4th Annual Washington University
Wolfram Syndrome Research Clinic
Research Update, Clinical Q&A
July 20, 2013
The Jack and J.T. Snow
Scientific Research Foundation
Agenda
• 8:00
Announcements
• 8:10 – 8:45 WU WFS Study Group Progress
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International meeting
Human Research: Dr. Hershey
Cellular Research and Drug screening: Dr. Urano
Clinical: Dr. Marshall
• 8:45 – 9:15 Brief clinical presentations
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Dr. Reierson – Child Psychiatry
Dr. Yamada – Sleep
Dr. Gronski – Occupational Therapy
Dr. Marshall – Endocrinology; Treatment of Diabetes Insipidus
• 9:15 – 10:00
Q&A to physicians, researchers
• 10:00- 10:30
Family/parent open discussion
A new world’s record…
• 21 MRIs
• 326 individual appointments
• In 3.5 days!
Announcements
• Pick up handouts on table
• Fill out Medical Release forms for relevant doctors
– Return to Samantha or give to your doctor
• Fill out reimbursements forms, if necessary
– Return to Samantha
• Return any questionnaires that you still have
– Return to Samantha
• Questions after you get home?
– Samantha Ranck (314-362-6514; rancks@npg.wustl.edu)
– Dr. Hershey (number on consent; 314-362-5593;
tammy@wustl.edu)
– Dr. Marshall (office 315-454-6051)
• Skin Biopsy Care
• Speakers from US, Japan, UK, France, Spain
• Attendees from these and other countries
• Topics:
– Progress in research
– Establishment of new collaborations
– Discussion of
• Basic biology of wolfram protein
• Development of new biomarkers for monitoring disease progress
• Development of new treatments for Wolfram syndrome
– Harmonization of clinical management
• Guidelines being written
Wolfram Research @ WU
Natural history of
neurological &
other features
WFS1 patients
WU Wolfram
Syndrome Study
Group
iPSCs
Neurons, β cells
Serum
biomarkers
Wfs1 & Wfs2
knock-out mice
Funded by NIH, ADA, JDRF, Snow Foundation
Characterization
of phenotype
Human Research
• Why do longitudinal patient studies?
– Clinical trials require:
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Knowledge of natural history of disease
Methods for capturing overall disease severity (rating scale)
Reliable and sensitive markers of change in disease status
Identification of the most important clinical targets of treatment
• This information did not exist prior to our study
• We have made significant progress on addressing these
questions, but need more longitudinal data to improve
our understanding.
Human Research Progress
• We have:
– Defined specific brain structural differences
– Determined that balance & gait differences are apparent
– Developed, and shown reliability and validity of the
Wolfram Unified Rating Scale (WURS)
– Described auditory and vestibular findings
– Described overall clinical phenotype
Human Research Progress
• Papers from human research:
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1. Hershey et al: (2012) Early brain vulnerability in Wolfram syndrome; PLOS ONE; 7(7).
2. Pickett et al: (2012) Balance impairment in Wolfram syndrome. Gait and Posture; Jul,
36(3): 619-624.
3. Nguyen et al: Reliability and validity of the Wolfram Unified Rating Scale (WURS).
Orphanet J of Rare Disorders
4. Marshall et al: Clinical phenotype of early Wolfram syndrome. Orphanet J of Rare
Disorders
5. Karzon et al: Audiologic and Vestibular Findings in Wolfram Syndrome. Ear and Hearing
6. Pickett et al: Early presentation of gait impairment in Wolfram Syndrome. Orphanet J of
Rare Disorders
7. Chisolm et al.: Vision deficits in Wolfram syndrome. In preparation
8. Lugar et al: Longitudinal brain change in early Wolfram Syndrome. In preparation
• Grants for Human Research:
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NIH 5 year grant for clinic (in 2nd year)
ADA, JDRF, Snow Fund
Preliminary data on change over time
Cerebellar gray
Cerebellar white
Midbrain
Pons
Medulla
Lugar et al: 2013 ADA poster
Conclusions
• Direct, quantified measurement of Wolfram features
reveal subtle brain structure and functional differences at
an early stage.
• Understanding the developmental vs. degenerative
course of these features will be important.
• All of this information is crucial for preparing for future
clinical trials.
Human Research Progress
• Research clinic funded until 2016
• Next year’s dates: 7/15/14 – 7/19/14
• Possible additional research clinics during the year or
overlapping clinics
– e.g. 7/14-7/16 and 7/16-7/19
• Add siblings?
