dr. tim benke - the rett clinic at children's hospital colorado

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


• 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


abnormality

EKG every 1-2 Years


abnormality

EKG every 1-2 Years


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


age 4yo



curvature appears




Exam


age 4yo



curvature appears




Exam


age 4yo



curvature appears




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


D and calcium daily


BMI


D and calcium daily


BMI


D and calcium daily


BMI

Eye and Dental Exams

Regular Eye exams

Dental exams every 6

months/as needed

Yearly Eye exams


months/as needed

Yearly Eye exams


months/as needed

Regular Eye exams


months/as needed

Therapies

Lifelong PT(ranging from 1-

2x/week- 1x/month)

AAC assessment


Regular seating

assessments

Lifelong PT (ranging from 1-

2x/week- 1x/month)

Vision therapy if needed

AAC assessment


Regular seating

assessments

Lifelong PT(ranging from 1-

2x/week- 1x/month)

Vision therapy if needed

AAC assessment


Regular seating

assessments

Lifelong PT (ranging from 1-

2x/week- 1x/month)

AAC assessment


Other

Regular Vaccines including

Flu

Boosters in adolescence

and adulthood


Flu


and adulthood


Flu


and adulthood


Flu


and adulthood

Immunologist referral


• 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

dr. tim benke - the rett clinic at children's hospital colorado

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