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Expanding the Clinicoradiologic Phenotype of the CTSA-Associated Small Vessel Disease CARASAL: A Comparison With
Minne N Cerfontaine1, Gido Gravesteijn1, Remco J Hack1
1Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.
Insights
Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) presents with diverse stroke types and distinct neuroimaging findings, including a higher white matter lesion load and an orbital check-mark sign. These features aid in diagnosing CARASAL, differentiating it from CADASIL.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Genetic small vessel diseases (SVDs) like CARASAL and CADASIL cause early stroke and dementia.
- CARASAL is a rare SVD mimicking CADASIL, the most common genetic SVD.
Purpose of the Study:
- To describe CARASAL patients and compare their stroke subtypes and radiologic features with CADASIL patients.
- To identify diagnostic clues for CARASAL.
Main Methods:
- Retrospective and prospective data collection from 21 CARASAL patients across 3 pedigrees.
- Neuroimaging comparison between CARASAL patients and age/sex-matched or nWMHv-matched CADASIL patients.
- Quantification of enophthalmos in CARASAL patients via MRI.
Main Results:
- CARASAL patients exhibited variable stroke subtypes, including subcortical, cortical, and intracerebral hemorrhage.
- CARASAL patients had a significantly higher total white matter hyperintensity volume (nWMHv) than CADASIL patients.
- CARASAL patients showed distinct MRI findings: higher pontine nWMHv, fewer lacunes, a higher brain parenchymal fraction, and frequent enophthalmos with an "orbital check-mark sign".
Conclusions:
- Stroke presentation in CARASAL is heterogeneous, necessitating specific management guidelines.
- Elevated white matter hyperintensity load, particularly in the pons, and the "orbital check-mark sign" are key radiologic indicators for CARASAL diagnosis.
Background And Objectives:
Genetic small vessel diseases (SVDs) are associated with early onset of stroke and dementia. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is an extremely rare genetic SVD caused by a single heterozygous CTSA variant, which can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common genetic SVD. In this study, we describe a series of patients with CARASAL and compare stroke subtypes and radiologic features with those of patients with CADASIL.
Methods:
Twenty-one patients with CARASAL were included from 3 pedigrees; 7 participated in a prospective genetic SVD cohort study, and for 14, data were collected retrospectively. Clinical characteristics were assessed, and 2 analyses of neuroimaging outcomes were performed: (1) a comparison between patients with CARASAL (n = 7) and age- and sex-matched patients with CADASIL (n = 28) and (2) a comparison between patients with CARASAL and normalized white matter hyperintensity volume (nWMHv)-matched patients with CADASIL (n = 28). Enophthalmos in patients with CARASAL was investigated and quantified on MRI.
Results:
Stroke patients with CARASAL (n = 9) had variable stroke subtypes, including subcortical stroke (n = 3/9), cortical stroke (n = 4/9), and (fatal) intracerebral hemorrhage (n = 4/9). Total nWMHv was higher in patients with CARASAL than in those with CADASIL (mean difference: 5.0% of intracranial volume, 95% CI [2.0-8.0], p = 0.0007). Compared with nWMHv-matched patients with CADASIL, patients with CARASAL had higher pontine nWMHv (mean rank difference: 25.5, p = 0.0019), but fewer lacunes and a higher brain parenchymal fraction (both p < 0.05). Overall, 13 of 14 patients with CARASAL had an enophthalmos, with reduced volumes of the extraocular rectus muscles and intraorbital fat, and an "orbital check-mark sign" on MRI.
Discussion:
Stroke in CARASAL is heterogeneous, suggesting that CARASAL-specific guidelines for stroke management are warranted. The high white matter hyperintensity lesion load, including the pons, in combination with the orbital check-mark sign, can serve as radiologic clues for the diagnosis of CARASAL.
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