Post on 21-Jan-2017
The Rett Clinic at Children’s Hospital ColoradoOverview & Research
Tim Benke, M.D., Ph.D.
Assoc. Prof. Pediatrics, Neurology, Otolaryngology and Pharmacology
University of Colorado School of Medicine and
Medical Director, Rett Clinic
Research Director, Neurosciences Institute
Children’s Hospital Colorado
Tristen Dinkel, BSN RN; Rett Clinic Coordinator
The Rett Clinic Team
Disclosures1. RO1 NS076577 (Benke)
NIH/NINDS
Molecular mechanisms linking early life seizures, autism and intellectual disability
Role: PI.
2. Questcor Pharmaceuticals (Benke)
Whole-exome sequencing and ACTH responsiveness in Infantile Spasms
Role: PI.
3. 1U10NS077277(Vollmer)
NIH/NINDS
Rocky Mountain Network for Neuroscience Clinical Studies (NeuroNext Clinical Site)
Role: Co-I.
4. U54 HD061222 (Percy)
NICHD
Rett syndrome, MECP2 Duplication Disorder, and Rett-related Disorders Natural History.
Role: Site Director, Co-I, 5212 sub-protocol CoI.
5. Rett Clinic at Children’s Hospital Colorado (Benke)
Rocky Mountain Rett Association
Role: PI/Medical Director
6. CDKL5 Center of Excellence (Benke)
International Foundation for CDKL5 Research
Role: PI
7. Neuren: Study of trofinetide, also known as NNZ-2566, for females with Rett Syndrome
Role: site PI
8. RSRT (Benke). OMBD: Outcome Measures and Biomarker Development for Rett Syndrome.
Role: site PI
9. CURE (Traynelis). Functional and clinical evaluations of glutamate receptor mutations in epileptic encephalopathies.
Role: site PI
Topics today
• The Rett Clinic at Children’s Hospital Colorado• Clinic profile
• Research approach in a clinical setting
• Research in Rett and Rett-related disorders at Children’s Hospital Colorado/University of Colorado School of Medicine
The Rett Clinic at Children’s Hospital Colorado:
Established thanks to a generous and repeated gifts from the Rocky Mountain Rett Association (RMRA). Started December 14, 2011. Only clinic in multi-state region.
Purpose:
Consultation and evaluation for all people with Rett Syndrome and genetically related disorders (MeCP2, MeCP2dup, CDKL5, FOXG1 and other related)
Ensure they are receiving the needed therapies, treatments and services to live a quality life.
We serve people of all ages.
Provide up-to-date information on Rett Syndrome, CDKL5 and FOXG1 to parents, physicians, therapists and care providers.
Participate in ground-breaking clinical research trials.
Partner with support organizations
Work as a team with the family and the primary care providers.
Train future providers
Family support
What it looks like:
Integration through a multi-disciplinary approach to provide optimal care
RN coordinator driven (Tristen Dinkel RN BSN)
6x/year clinic
Providing new and follow-up assessments
Clinic appointment involves a four hour block with consultation by all pertinent specialists in one centralized location
The patient/family stays in one room with providers moving to the families’ location in a round-robin format. Specialized Multi-Discipline area since 2015.
4-5 new and 4-5 follow-up patients seen per session-
Intake packets filled out prior to visit (3 weeks)
• Team reviews over lunch 1 week prior to clinic
• Outside records reviewed and archived for completion
• Insurance pre-authorizations
• Parent/therapist/provider questions
Team addresses questions/concerns while in clinic.
