Vascular Ehlers-Danlos syndrome: expanding our understanding

Vascular Ehlers-Danlos syndrome:
Placing recent studies into context
Mitzi L. Murray, MD, MA
EDNF Annual Learning Conference
August 10, 2012
For me context is the key - from
that comes the understanding of
Kenneth Noland
(American artist 1924-2010)
Heat, 1958
• Review different types of medical research
• Discuss genotype-phenotype correlations
in vEDS focusing on recent COL3A1
haploinsufficiency study
• Discuss recent clinical trial of celiprolol
• Propose future directions
• Review different types of medical research
• Discuss genotype-phenotype correlations in
vEDS, focusing on COL3A1
• Discuss recent clinical trial of celiprolol
• Propose future directions
Provide context
EDS type IV – the vascular type
Clinical Features
– Risk of arterial, organ & pregnancy complications
– Variability within and between families
Cause and diagnosis
– Due to mutations (changes) in the gene COL3A1
– Diagnosis
• Clinical
• Biochemical (Protein studies of type III collagen)
• Molecular (Genetic)
Questions yet unanswered
Why is there variability?
What factors contribute to risk for complications?
Should we perform surveillance studies? How?
Can medications/treatments reduce risk?
Can we change the course of the condition?
How are complications best managed?
What is medical research?
• Focuses on human health and disease
• Can mean many different things
Medical Research
Medical Research
Animal studies
Doxycycline in mouse model of vEDS
Cell studies
Allele-specific siRNA in vEDS
Genetic studies
Medical Research
Medication Trials
Natural History
Interview, Qualitative, etc
Medical Research
Population frequency
Environmental influences
Points about research to consider
• A single study rarely answers the question
– Important to prove a result is replicable
– Findings may not be generalizable
• Premature translation of research findings
into the clinical realm can be harmful
– Ex: autism and vaccines
“One hypothesis to explain the failure to identify
this class of mutations is that the phenotype caused
by COL3A1 haploinsufficiency differs, with respect to
its severity or its symptomatic range, from the usual
presentation of EDS type IV…”
2 Copies of the COL3A1 gene
Each gene copy makes protein chains
Three protein chains come
together to form type III collagen
Quality vs. quantity…
• Clinical observational study
• 19 of 508 families with vEDS
– 54 total affected persons
• 19 index patients
• 35 affected family members
• Major complications
– 18/19 index patients, 10/35 family members
– All major complications were arterial
Genetics in Medicine 13(8); 2011.
Age distribution
Conclusions from this study
• Most individuals with null mutations have
different clinical course
Longer life expectancy
Later age of first complication
Complications primarily vascular
Less frequently have minor clinical features
• Limitations
– Relied on available medical history
– Families identified because of complication, risk
of complications likely over-estimated
• For those with null mutations, information
may be somewhat reassuring
• At this time, my clinical recommendations are
the same for families with null mutations
• Future interventional studies should take
mutation type (protein altering vs. null) into
account in design
Directions for future research
Basic research
– Further explore use of animal models in
vascular EDS research
– Further studies using allele-specific siRNA
– Better understanding the role of type III
collagen in more come forms of aneurysms
and dissections.
Directions for future research
Clinical research
– Observational
• Ongoing NIH study on natural history
• Pregnancy outcomes in vascular EDS
– Interventional
• Doxycycline in humans?
• Is celiprolol study replicable in study of only
persons with COL3A1 mutations?
• Imaging surveillance and intervention studies?
Directions for future research
Epidemiological research
– Are the identifiable environmental risk factors
for complications?
– How common is vascular EDS? - especially
considering many families with null mutations
may be unidentified
In summary
• We continue to make progress but there is
much much more to be learned
• We need to continue working together in
research efforts to improve the clinical
care for individuals and families with
vascular EDS
Thank you!
Individuals and families living with Ehlers-Danlos syndrome
or other heritable connective tissue disorders.
Collagen Diagnostic Laboratory
Peter Byers
Melanie Pepin
Shawna Pyott
Margaret Yang
Diana Chen
Lily Hoang
Dept of Pathology
Arnold Altamira
Dept of Medicine,
Alex Launderdale
Div of Medical Genetics Barbara Kovacich
Ulrike Schwarze
Dru Leistreitz
Jennifer Schleit
Thao Tran
Dennis Sarroza
Susan Stowers
Catherine Nguyen
Freudmann Fund for Ehlers-Danlos Syndrome Research
Briest, et al. Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the
vascular type of Ehlers-Danlos syndrome. J Pharmacol Exp Ther. 2011;337(3):621-627.
Leistritz, et al. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with
delayed onset of complications and longer life expectancy. Genet Med. 2011;13(8):717-22.
Muller, et al. Allele-specific siRNA knockdown as a personalized treatment strategy for vascular EhlersDanlos syndrome in human fibroblasts. FASEB J. 2012;26(2):668-77.
Pepin, et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J
Med. 2000;342(10):673-80.
Ong, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos
syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376(9751):1443-4.
Tae, et al. Chronic Treatment with a Broad Spectrum MMP Inhibitor, Doxycycline, Prevents the
Development of Spontaneous Aortic Lesions in the Mouse Model of Vascular Ehlers-Danlos Syndrome. J.
Pharmacol Exp Ther. 2012 Jul19. [Epub ahead of print]
• Clinical interventional study
• Goal: “to assess the preventive effect of celiprolol for
major cardiovascular events in patients with vascular
Ehlers-Danlos syndrome”
Lancet 376; 2010
Who did they study?
1 major + 2 minor OR 4 minor criteria
Personal or first degree
relative history of arterial
rupture or dissection
Personal or first degree
relative history of uterine
or intestinal rupture
Known COL3A1 mutation
Characteristic appearance
Club foot
Small joint hypermobility
Tendon rupture
Varicose veins
AV fistula
Recessed gums
Absence of inferior frenula
Enrolled 53 individuals
25 received celiprolol
28 received no treatment
Observe rate of complications in both groups over
5 year period or until complication event occurred
• Study stopped short due to difference seen
between groups and small number remaining
without complications
• Observed a 69% risk reduction in group
treated with celiprolol without reduction in
heart rate or blood pressure
Study limitations
• COL3A1 testing was not done prior to
– Treated group 12-13/25 (48-52%)
– Untreated group 20/28 (71%)
• Celiprolol did not have the expected effect
on blood pressure
– If beneficial, mechanism is unknown
Study conclusions
“We suggest that celiprolol might be the
treatment of choice for physicians aiming to
prevent major complications in patients with
vascular Ehlers-Danlos syndrome.”
“…results in the mutated population must be
assessed cautiously…”

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