis and function.
IGF increases BDNF
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Slide 38 IG-F1 and BDNF
MeCP2 IGF-1 BDNF P13K PSD95Synaptic
Function
IGF-1 BDNF P13K PSD95Synaptic
FunctionMeCP2
Rett
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Slide 39 IG-F1 and BDNF
IGF-1 BDNF P13K PSD95Synaptic
FunctionMeCP2
Treatment
1-3 IGF
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Slide 40 Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice
with active peptide fragment of Insulin-like Growth Factor 1 (IGF-1).
Tropea D et al. PNAS 2009;106:2029-2034
©2009 by National Academy of Sciences
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Slide 41 Changes in brain structure in MeCP2 mutant mice and the effects of IGF-1 treatment.
Tropea D et al. PNAS 2009;106:2029-2034
©2009 by National Academy of Sciences
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Slide 42 Mecasermin (recombinant human IGF-1)
Walter Kaufmann, MD
Safety Study with 12 girls (3 to 10 years) Post regression
Daily injections, twice a day
4 weeks ascending dose
20 weeks Open Label
Findings:
No side effect
Increase IGF in serum and CSF
Some improvement in cardio-respiratory measurements.
Some improvement in resp-cardio in sleep
Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin
(recombinant human IGF-1) for the treatment of Rett syndrome . Omar S. Khwaja et al.
PNAS, March 25, 2014 Vol. 111 no. 12
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Slide 43 Mecasermin (recombinant human IGF-1)
Walter Kaufmann, MD
Improved anxiety
Improved social
avoidance behaviors
Less breath-holding
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Slide 44 Mecasermin (recombinant human IGF-1)
Walter Kaufmann, MD
No improvement in irritability, aggressiveness,
disruptive/hyperactive behavior, communication,
and motor domains
Started Phase 2 (N=30)
Double blind, cross over
20 weeks
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Slide 45 NNZ-2566
Jeffrey Neul, MD, PhD
Tropea study used a tripeptide [1-3] IGF-1
NNZ-2566 is a peptidase-resistant (no digested in
stomach) analogue to [1-3] IGF-1
Helped in mice
On Phase 1 Clinical Study
Adults 16-45 y
5 days in hospital, multiple measurements (behavior, EEG,
physiologic, ECG, breathing, etc)
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Slide 46 Lab research
MeCP2
IGF-1 BDNF P13K PSD95Synaptic
FunctionIGF-BP
Treatment
BDNF antisense RNA (BDNF-AS)
BD2-4 activates TrKB (receptor for BDNF)
Abnormal Cholesterol
Statins
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Slide 47
Glutamate- NMDA receptors
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Slide 48 Dextromethorphan
Glutamate increased in patients with RTT at younger ages
Glutamate increased in Mice model (Bird)
NMDA receptors are increased in young patients
Glutamate activates NMDA receptors
Overflow of Glutamate have toxic effect
Dextromethorphan is a non-competitive NMDA receptor antagonist
Test for rapid metabolizers (P450 system)
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Slide 49 Dextromethorphan (ongoing study)
Naidu, S @ John Hopkins
Selected girls with high spike activity in EEG.
35 patients randomized , very low dose (control), low dose (2.5 mg), high dose (5 mg)
No adverse effects
Increased Receptive Language at high dose.
Some increase in Expressive language (trend) both doses
On the Mullen scale there was improvement in Receptive language
Improved visual perception on the high dose.
Seizure frequency reduced in 6/10 children with szs below the age of 10 yrs
Better gait (low dose)
Parents report that made girls more alert
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Slide 50
Supplemental Information
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Slide 51
Clinical Issues
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Slide 52
Breathing
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Slide 53 Breathing Abnormalities
Hyperventilation
Breath holding
Apneas: Decreased O2 can result in cyanosis
and fainting
Dysregulation occurs during breathholding as
well as during "normal" breathing
In general better during sleep
Likely explanation for sudden death
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Slide 54 Autonomic System:
Breathing and heart
RS girls have autonomic dysfunction
Most patients with RS have apnea, shallow breathing, or hypoventilation, when awake and during sleep.
Cold hands and feet
They can have:
Bradycardia or tachycardia
Abnormal cardiac conduction
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Slide 55 Air Swallowing
60 % have air bloat,
Apneas and air bloat are often worse when
individuals are distressed
May be reduced with anxiolytic medications.
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Slide 56 Breathing:
Naltrexone (opioid receptor antagonist) if central
apneas with cyanosis. Can improve disorganized
breathing
One study showed a decline in motor function and more
rapid progression of the disorder suggesting a deleterious
effect.
Buspirone (one case described) Serotoninergic
agonist. Improved breathing and oxygen. Also
increase alertness noticed.