Our Team:
18 members representing individual professional disciplines:
Timothy Benke, PhD, MD
Neurology/Medical Director
Tristen Dinkel, RN, BSN
Nurse Clinic Coordinator
Anne Stratton, MD
Rehabilitation
Sandra Friedman, MD, MPH
Developmental Pediatrics
Sumeet Garg, MD
Orthopedic Surgery
Terry Katz, PhD
Neurodevelopment & Behavioral Pediatrics
Margarita Saenz, MD
Clinical Genetics
Michael Schaffer, MD
Cardiology
Oren Kupfer, MD
Pulmonary
Jaime Guthrie, PT, DPT, CFMT
Physical Therapy
Margaret Spring, M.S., OT
Occupational Therapy
Meghan Roe M.Ed., CCC-SLP
Augmentative Communication Specialist
Laura Watne, MS RD
Nutrition
Ed Liu, MD
GI/Nutrition
Scott Demarest, MD
Neurology/Epilepsy
Katie Angione, MS, CGC
Certified Genetic Counselor
Joanna Reeder, LCSW
Social Work
Carrie Rose-Matens
RMRA Representative
Our Team:
Who is missing? (how is this filled in…)
• Ophthalmology (Neurology)
• Gynecology (available by consultation and here today!)
• Movement specialist (Neurology, Rehabilitation)
• Immunologist (Pulmonary)
• Sleep (Neurology, Pulmonary, Development/Behavior)
• Other?
Why have a multidisciplinary Rett clinic?Our patient population:
Rett syndrome: MeCP2 changes
• 91 followed in clinic
• Estimate: 250+ in region
Rett-related conditions: CDKL5, FOXG1
Unknown prevalence
• CDKL5: 36 seen in clinic, more than any other center
• FOXG1: 3 with FOXG1
• International CDKL5 Foundation “Center of Excellence”
Referrals from across the country
Research Questions, Specific Aims and Hypotheses, Status and Issues
• Questions:• What is the natural history?
• What are the associated features?
• What predicts natural history?
• Epilepsy?
• Biomarkers?
• Specific mutations?
• How does this impact families?
• How can we positively affect this?
• What are the best treatments?
• What are standards of care?
Research via the Rett Clinic(1): the NHS
• NIH-funded Natural History Study of Rett and Rett-related disorders• Has followed over 1000 patients over past 10 years• Genotype/phenotype, Epilepsy, GI, Scoliosis, life-expectancy: published
standards
• Renewed funding: 9/2014• Partnership with RettSyndrome.org• Revamped data instruments• Now enrolling at CHCO as of July 2017• New: more biomarkers (objective measures of severity and improvement)
• 5211: parent protocol (now enrolling)• 5212: neurophysiological biomarkers (enrolling fall 2016)• 5213: genetic and metabolic biomarkers (enrolling fall 2016)• 5214: Behavioral analyses (2017)
• Study visits occur separately for regular Rett Clinic• 5211: Data gathered takes 2-3 hours (5211)• 5212: separate EEG/AEP/VEP (1 hour); controls needed!• 5213: additional blood draw• 5214: parental questionnaires
5211: Participating Institutions and InvestigatorsConsortium Study Chair: Alan K. Percy, MD, UAB
Study Administrator and CoPI: Jeff Neul MD, PhD, UCSD
CoPI: Walter Kaufmann, MD, Greenwood Genetics
Site PIs
Eric Marsh, MD, PhD, Children’s Hospital of Philadelphia
Tim Benke, MD, PhD, University of Colorado
Mustafa Sahin, MD, PhD, Boston Children’s Hospital
Sarika Peters, PhD, Vanderbilt University
Alexander Paciorkowski, MD, University of Rochester
Steve Skinner MD, Greenwood Genetics
Dan Glaze MD, Baylor College of Medicine
Peter Heydemann and Elizabeth Berry-Kravis, Rush
Mary Jones MD, UCSF
Steven Kaminsky, PhD, Rettsyndrome.org
Data Management and Coordinating Center Principal Investigator:
Jeffrey Krischer, PhD, University of South Florida
National Institutes of Health:
NICHD: Program Officer: Melissa Parisi, MD, PhD;Project Scientist: Danuta Krotoski, PhD
NINDS: Program Officer: Laura Mamounas, PhD
5211: Inclusion criteria
Females and males of all ages must have:
Testing for MECP2, CDKL5, and /or FOXG1 genetic changes.
AND must meet these requirements:
Gene positive for a sequence change, duplication or deletion in one of these 3 genes.
