Our objective is to find predictive biomarkers for disease progression in RVCL-S, a monogenetic small vessel disease, and to dissect disease mechanism to identify new treatment targets to improve health for RVCL-S patients, which may also serve as…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Eye disorders NEC
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Long-term disease course in RVCL-S
Long-term disease course will be determined by the occurrence of presumably
RVCL-S related symptoms; by cognitive performance testing and by use of the
modified Rankin Scale (mRS) and the Barthell Index. Standardised
questionnaires will be used for screening for depression, anxiety and
neuropsychiatric symptoms. Focal neurological symptoms will be evaluated by
physical examination and 3T MRI. Ophthalmological examination will be performed
for retinal involvement and organ involvement will be evaluated with
venepuncture and urine examination (liver, kidney and thyroid function and
blood count).
2. In vivo ocular and skin biomarkers
Eyes: ocular examination will be performed, including visual acuity,
intraocular pressure and fundus photography. With Optical Coherence Tomography
scans the retinal nerve fibre layer thickness will be measured. With
OCT-angiography scans the vessel density at the retina and the size of foveal
avascular zone will be quantified. In patients with vascular retinopathy these
scans will be combined with fluorescence angiography scans. Retinal oximetry is
applied to calculate the oxygen saturation of the blood vessels of the retina.
Skin: vessels will be visualized by nailfold capillaroscopy. Four images (1*×*1*
mm in size) from the nailfold in each finger will be evaluated. The modified
Maricq criteria will be used for grading the capillary morphology, density and
distribution.
3. Retinal angiogenesis
Optical Coherence Tomography Angiography (OCT-A) is a non-invasive technique
that will be used to visualize the vascular structures of the retina and
choroid three-dimensionally (without contrast).2 Quantitative assessment of
vasculature of different segments and retinal layers, such as
neovascularization or vascular dropout areas, and the creation of flow-density
maps and calculations allows for comparison over time.
4. Long term progression of RVCL-S specific and common cerebral small vessels
disease markers
Long term progression of RVCL-S specific and common MR-markers including i)
*active* RVCL-S lesions (i.e. T2 hyperintensities with contrast enhancement
and/or diffusion restriction, ii) brain (non-)lacunar infarcts, iii) white
matter hyper intensities, iv) widened perivascular spaces, v) microbleeds, vi)
permeability of the blood brain barrier, using both 3T and 7T MRI scanners.
5. Blood-brain-barrier dysfunction
To detect blood-brain-barrier (BBB) leakage, a late contrast leakage 7T MR
imaging protocol will be performed. Blood-brain-barrier leakage rate will be
adjusted for confounding variables in the gray matter, normal-appearing white
matter, deep gray matter and cortex.
6. Store blood for biobanking purposes and future research.
If participants give permission for LUMC Biobank RVCL onder Neurologische
Ziekten, blood samples will be stored for future (yet unknown) biomarker
analysis.
Secondary outcome
Not applicable.
Background summary
Retinal Vasculopathy with Cerebral Leukoencephalopathy with Systemic
manifestations (RVCL-S) is an autosomal dominant monogenic small vessel disease
caused by mutations in the TREX1 gene. It manifests as a microangiopathy with
retinal vasculopathy, focal and global neurological deficits and a wide range
of systemic symptoms. Recently, our group conducted a large cross-sectional
study (The RVCL-ID study, P13.286). However, the natural history of the
disease, especially the early stages, remain to be identified. By identifying
biomarkers predicting transition of the pre-symptomatic to symptomatic disease
stage and progression of disease in RVCL-S we will be able to further unravel
how TREX1 mutations cause disease. These findings will help define new
treatment targets for this currently incurable disease. Furthermore, we aim to
be able to give patients a more accurate prognosis. Additionally, as RVCL-S is
a monogenic model for more common disorders, such as stroke, vascular dementia
and migraine, we predict that our study will provide insights in the
pathophysiology of other (neuro)vascular disorders as well.
Study objective
Our objective is to find predictive biomarkers for disease progression in
RVCL-S, a monogenetic small vessel disease, and to dissect disease mechanism to
identify new treatment targets to improve health for RVCL-S patients, which may
also serve as biomarkers for patients suffering from associated disorders such
as stroke, and vascular dementia and other cerebral hereditary angiopathies in
the (near) future.
1. Perform an extensive clinical work-up using structured interviews, physical
examinations and venepuncture and urine examination (for identifying organ
dysfunction) during regular intervals to investigate long-term disease course
in RVCL-S.
2. Studying ocular and skin biomarkers in vivo.
3. Studying retinal angiogenesis by using ocular techniques to visualize the
retina in vivo.
4. Quantifying specific RVCL-S and common cerebral small vessel disease markers
and evaluating their progression over time on 3T- and 7T-MRI.
5. Quantifying and localizing blood brain barrier dysfunction using MRI.
6. Store blood for biobanking purposes and future research.
Study design
Prospective follow-up study.
Study burden and risks
Contra-indications will be carefully investigated per subject for different
parts of the study. If patients have contraindications for a part of the study
(e.g. the MRI) they can still participate in the other parts of the study.
Blood withdrawal is a routine procedure at the LUMC. MRI scans involve a
negligible risk to the participants* health. The burden of the MRI scan will be
kept at a minimum by using short protocols for the MRI study. Patients will be
informed extensively about the potential risks of these procedures, after which
written informed consent will be obtained. Relatives of RVCL-S patients who
wish to remain unaware of their genetic status can participate on a research
basis and test results will not be reported in the patients* hospital records
or to treating physicians. Identifying possible biomarkers for recognizing
(pre)clinical disease stages and for predicting outcome or future progression
would be valuable for RVCL-S patients. Altogether we feel the advantages of
this study outweigh the minimal risks.
Einthovenweg 20
Leiden 2333 ZC
NL
Einthovenweg 20
Leiden 2333 ZC
NL
Listed location countries
Age
Inclusion criteria
(Pre-)symptomatic mutation carriers:
- Age: >= 18 years
- Proven TREX1 mutation
- Ability and willingness to provide written informed consent
Control subjects:
- Age: >= 18 years
- Not genetically related to an RVCL-S patient or genetic testing has ruled out
TREX1 mutations
- Ability and willingness to provide written informed consent
Exclusion criteria
For all subjects:
- Subjects who do not want to be informed about unexpected findings that are
considered serious, with prognostic or therapeutic consequences. This does not
concern genetic test results.
- Contra-indications for 3T/7T MRI as determined by the 7Tesla safety
committee. (exclusion for a subpart of the study)
For controls:
- Presence of known (cerebro) vascular diseases such as overt manifestations of
hypertensive/ atherosclerotic vascular disease, excessive anticoagulation (INR
>3.0), CNS disorders, vascular malformation, vasculitis, blood dyscrasia,
diabetes mellitus, severe clinical relevant carotid artery stenosis.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL77441.058.21 |