Few case reports of improvement with Fluoxetine
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Slide 57 Breathing : No treatment yet, but
Norepinephrine:
• RTT have low synthesis of nor-epinephrine in Brain Stem
• Desipramine (antidepressant) inhibit the re-uptake of Nor-epi, so more stays in the synapsis.
• In mice increases life span and improves apneaZanella S, Mebarek S, Lajard AM et al. 2008. Oral treatment with desipramine improves breathing and life
span in Rett syndrome mouse model. Respir Physiol Neurobiol 160(1):116-121
Study being conducted in Europe
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Slide 58 Sarizotan (Bissonette, J et al, OHSU)
Is a Serotonin 1A Receptor Agonist, D2 partial agonist.
Is in Phase III for treatment of L-dopa induced dyskinesia in Parkinson
Respiratory abnormalities in RTT are due to lack of inhibition
Findings in Rett Mice
One injection: Corrected breathing (87 % less apneas, more regular RR). But, decreased motor activity in WT and Null/y.
Treatment for 7 days in +/- corrected breathing without decreased motor activity
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Slide 59 Use of Hands
Lack of use of hands –hand stereotypies
Use of elbow bracing to limit handwringing
Increases use of hands
Aron M. Brain Dev. 1990;12(1):162-3.
Sharpe PA, et al. Am J Occup Ther. 1990 Apr;44(4):328-32.
Sharpe PA. Am J Occup Ther. 1992 Feb;46(2):134-40.
Apraxia
VERY DELAYED reaction time
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Slide 60 Growth, Short stature
Some girls with RS can present with severe failure to
thrive during the period of regression.
A decrease in growth is apparent in 85-90% of the
patients, inspite of normal or even increased
appetite.[Motil et al. 1994]
Patients with RS show evidence of linear stunting
(height-for-age criteria) but with relatively normal
weight-for-height, BMI, and percentage of body fat [Motil KJ, et al. 1998. J Pediatr 132(2):228-233.
No evidence of thyroid hormones, estrogens or growth
hormone deficiency.[Huppke et al. 2001]
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Slide 61 Feeding and Nutrition
Patients with feeding problems with less preference to hard-to-
chew foods such as meats.
Have prolonged feeding times (92%),
They lack of self-feeding skills (92%),
Have poor oral motor control (69%).
Motil KJ et al. 1999. J Pediatr Gastroenterol Nutr 29(1):31-37.
25 % have GT
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Slide 62 Rett Syndrome and Gastrointestinal Function
GI Motility: Esophageal dysphagia
Gastro-Esophageal Reflux
Delayed gastric emptying
Constipation.
Gallbladder stones
Air swallow
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Slide 63 Heart
Prolonged QT.
Obtain Electrocardiogram - ECG
Consult with cardiology if abnormal
Ellaway CJ, et al. Prolonged QT interval in Rett
syndrome. Arch Dis Child. 1999 May;80(5):470-2.
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Slide 64 Sleep
Abnormal sleep is very common (80 %)
Sleep pattern
Awakening – laughing
Abnormal sleep cycles
Apneas
Snoring
More problems in cases with a large deletion of
the MECP2 gene
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Slide 65 Sleep
No specific treatment:
Routine: Decrease stimulation and Maintain shedule
Medications
Melatonin
Other: Trazodone, Klonopin, Ambien
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Slide 66 Behavior: Agitation-aggressive
Look for a cause (medical, environment)
Responds to Functional communication / Applied behavioral analysis
Use calming activities
No specific medication
Depending on main behavior problem:
Buspar
Ativan
SSRI (Prozac, Paxil)
Antipsychotic medication
Risperidal (Risperidone)
Zyprexa (olanzapine)
Naltrexone (Tranxene)
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Slide 67 Motor impairment
Decrease balance and motor control
Physical therapy, keep them walking
Walking aids, other therapies (hydro, hippo)
Contractures
Maintain range of motion, orthesis (AFO)
Botox
Hypotonia
Carnitine (can also improve sleep and alertness)
Dystonia
Baclofen, Valium, Klonopin
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Slide 68 Communication
Eye movements can be used for communication
Augmentative Communication, i.e.
Tobii
EagleEye
(www.opportunityfoundationofamerica.org/eagleeyes/ )
Make choices
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Slide 69 Others
Few case reports of increased sensitivity to
anesthesia with long recovery time
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Slide 70 Orthopedics:
Scoliosis
Very Frequent ( 45 to 75 %)
Frequency increases with age (stage IV)
Can progress after 18 years of age
Poor response to conservative treatment
TLSO –Thoraco Lumbar Sacral Orthosis
Often needs surgery
Surgery if more than 40 degrees.
Contractures
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