OR
Meet consensus criteria for Rett syndrome (typical or atypical)
5211: Enrollment
This study plans to enroll at least (over 5 years):
All ages
1000 subjects with RTT
100 subjects with MECP2 duplication
100 subjects with RTT related disorders
50 with FOXG1
50 with CDKL5
< 10 years of age: Annual
10-20 years of age: Bi-annual
>20 years old: Every four years (twice during funding cycle)
5211: Data Instruments
Clinician or Coordinator completed or confirmed data forms and logs Clinical Assessment Form Physician’s Initial History Form Motor Behavioral Assessment Score (computer generated score from clinical assessment) Clinical Severity Assessment Score (computer generated score from clinical assessment) Demographic and Birth History Form Interval History Form Log Master Form Abnormal Movements Log Allergies Log Bone Fracture Log Current Living Arrangements Log Demographic and Birth History Form Developmental Log Diagnosis and Genetics Log Diet Log EEG Log Hospitalizations and ER Visits Log Infections Log Labs Log Medical History Log Medications Log Other Research Log Pregnancy and Siblings Log Puberty Log Seizures and Other Spells Log Surgical Log Tests Log
Parent completed instruments
SF-36 QOL (all disorders)
CHQ QOL (all disorders)
Beach Family Center QOL – (MECP2 Dup and RTT-related)
Aberrant Behavior Checklist – (MECP2 Dup)
Autism Diagnostic Interview-revised – (MECP2 Dup)
5212: Participating Institutions and InvestigatorsConsortium Study Chair: Alan K. Percy, MD, UAB
Principal Investigator and Study Lead Investigator:
Eric Marsh, MD, PhD, Children’s Hospital of Philadelphia
Principal Investigator and Study Co-Lead Investigator:
Tim Benke, MD, PhD, University of Colorado
Principal Investigator: Mustafa Sahin, MD, PhD, Boston Children’s Hospital
Principal Investigator: Sarika Peters, PhD, Vanderbilt University
Principal Investigator: Alexander Paciorkowski, MD, University of Rochester
Principal Investigator: Steven Kaminsky, PhD, Rettsyndrome.org
Data Management and Coordinating Center Principal Investigator:
Jeffrey Krischer, PhD, University of South Florida
National Institutes of Health:
NICHD:
Program Officer: Melissa Parisi, MD, PhD
Project Scientist: Danuta Krotoski, PhD
NINDS:
Program Officer: Laura Mamounas, PhD
Neurophysiology Consultants:
Charles A. Nelson, PhD, Boston Children’s Hospital
Michela Fagiolini, PhD, Boston Children’s Hospital
Timothy P. Roberts, PhD, Children’s Hospital of Philadelphia
5212 Background
Multiple lines of evidence for synaptic pathophysiology resulting in network dysfunction in animal and humans with Rett and Rett-related disorders
5212: Background
Abnormal VEP in RTT. The red graph shows reductions in VEP (N1-P1) amplitude in RTT while the right graph depicts increases in latency in RTT, in this case P1-N2 time. LeBlanc JJ, DeGregorio G, Centofante E, Vogel-Farley VK, Barnes K, Kaufmann WE,
Fagiolini M, Nelson CA (2015) Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann Neurol78: 775-786.
5212: Background
Cortical physiology of Cdkl5 mice. A. EEG from Cdkl5 ko and wt animals. B and C. Raw AEP wave form and quantification of AEP amplitude. D. Gamma band frequency is calculated and different between genotypes. Wang IT,
Allen M, Goffin D, Zhu X, Fairless AH, Brodkin ES, Siegel SJ, Marsh ED, BlendyJA, Zhou Z (2012) Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc Natl Acad SciUSA 109: 21516-21521.
5212: Background
Grand average time-frequency representations and topographies from the preliminary data auditory EEG paradigm. Induced gamma power differed for familiar and unfamiliar voices in the RTT group (left) and the MECP2 Dup group (right), showing opposite trends. Peters SU, Gordon RL, Key AP (2015) Induced gamma oscillations
differentiate familiar and novel voices in children with MECP2 duplication and Rett syndromes. J Child Neurol 30: 145-152.
