Neurology · Cathepsin A-related arteriopathy with strokes and leukoencephalopathy

Understanding Your CARASAL Diagnosis

At a Glance

CARASAL is a rare CTSA-related disorder of the brain’s small blood vessels and white matter. MRI changes can look extensive even when symptoms are mild, so diagnosis and follow-up rely on genetic results, symptoms, and specialist review.

Receiving a diagnosis of CARASAL often marks the end of a long and frequently confusing diagnostic journey. Because this condition is exceptionally rare, it is common for patients to have seen multiple specialists before finding an answer ^[1]. This page is designed to help you understand what researchers currently propose is happening in your body at a cellular level and why your imaging might look more concerning than your current symptoms suggest.

What is CARASAL?

CARASAL is an acronym that describes the core features of the condition:

Cathepsin A-related
Arteriopathy (disease of the small arteries)
with Strokes
And Leukoencephalopathy (disease of the brain’s white matter) ^[1].

It is an ultra-rare genetic disorder. While the exact number of people with CARASAL worldwide is unknown, the medical literature has only formally documented a small number of families and individuals—one recent study followed just 21 patients from three separate family lines ^[2]^[1]. Because it is so rare, your local neurology team may never have encountered a case before, and your diagnosis likely required specialized genetic testing ^[3].

The Proposed Biological Mechanism

The root cause of CARASAL is a mutation in the CTSA gene ^[1]. This gene provides instructions for making a protein called cathepsin A, which lives inside the lysosomes (the recycling centers of your cells) ^[4].

In a healthy body, cathepsin A performs several vital “housekeeping” tasks:

Stabilization: It helps protect other important enzymes (proteins that speed up chemical reactions) from being broken down too early ^[4].
Breakdown of Endothelin-1: Most importantly for CARASAL, cathepsin A is responsible for breaking down a protein called endothelin-1 ^[1].

Endothelin-1 is a powerful vasoconstrictor, meaning it tells your blood vessels to tighten and narrow ^[1]. Researchers propose that when cathepsin A isn’t working correctly, endothelin-1 can build up to high levels. This constant signal to constrict eventually damages the walls of the small vessels in the brain, leading to the “arteriopathy” seen in CARASAL ^[4].

Why MRI Results Can Be Misleading

One of the most striking features of CARASAL is what doctors call clinicoradiological dissociation ^[4]. This means that the “white matter changes” (leukoencephalopathy) seen on a brain MRI often look much more severe than the actual symptoms you are feeling ^[4].

Researchers suggest this happens because of how endothelin-1 might affect the brain beyond just the blood vessels:

Oligodendrocyte Progenitors: These are “starter cells” that eventually become the insulation (myelin) for your brain’s wiring ^[4].
The Blockage: High levels of endothelin-1 might prevent these starter cells from maturing into the functional insulation your brain needs ^[4]^[5].
Widespread Changes: This proposed mechanism could explain why large areas of the white matter look “thin” or damaged on an MRI scan, even if the actual blood vessel damage (which causes strokes) is less extensive ^[4].

Because of this, you may have extensive white matter signal abnormalities on your scans even if you feel relatively well today ^[4]^[2]. However, it is important to remember that MRI findings still matter clinically, and the imaging burden alone cannot perfectly forecast your individual outcome.

Age of Onset and Progression

CARASAL is typically an adult-onset condition. While the exact age can vary significantly, symptoms are often reported to appear between the ages of 40 and 60 ^[4]^[6]. Because the genetic mutation is present from birth but the damage to the small vessels and white matter takes time to accumulate, patients may have a variable history of minor symptoms—such as migraines or balance issues—before a formal diagnosis is made ^[1]^[6].

Looking Beyond the Brain

While CARASAL primarily affects the brain, the high levels of endothelin-1 can sometimes cause subtle changes elsewhere as a supportive diagnostic clue. One such feature reported in some patients is enophthalmos, where the eyes appear slightly deep-set due to changes in the fat and muscle behind the eye ^[2]. On an MRI, this may appear as an “orbital check-mark sign,” which can help specialists distinguish CARASAL from other similar-looking conditions ^[2]. Note that this sign may be absent, and similar findings alone do not prove CARASAL.

Common questions in this guide

What exactly is CARASAL?

CARASAL is an ultra-rare genetic disorder affecting the brain’s small arteries and white matter. Its name refers to cathepsin A-related arteriopathy with strokes and leukoencephalopathy. It can cause strokes and symptoms such as migraines or balance problems.