• Possibly move some assessments to the clinical side only
• Collaboration with Dr. Barrett in UK
– Blending registries
– Harmonizing data collection, disseminate WURS
Biomarker and Treatment
For Wolfram Syndrome
Fumi Urano, MD, PhD
Washington University
@ Wolfram syndrome Workshop
July 20th, 2013
Three Step Formula
Treat
Clinical Study
Identify
Biomarkers Compounds
Understand
Registry & Clinic
iPSC & Animal Models
Wolfram Syndrome
• Insulin dependent diabetes
• Optic atrophy
• Neurodegeneration
• Sensorineural deafness
• Diabetes insipidus
• Neuropathic bladder
ER-cytosol shunt
Calcium Leakage
?
Cell Death
International
Registry
90 patients
26 patients
Wolfram
Clinic
Understand
Wolfram
Induced Pluripotent Stem Cells
(iPS cells)
Beta Cells
Skin fibroblasts
iPS Cells
Neurons
Neurons derived from Wolfram-iPSCs
Control subjectl
Wolfram patient
Dysregulated calcium homeostasis
in Wolfram iPSC-derived neural progenitor cells
Cytoplasmic calcium levels
0.56
0.55
0.54
0.53
0.52
0.51
0.5
0.49
0.48
0.47
1
2
3
Increased Calpain 2 expression and
activation in patients’ neurons
Control Wolfram
Cleaved-Spectrin
CAPN2
Chop expression is increased in Wolfram
iPSC-derived neural progenitor cells
Neual Progenitor Cell Day 0
CHOP
Relative RNA level
2.5
2
1.5
1
0.5
0
1
2
3
4
ER-cytosol shunt
MOLECULAR PROSTHESIS
Calcium Leakage
Calpain 
Chop 
Cell Death
ANTI CELL DEATH
Gel_1
C33 /
WS5
1
110 kDa
6
4
5
9
7
8
75 kDa
11
50 kDa
2 3
12
Transferring
10
14
Albumin
13
Molecules increased in
patients’ sera
17
15
16
18
40 kDa
19
20
21
23
27 28
25 kDa
24 25 26
22
Three candidates
1. Caspase-12
2. MANF
3. Genomic DNA from beta cells
20 kDa
29
30
14 kDa
pH
4.0
5.0
5.5
6.0
6.5
7.0
8.0
9.0
24
Clinical Progress
• Center of Excellence – in progress. Call or
email if interested.
• Clinically valid genetic testing now available at
WUSM
Clinical Presentations
5 min each
• Angela Reierson, MD
– Child and adolescent psychiatrist
• Kel Yamada, MD
– Pediatric neurology; Sleep and epilepsy specialist
• Meredith Gronski, OTD
– Pediatric occupational therapist; school specialist
• Bess Marshall, MD
– Pediatric endocrinologist; Medical director of
Wolfram Research Clinic
OT Services for Children and Youth
Meredith Gronski, OTD, OTR/L
Occupational Therapist
Washington University Program in Occupational Therapy
Community Practice Program: Children, Youth & Families
Occupational therapy…
• Enables people with illness, injuries and
chronic conditions to live life to its fullest
• Designing strategies for everyday life and
customizing environments to develop and
maximize performance.
How many of you utilize OT services?
Areas of Concern
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Fine motor
Gross motor/Balance
Attention
Behavior
Multisensory Processing
Visual Perception
Social Interaction
Executive Function/Cognition
Play Skills
Self-Care/Adaptive Skills
Feeding & Eating
Environmental barriers
Motor Strategies
• Stabilization
• Energy Conservation
• Cognitive Oriented Approach
– Develop strategies for success
Low Vision Strategies
• Low vision rehab
– Lighthouse for the Blind:
http://lighthouse.org/?gclid=CJ29z_nTu7gCFeoWMgodpzkAiA
– American Foundation for the Blind: http://www.afb.org/default.aspx
– Find local resources…
• St. Louis- StL Soc for Blind and Visually Impaired; Delta Gamma
• Occupational therapy strategies:
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Magnification
Increase Contrast
Lighting
Visual scanning techniques/ Eccentric viewing
• Hearing Loss
– Alexander Graham Bell Association: www.agbell.org
WU Program in OT: Community
Practice
• Community practice vs clinical practice
– Home-school-neighborhood connections
• Objective, comprehensive evaluation for children & youth
receiving public special education services
• Social skills and other therapeutic group programming
• Early Intervention providers
• Consultation to private/parochial schools
– Advocacy and navigating school-based services
314-362-5079
Questions?
gronskim@wustl.edu
286-1109
Endocrinology updates
• Diabetes insipidus in Wolfram
– Very difficult to manage due to confusion of cause
of excessive urine output.
– Working on obtaining home sodium monitors
– Contact me if you would like a letter to send to
your insurance regarding getting a home sodium
meter
• Letters – insurance appeals, disability, school,
etc. – please feel free to request