ISC 2024 | Introduction to CADASIL: scientific advances and clinical perspectives
Cerebral autosomal dominant arteriopathy with subcortical infarct (CADASIL) is a rare, monogenic, cerebral small vessel disease caused by variants in the NOTCH3 gene. CADASIL is a genotypically and phenotypically diverse condition, with its heterogeneous presentation often leading to misdiagnosis. Common presenting manifestations include migraine, mood disorders, recurrent strokes, and cognitive decline. Characteristic white matter changes on MRI indicate the need for NOTCH3 testing. Elisa Ferrante, PhD, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, discusses ongoing efforts to establish the mechanisms underlying CADASIL and to identify potential treatments for future study. While the genetic cause of CADASIL is known, the molecular mechanisms at play remain unclear, as the disease-causing variants span the entire length of the NOTCH3 gene. Granular osmiophilic material deposits (GOMs) are a pathological hallmark of CADASIL, but their role has not been fully elucidated. Dr Ferrante comments on the need for natural history studies to learn more about CADASIL and to identify potential biomarkers and therapeutic targets. This interview took place during the International Stroke Conference 2024 in Phoenix, AZ.
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Transcript (edited for clarity)
CADASIL is a monogenic vascular dementia condition. It is caused by variants in the NOTCH3 gene that span pretty much that entire gene. So the disease presentation can be very heterogeneous depending on where the location is, possibly also depending on modifiers, risk factors, environmental factors. All of that research is still kind of undergoing review. The most common presentation will be people in their 30s and 40s, start with migraines, recurring strokes, and then cognitive decline, kind of at an early age compared to other conditions like Alzheimer’s or just, older age causing those problems...
CADASIL is a monogenic vascular dementia condition. It is caused by variants in the NOTCH3 gene that span pretty much that entire gene. So the disease presentation can be very heterogeneous depending on where the location is, possibly also depending on modifiers, risk factors, environmental factors. All of that research is still kind of undergoing review. The most common presentation will be people in their 30s and 40s, start with migraines, recurring strokes, and then cognitive decline, kind of at an early age compared to other conditions like Alzheimer’s or just, older age causing those problems. And so a lot of the people that come up with CADASIL at first get misdiagnosed, like MS. And then depending on what imaging is done, usually if they get an MRI of their brain, the presentation for CADASIL is kind of specific with the white matter changes and their localization. And that’s when that light bulb goes off on people to get the NOTCH3 testing. So most people nowadays get diagnosed with a targeted NOTCH3 genetic test. Before then it was a skin biopsy and looking around the blood vessels for these deposits that are called GOMs or granular osmiophilic materials, they’re very striking, very unique to CADASIL. But unfortunately, not every CADASIL patient has those.
We know what the genetic cause of CADASIL is. We don’t actually know what the mechanism of CADASIL is because it spans the whole gene. It modifies the protein that is on people’s smooth muscle cells in different ways. It could be in the extracellular space, it could be in the intracellular portion of the molecule. And so it’s been very difficult to figure out what is actually happening on the molecular level. We know the GOMs are happening right outside those smooth muscle cells or those pericytes around the blood vessels. And we think that is what is causing the decline of the blood vessel health there. The smooth muscle cells kind of start degrading and then that communication of endothelial cells also starts breaking down, and then the blood vessels become leaky, and in particular, the brain blood vessels are more affected than anywhere else in the body, even though this NOTCH3 is expressed in the whole body.
So because we don’t know the mechanism, it is actually very difficult to know how to treat CADASIL. So right now there is no cure and everything that is done is to just address the individual symptoms that people are presenting with. So a natural history protocol or study, like what we have, allows us to look at the phenotype of the disease and understand what’s happening from the symptomatic side and try to link it to the genetic side. So we’re trying to make phenotype-genotype correlations. But it also allows us to obtain samples from the patients, whether it’s blood or a skin biopsy or even spinal fluid, to one: try to find biomarkers that can help us, should we find a treatment, figure out if it’s helping or not. So say that there is a circulating molecule in the plasma of patients with CADASIL that we can identify. Then that can be an endpoint for a future trial. And two: obtaining blood and skin biopsies allow us to create cell lines from these patients that eventually will allow us to make in vitro models of the disease and study the molecular mechanism in more detail. So the natural history studies are extremely useful to understand the disease, but also as preliminary data for FDA to be able to make a call on a treatment or not down the line.
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