5212: Background
Right-sided frontal alpha band
EEG asymmetry is common in RTT
and shows a trend toward reversal
with IGF-1 treatment. Six subjects
evaluated before IGF-1 treatment
(Pre-OLE) demonstrated R > L
asymmetry. Although the degree of
asymmetry was variable after
treatment (Post-OLE), five of the six
showed a decrease in the asymmetry
index and in three there was a
reversal. A paired-samples t test
revealed significant group differences
Pre- and Post-OLE. Khwaja OS, et al (2014)
Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human-IGF1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A 111: 4596-4601.
Purpose of 5212
Gap addressed:
The relationship(s) between neurophysiological findings:
• Visual evoked potentials
• Auditory evoked potentials
• EEG
and
disease evolution,
severity and
specific clinical features
in Rett and Rett-related disorders is unknown.
Purpose of 5212
• Advance understanding of the neurophysiological features of: • Rett syndrome (RTT)
• MECP2 Duplication (MECP2 Dup)
• CDKL5
• FOXG1
• Gain insight into disease pathogenesis
• Identify biomarkers of disease evolution and severity
• Intertwined to the core study Natural History of Rett Syndrome and Related Disorders (RTT5211)
• Serve as basis of future translational investigations• Refinement of biomarkers & development of outcome measures
5212: Primary Outcome measures
1. Auditory Evoked Potential (AEP) latency (ms)
2. Auditory Evoked Potential amplitude of P1, P2 and N1 peaks (uV)
3. Visual Evoked Potential P1-N2 time (ms)
4. Visual Evoked Potential (VEP) amplitude of N1-P1 (uV)
latency amplitude
5212: Secondary Outcome Measures
1. AEP: Change in power of gamma band activity (delta dB at 30-70Hz band between pre-stimulus and post-stimulus).
2. Frontal alpha band activity asymmetry index
3. Other AEP and VEP parameters.
5212: Enrollment: Inclusion criteria
Females and males of all ages must have:
Testing for MECP2, CDKL5, and /or FOXG1 genetic changes.
AND must meet these requirements:
Gene positive for a sequence change, duplication or deletion in one of these 3 genes.
AND
Those with Rett syndrome phenotype should meet consensus criteria for typical or atypical Rett syndrome.
AND
Enrolled in RTT5211.
5212: Enrollment
• RTT: 60 female subjects evaluated up to 3 times (annual evaluations)20 in stage 2 (active regression) or <12 months since last skill loss (~2-5 y.o.)20 children in stage 3 (post-regression, >12 months since last skill loss; ~5-12 y.o.)20 adolescents/adults (all in stage 3, post-regression; >12 y.o.)
• CDKL5: 18 female subjects evaluated three times (annual evaluation)6 in infancy, during the period associated with infantile spasms (~2mo-2 y.o.)6 in childhood, after the cessartion of infantile spasms (~2-12 y.o.)6 adolescents/adults (>12 y.o.)
• MECP2 dup: 18 male subjects evaluated three times (annual evaluation)9 in early childhood, prior to onset of epilepsy (~2-10 y.o.)9 adolescents/adults, post onset of epilepsy (>10 y.o.)
• FOXG1: 14 male/female subjects evaluated three times (annual evaluation)
6 in infancy, during the period associated with infantile spasms (~2mo-2 y.o.)5 in childhood, after the cessation of infantile spasms (~2-12 y.o.)3 adolescents/adults (>12 y.o.)
5212: Enrollment: Controls
30 females evaluated up to 3 times (annual evaluation)10 females in early childhood (~2-5 y.o.)
10 females in late childhood (~5-12 y.o.)
10 female adolescents/adults (>12 y.o.)
30 males evaluated up to 3 times (annual evaluation)10 males in early childhood (~2-5 y.o.)
10 males in late childhood (~5-12 y.o.)