What gene change causes CARASAL?

CARASAL is caused by a mutation in the CTSA gene, which provides instructions for making cathepsin A. Researchers think reduced cathepsin A activity may allow endothelin-1 to build up, keeping small blood vessels narrowed and damaging them. This is a proposed biological mechanism and may not explain every feature in every person.

Why can my CARASAL MRI look worse than my symptoms?

CARASAL can cause clinicoradiological dissociation, meaning the white matter changes on an MRI appear more extensive than a person’s symptoms. Researchers think endothelin-1 may also interfere with cells that help form myelin, causing widespread MRI changes beyond the areas of blood-vessel injury. MRI findings remain important, but their extent alone cannot predict an individual’s outcome.

When do CARASAL symptoms usually begin?

CARASAL usually begins in adulthood, often between ages 40 and 60, although the timing varies. Migraines or balance problems may occur before diagnosis, and symptoms can build gradually as blood-vessel and white-matter changes accumulate.

Does the orbital check-mark sign confirm CARASAL?

No. The orbital check-mark sign, which may be associated with slightly deep-set eyes on MRI, can provide a supportive clue in some patients, but it may be absent and similar findings alone do not establish the diagnosis. Genetic testing and the overall clinical and imaging picture are also important.

What should I ask about my CTSA genetic test result?

Ask which CTSA variant was found and whether the laboratory classifies it as pathogenic or likely pathogenic. You can also ask whether a medical geneticist or vascular neurologist should be part of your care team and how the result affects monitoring.

Do extensive white matter changes mean my CARASAL symptoms will get worse?

Not necessarily. CARASAL can produce extensive MRI abnormalities even when symptoms are relatively mild, so the amount of white matter change alone cannot forecast an individual’s course. Your specialists will interpret the scans together with your symptoms, history, genetic result, and follow-up findings.

Answer a question to get research tailored to you. Your answers are private.

Get notified when new evidence is published on Cathepsin A-related arteriopathy-strokes-leukoencephalopathy.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

Curated prompts to bring to your next appointment.

1.What specific CTSA variant was found in my genetic testing, and is it classified as pathogenic or likely pathogenic?
2.Given the extent of my white matter changes, how do you expect my symptoms to progress compared to other small vessel conditions?
3.Have you looked for the 'orbital check-mark sign' as a supportive clue on my MRI?
4.Are there any other specialists, such as geneticists or vascular neurologists with experience in small vessel disease, who should be on my care team?
5.How does the proposed mechanism of endothelin-1 accumulation influence how we monitor my blood vessel health?

References (6)

1
Update on hereditary, autosomal dominant cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).
Finsterer J, Scorza CA, Scorza FA, Wakil SM
Acta neurologica Belgica 2019; (119(3)):299-303 doi:10.1007/s13760-019-01158-8.
PMID: 31177426
2
Expanding the Clinicoradiologic Phenotype of the CTSA-Associated Small Vessel Disease CARASAL: A Comparison With CADASIL.
Cerfontaine MN, Gravesteijn G, Hack RJ, et al.
Neurology. Genetics 2026; (12(2)):e200358 doi:10.1212/NXG.0000000000200358.
PMID: 41908989
3
Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.
Mancuso M, Arnold M, Bersano A, et al.
European journal of neurology 2020; (27(6)):909-927 doi:10.1111/ene.14183.
PMID: 32196841
4
Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).
Bugiani M, Kevelam SH, Bakels HS, et al.
Neurology 2016; (87(17)):1777-1786 doi:10.1212/WNL.0000000000003251.
PMID: 27664989
5
Endothelin-1 signaling maintains glial progenitor proliferation in the postnatal subventricular zone.
Adams KL, Riparini G, Banerjee P, et al.
Nature communications 2020; (11(1)):2138 doi:10.1038/s41467-020-16028-8.
PMID: 32358570
6
A rare cause of monogenic cerebral small vessel disease and stroke: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).
Budhdeo S, de Paiva ARB, Wade C, et al.
Journal of neurology 2022; (269(12)):6673-6677 doi:10.1007/s00415-022-11302-9.
PMID: 35904593

This page is for informational purposes only and does not constitute medical advice. Discuss your CTSA result, MRI findings, symptoms, and follow-up plan with your neurologist and genetics team.

Guide Contents