Expanding the Clinicoradiologic Phenotype of the CTSA -Associated Small Vessel Disease CARASAL

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Abstract
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. 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. 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. 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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