10 male adolescents/adults (>12 y.o.)
5212: Timeline
NIH approval of 5212 protocol: 5/13/2016; 8/2016 (amendments)
Local IRB approvals: submitted/in-process. Due 9/1/2016
Validation of local data/technology
Human “phantoms” (Marsh and Roberts)
Visits to establish cross-site data parity: 10/2016
Initial visits: September 2016 (year 1)
2nd visit/Year 2: September 2017
3rd visit/Year 3: September 2018
5212: Challenges and Limitations
Technical:
Establishing uniformity across sites
Translating protocol into clinical practice
EEG:
Not a surrogate for epilepsy assessment
limited sample (no sleep or other behaviors)
EEG “e-bank” needed
Frequency analysis:
Alternative behavioral correlates (other than AEP/VEP)
Patient numbers/statistical power
Phenotypic & genotypic variability
RTT versus Rett-related
Research via the Rett Clinic(2)
• Outcome Measures and Biomarker Development• Sponsored by Rett-syndrome Research Trust (RSRT)
• Funding 9/2016, enrolling fall 2016 in parallel but separate with 5211
• Enrollment: Patients with RTT only
• Biomarkers
• Breathing
• Anxiety/stress
• Genetic
• Gait
• Movement
Research via the Rett Clinic(3)
• CDKL5 research consortium: IFCR Centers of Excellence• University of Colorado/Children’s Hospital Colorado
• Lead: Benke
• Boston Children’s/Harvard• Lead: Olson
• Cleveland Clinic• Lead: Parikh
• Greenwood Genetics• Lead: Kaufmann (from Boston)
• Goals: • Clinical Care tailored to CDKL5 syndrome
• Advancing Research as fast as possible
• Determining Standards of Care
• Enrollment: all patients seen in clinic with CDKL5
• Funding 2014-2015; enrolling since 2014
COE: Aims
1. Longitudinal and very structured evaluations can define the natural history of CDKL5 syndromes. We will perform structured clinical evaluations in our CDKL5 patients as part of their Rett clinic evaluations.
2. Structured laboratory (MRI, EEG, etc) data collection obtained from clinical evaluations will define biomarkers that can predict clinical course. We will collect structured laboratory data in our CDKL5 patients.
3. A defined natural history is necessary to determine the efficacy of future clinical trials. We will serve as sites for future clinical trials.
COE: Approach
• Implement structured clinical questionnaire• RedCAP
• Must address research questions, amenable to statistics/quantitative
• Efficient • Patient elements completed during “standard visit”
• Family elements complete but not overly burdensome
• Perfect not enemy of good
• Review of outside records (EEG, MRI, genetics, etc)• Completed outside of clinic
• Common, shared international data instrument, single database (or multiple linked dbs)• Governance, ownership, authorship, IRBs, standardization
• Collaboration/Confederation/Federation
COE: Status and Issues
• Deliverables• 3 papers by end of 2016 submitted (hopefully)
• 4th paper by mid 2017 submitted
• 5th paper: standards of care, mid 2017
• Threading together the data across sites
• New sites/collaborations/data sharing requests
• New questions/adding to the forms/circling back
• Similar/dissimilar approaches
• Low budget (vs NHS) but nimble
• Time• Record review especially EEG review (not just reports)
• Data entry, analysis
Emerging standards of care: Quick view
• Multidisciplinary team; every 1-2 years• Convenient, accessible, interested
• Genetic consultation and counseling• Missense mutations: parental confirmation
• Yearly EKG (looking for prolonged QTc)• Referral, prolonged/halter if abnormal
• Yearly clinical spine evaluation; every 6 months if abnormal• Imaging if abnormal; referral to orthopedics if > 10deg; correction > 30-
40deg
