Diagnosis, MRI Findings, and Look-Alikes
At a Glance
CARASAL is diagnosed by combining a characteristic MRI pattern—often extensive white-matter changes with prominent pons involvement—with a pathogenic or likely pathogenic heterozygous CTSA variant. The orbital check-mark sign can support diagnosis but is not required.
Navigating the diagnosis of a rare disease like CARASAL requires looking for specific clues that distinguish it from more common “look-alike” conditions. Because the symptoms of small vessel diseases often overlap, doctors rely on a combination of clinical history, highly specific MRI patterns, and crucial genetic testing to confirm the diagnosis [1][2].
The MRI “Check-Mark” and Orbital Signs
One of the supportive clues that can help differentiate CARASAL from other brain disorders is how it affects the area around the eyes. In a small study of 14 patients with CARASAL, 13 showed a feature called enophthalmos, where the eyes appear slightly deep-set or “sunken” [1].
On an MRI, this creates what specialists call the orbital check-mark sign [1]. This happens because the condition causes a reduction in the fat and muscle (extraocular rectus muscles) behind the eye [1]. While this may not affect your vision, it is a reported supportive diagnostic clue. It is not an absolute requirement; it may be absent or simply not visible on routine scans, and similar findings alone do not prove CARASAL [1].
Brainstem and White Matter Patterns
While many small vessel diseases show “white matter hyperintensities” (bright spots on an MRI), the location and severity of these spots in CARASAL can be revealing:
- The Pons: CARASAL typically shows a heavier “burden” or concentration of damage in the pons, a vital part of the brainstem, compared to conditions like CADASIL [1].
- Widespread Damage: The white matter changes in CARASAL are often very extensive, covering large areas of the deep brain, even in patients who have relatively mild symptoms [3][4].
- Fewer Lacunes: Interestingly, patients with CARASAL may have fewer lacunes (small “holes” or cavities left by previous tiny strokes) than patients with CADASIL, despite having more overall white matter damage [1].
Distinguishing CARASAL from Look-Alikes
Your medical team likely considered several other genetic conditions before settling on CARASAL. Understanding these “look-alikes” helps clarify why your specific diagnosis requires careful review.
| Feature | CARASAL | CADASIL | CARASIL & HTRA1-related disease |
|---|---|---|---|
| Gene Mutation | CTSA (Heterozygous) [3] | NOTCH3 [5] | HTRA1 (Biallelic or Heterozygous) [5] |
| Supportive Clue | Orbital check-mark sign & enophthalmos [1] | Spots in the anterior temporal lobes [6] | Alopecia (hair loss) & spine disease [5] |
| Brainstem | Prominent involvement of the pons [1] | Less prominent pontine involvement | Severe involvement common |
The Gold Standard: Genetic Testing
The critical step in confirming a CARASAL diagnosis is genetic testing of the CTSA gene interpreted in the right clinical context [7].
Most reported cases of CARASAL are linked to a specific mutation known as c.973C>T (p.Arg325Cys) [3][4]. CARASAL is a “dominant” condition, meaning one copy of the mutated gene (heterozygous) places a person at risk for the disease [3]. This variant can be inherited or, less commonly, occur completely anew (de novo).
It is vital that a specialist with genetics expertise interprets your report. The variant must be classified as pathogenic (disease-causing) or likely pathogenic. Finding a “Variant of Uncertain Significance” (VUS) or a benign variant does not establish the disease. Furthermore, if a person carries two copies of certain mutated CTSA genes, they may develop a different disorder called galactosialidosis, which has varied infantile, juvenile, or adult presentations [8].
What to Look for in Your Reports
If you are reviewing your own records, these data points support a CARASAL diagnosis:
- Genetic Findings: Presence of a pathogenic or likely pathogenic heterozygous CTSA mutation (like p.Arg325Cys) [3].
- Radiology: Extensive white matter hyperintensities with prominent involvement of the pons [1].
- Physical Findings: Mention of enophthalmos or the orbital check-mark sign on imaging as a supportive clue [1].
Common questions in this guide
What MRI findings can support a CARASAL diagnosis?
Does the orbital check-mark sign confirm CARASAL?
What genetic test is used to confirm CARASAL?
How is CARASAL different from CADASIL and CARASIL?
Can one CTSA variant cause CARASAL?
Questions For You
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Questions to Ask Your Doctor
Curated prompts to bring to your next appointment.
- 1.Does my MRI show the 'orbital check-mark sign' or 'enophthalmos,' and how are we using that as a supportive clue?
- 2.How severe is the involvement of my pons compared to other areas of my brain, and what does that tell us about my diagnosis?
- 3.Can we confirm that the CTSA variant found in my genetic testing is classified as pathogenic or likely pathogenic?
- 4.Given my MRI results, were other genes like NOTCH3 (CADASIL) or HTRA1 definitively ruled out?
- 5.Are there specific features on my radiology report, such as the burden of lacunes or microbleeds, that you are using to track my condition?
References
References (8)
- 1
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 - 2
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 - 3
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 - 4
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 - 5
Monogenic causes of cerebral small vessel disease and stroke.
Guey S, Chabriat H
Handbook of clinical neurology 2024; (204()):273-287 doi:10.1016/B978-0-323-99209-1.00018-1.
PMID: 39322384 - 6
Mechanistic advances in factors influencing phenotypic variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a review.
Zhao Y, Lu Y, Wang F, et al.
Frontiers in neurology 2025; (16()):1573052 doi:10.3389/fneur.2025.1573052.
PMID: 40470487 - 7
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 - 8
Phenotypic Divergence in Siblings with the Same Genotype: Diffuse Dermal Melanocytosis in Infantile-Onset Galactosialidosis.
Gürbüz BB, Özalp Ö
Molecular syndromology 2026; (17(4)):409-416 doi:10.1159/000549013.
PMID: 41409303
This page is for informational purposes only and does not constitute medical advice. A neurologist, radiologist, or genetics specialist should interpret your MRI and CTSA results in your clinical context.