Abstract
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.