• Prolonged EEG; sleep studies• For new spell types, evolving spell types; sleep issues
• Therapies• Lifelong, Multifaceted• Accommodations for visual impairment in the classroom
• Bone health (Vitamin D 400-800U/calcium/day)• Regular dental exams; regular eye exams• GYN health
Emerging standards of care
Rett Program Recommendations
Childhood Through AdulthoodRETT CDKL5 FOXG1
MECP2
Duplication
Cardiac Evaluations
EKG every 1-2 Years
Cardiology referral for any
abnormality
EKG every 1-2 Years
Cardiology referral for any
abnormality
EKG every 1-2 Years
Cardiology referral for any
abnormality
EKG every 1-2 Years
Cardiology referral for any
abnormality
Spine evaluations
Yearly Physical Exam after
age 4yo
Upright (sitting or standing)
Spine x-ray imaging if
curvature appears, then
Physical Exam every 6
months until stable through
puberty
Orthopedics referral for
curvature >10 degrees
If corrected, yearly Physical
Exam
Yearly Physical Exam after
age 4yo
Upright (sitting or standing)
Spine x-ray imaging if
curvature appears
Orthopedics referral for
curvature >10 degrees
If corrected, yearly Physical
Exam
Yearly Physical Exam after
age 4yo
Upright (sitting or standing)
Spine x-ray imaging if
curvature appears
Orthopedics referral for
curvature >10 degrees
If corrected, yearly Physical
Exam
Yearly Physical Exam after
age 4yo
Upright (sitting or standing)
Spine x-ray imaging if
curvature appears
Orthopedics referral for
curvature >10 degrees
If corrected, yearly Physical
Exam
Vitamin D and calcium
supplements
Vitamin D Level
Nutritional assessments
At least 400-800 U Vitamin
D and calcium daily
Follow levels yearly
BMI
At least 400-800 U Vitamin
D and calcium daily
Follow levels yearly
BMI
At least 400-800 U Vitamin
D and calcium daily
Follow levels yearly
BMI
At least 400-800 U Vitamin
D and calcium daily
Follow levels yearly
BMI
Eye and Dental Exams
Regular Eye exams
Dental exams every 6
months/as needed
Yearly Eye exams
Dental exams every 6
months/as needed
Yearly Eye exams
Dental exams every 6
months/as needed
Regular Eye exams
Dental exams every 6
months/as needed
Therapies
Lifelong PT(ranging from 1-
2x/week- 1x/month)
AAC assessment
Occupational Therapy
Regular seating
assessments
Lifelong PT (ranging from 1-
2x/week- 1x/month)
Vision therapy if needed
AAC assessment
Occupational Therapy
Regular seating
assessments
Lifelong PT(ranging from 1-
2x/week- 1x/month)
Vision therapy if needed
AAC assessment
Occupational Therapy
Regular seating
assessments
Lifelong PT (ranging from 1-
2x/week- 1x/month)
AAC assessment
Occupational Therapy
Other
Regular Vaccines including
Flu
Boosters in adolescence
and adulthood
Regular Vaccines including
Flu
Boosters in adolescence
and adulthood
Regular Vaccines including
Flu
Boosters in adolescence
and adulthood
Regular Vaccines including
Flu
Boosters in adolescence
and adulthood
Immunologist referral
Research via the Rett Clinic(4)
• Clinical trials• Neuren
• First drug to be specific for Rett syndrome
• Stimulates brain growth and development; targets deficiency of brain growth factors
• Phase 2-now, Phase 3-2018?
• Enrolling at CHCO! RTT, ages 5-15yo
• IFCR CDKL5 Clinical Trials Committee (emerging)
• Streamline approach when PhRMA comes calling
• Agreed protocol generalities
Special Thanks!!! Tristen DinkelScott Demarest
Margarita SaenzGina VanderVeen
Rett Clinic Team
IFCR-COE collaborators:Heather Olson, Sumit Parikh, Walter
Kaufmann, Elia Pestana-Knight
NHS-Natural History Study: Eric Marsh, Alan Percy, Jeff Neul, Alex Paciorkowski, Laura Mamounas, Tim Roberts, Chuck Nelson, Sar Peters, Michaela Fagiolini, etc
Rocky Mountain Rett AssociationPonzio Family Chair in Neuroscience
Research
Our patients and families