Recent Advances in Rett Syndrome

Recent Advances in Rett Syndrome Mario Petersen, MD Associate Professor of Pediatrics Institute on Developmental Disabilities Child Development and re...
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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. Byiers, B. J., A. Dimian and F. J. Symons (2014). "Functional communication training in rett syndrome: a preliminary study." Am J Intellect Dev Disabil 119(4): 340-350. Downs, J., S. Parkinson, S. Ranelli, H. Leonard, P. Diener and M. Lotan (2014). "Perspectives 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): 16531661. 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

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RETT SYNDROME UPDATE

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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 Syndrome Dr. 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) 

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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.





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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

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Neul J L et al, Ann Neurol 2010; 68:944–950.

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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

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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.

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Weaving L S et al. J Med Genet 2005;42:1-7

©2005 by BMJ Publishing Group Ltd

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History of Rett Syndrome

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MeCP2 identified in 1999 in Huda Zoghbi ‘s lab Amir et al, Nat Genet 1999;23:185–188

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MeCP2 mutations  1.

2.

3.



MeCP2 contains three functional domains: a methyl-binding domain (MBD) on the N-terminus allowing binding to DNA a nuclear localization sequence allowing trafficking of MeCP2 to the nucleus a transcriptional repression domain (TRD), which modulates gene transcription. 80 % have MeCP2 mutation    

Missense mutations Nonsense mutations Frame shift mutations Large deletions

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39% 28% 17% 14.5%

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Slide 13

2001 - KO mice (MeCP2 -) at Huda Zoghbi lab

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Develops progressive symptoms

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 Paws

wringing movements  Poor motor coordination  Smaller brain  Abnormal breathing 

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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 develops Rett  Abnormal gait, hind-limb clasping, tremor, irregular breathing, and poor general condition  Early death

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 Mice





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MECP2 is activated with Tamoxifen When MECP2 is activated with Tamoxifen  Increase

MeCP2 in the brain symptoms, long survival

 Decreased

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Guy, J et al. Science Vol313, 1143-1147

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Slide 16

MeCP2 Reversal of deficit Guy, J et al. Science Vol313, 1143-1147

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Slide 17

Male

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Female

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MeCP2 Reversal of deficit

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Guy, J et al. Science Vol313, 1143-1147 

Developmental absence of MeCP2 does not irreversibly damage neurons.

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Guy, J et al. Science Vol313, 1143-1147

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Slide 19

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MeCP2 function

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Slide 20

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MeCP2 • • •

• •

Binds to DNA activates or inhibits transcription Increased MeCP2increased 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.

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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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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



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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, Brainstem = Activity

activity,

dendrites

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:

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 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: 

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 Hand

stereotypies  Breathing abnormalities

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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



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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) hand movements  Lack of purposeful hand use  Acquired microcephaly  Hypotonia  One case with classic Rett

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 Stereotypic

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Slide 31

Atypical Rett (Forkhead box G1 -FOXG1 Deletion)

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The Forkhead box G1 (FOXG1) is a transcription factor that promotes progenitor proliferation and suppresses premature neurogenesis. Typical stereotypic hand movements with handwashing and hand-mouthing activities Early Symptoms

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 Microcephaly

at birth

 Hypotonia  2-4

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% of Atypical Rett Sx

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Slide 32

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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?

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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

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Garg, S et al J. Neurosci., August 21, 2013 • 33(34):13612–13620

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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

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IG-F1 and BDNF MeCP2

IGF-1

BDNF

P13K

PSD95

Synaptic Function

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Rett MeCP2

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IGF-1

BDNF

P13K

PSD95

Synaptic Function

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Slide 39

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IG-F1 and BDNF

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Treatment MeCP2

IGF-1

1-3 IGF

BDNF

P13K

PSD95

Synaptic Function

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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)

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.

___________________________________ ___________________________________ ___________________________________ Tropea D et al. PNAS 2009;106:2029-2034

©2009 by National Academy of Sciences

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Changes in brain structure in MeCP2 mutant mice and the effects of IGF-1 treatment.

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Tropea D et al. PNAS 2009;106:2029-2034 ©2009 by National Academy of Sciences

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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

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 

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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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Mecasermin (recombinant human IGF-1) Walter Kaufmann, MD

Slide 43

 Improved

anxiety social avoidance behaviors  Less breath-holding  Improved

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Slide 44 



Mecasermin (recombinant human IGF-1) Walter Kaufmann, MD

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No improvement in irritability, aggressiveness, disruptive/hyperactive behavior, communication, and motor domains

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Started Phase 2 (N=30)

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Double

blind, cross over 20 weeks

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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 16-45 y  5 days in hospital, multiple measurements (behavior, EEG, physiologic, ECG, breathing, etc)

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 Adults

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Slide 46

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Lab research

IGF-BP

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Treatment

MeCP2

IGF-1

BDNF

P13K

PSD95

BDNF antisense RNA (BDNF-AS) BD2-4 activates TrKB (receptor for BDNF)

Synaptic Function

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

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Supplemental Information

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Slide 51

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Clinical Issues

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Slide 52

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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  Abnormal

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or tachycardia

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 study showed a decline in motor function and more rapid progression of the disorder suggesting a deleterious effect.

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 One





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 reuptake of Nor-epi, so more stays in the synapsis. • In mice increases life span and improves apnea Zanella 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. 

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Apraxia  VERY

DELAYED reaction time

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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-tochew foods such as meats. Have prolonged feeding times (92%), They lack of self-feeding skills (92%), Have poor oral motor control (69%).

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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

Reflux  Delayed gastric emptying  Constipation.

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 Gastro-Esophageal

Gallbladder

Air

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stones

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

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Sleep  

Abnormal sleep is very common (80 %) Sleep pattern  Awakening  Abnormal



– laughing sleep cycles

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Apneas

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 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



Naltrexone (Tranxene)

  

 

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Risperidal (Risperidone) Zyprexa (olanzapine)

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Slide 67

Motor impairment 

Decrease balance and motor control  



Physical therapy, keep them walking Walking aids, other therapies (hydro, hippo)

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Contractures  

Maintain range of motion, orthesis (AFO) Botox



Hypotonia



Dystonia





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Carnitine (can also improve sleep and alertness) Baclofen, Valium, Klonopin

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Slide 68

Communication 

Eye movements can be used for communication  Augmentative

Communication, i.e.

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 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.

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Contractures

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