A rare cause of monogenic cerebral small vessel disease and stroke: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)

Abstract

BackgroundCathepsin-A related arteriopathy with strokes and leukoencephalopathy (CARASAL) is a rare monogenic cause of cerebral small vessel disease. To date, fewer than 15 patients with CARASAL have been described, all of common European ancestry. MethodsClinical and imaging phenotypes of two patients are presented. Genetic variants were identified using targeted Sanger and focused exome sequencing respectively. ResultsBoth patients carried the same pathogenic p.Arg325Cys mutation in CTSA. One patient of Chinese ethnicity presented with migraine, tinnitus and slowly progressive cognitive impairment with significant cerebral small vessel disease in the absence of typical cardiovascular risk factors. She later suffered an ischaemic stroke. A second patient from Brazil, of Italian ethnicity developed progressive dysphagia and dysarthria in his 50s, he later developed hearing loss and chronic disequilibrium. Magnetic resonance imaging in both cases demonstrated extensive signal change in the deep cerebral white matter, anterior temporal lobes, thalami, internal and external capsules and brainstem. ConclusionsCARASAL should be considered in patients with early onset or severe cerebral small vessel disease, particularly where there are prominent symptoms or signs related to brainstem involvement, such as hearing dysfunction, tinnitus or dysphagia or where there is significant thalamic and brainstem involvement on imaging.

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association

“…48 Although there are no high-quality data on the safety or efficacy of antiplatelet therapies in patients with CADASIL, low-dose aspirin likely carries low risk and is frequently given in patients with prior ischemic stroke. Recurrent lacunar strokes have been seen in PADMAL 49 and in CARASAL 10 despite antithrombotic therapy.…”

“…8,9 CARASAL (cathepsin-A-related arteriopathy with strokes and leukoencephalopathy) has prominent brainstem symptoms (tinnitus, hearing loss, and dysphagia). 10 TREX1 gene mutations can cause RVCL-S (retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations), including liver and kidney disease. 11 Some COL4A1/2 gene mutations cause HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome.…”

Advances in Management of the Stroke Etiology One-Percenters

“…Recently, cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL), an extremely rare monogenic autosomal dominant cause of adult-onset small vessel cerebral arteriopathy and leukoencephalopathy caused by point mutations in the p.Arg325Cys in CTSA encoding cathepsin-A.27664989, has been described [ 198 , 201 ]. CARASAL is characterized by therapy-resistant hypertension, and a wide spectrum of neurological symptoms, including migraine, facial pain, non-positional vertigo, cognitive dysfunction, behavioral disinhibition, rapid eye movement-sleep behavioral disorder, depression, and strokes with predilection to the thalami and brainstem [ 202 ].…”

“…MRI findings include signal changes in the frontoparietal periventricular and deep white matter, and small multifocal areas of signal abnormality specifically involving the basal nuclei, thalami, internal and external capsules, and brainstem. Unlike CADASIL, temporal white matter and the temporal poles are relatively spared [ 201 ]. Microbleeds may occur.…”