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Evaluating Cell Death Signaling by Immunofluorescence in a Rat Model of Ischemic Stroke
Published on: January 3, 2025
Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)
Marianna Bugiani1, Sietske H Kevelam1, Hannah S Bakels1
1From the Departments of Child Neurology (M.B., S.H.K., H.S.B., T.E.M.A., M.S.v.d.K.) and Pathology (M.B., H.W.M.N.), Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam; Department of Clinical Genetics (Q.W.), VU University Medical Center, Amsterdam, the Netherlands; Laboratory for Ultrastructural Neuropathology (C.C.-d.G.), Institute Born-Bunge and University of Antwerp, Belgium; Department of Clinical genetics (S.A.M.J.L.O.), Leiden University Medical Center, Leiden; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
Objective:
To characterize the clinical and MRI features of 2 families with adult-onset dominant leukoencephalopathy and strokes and identify the underlying genetic cause.
Methods:
We applied MRI pattern recognition, whole-exome sequencing, and neuropathology.
Results:
Based on brain imaging, 13 family members of 40 years or older from 2 families were diagnosed with the disease; in 11 family members of the same age, MRI was normal. In the affected family members, MRI showed a leukoencephalopathy that was disproportionately severe compared to the clinical disease. The clinical picture was dominated by ischemic and hemorrhagic strokes, slow and late cognitive deterioration, and therapy-resistant hypertension. With whole-exome sequencing, we identified one variant shared by both families and segregating with the disease: c.973C>T in CTSA. Haplotype analysis revealed a shared 1,145-kb interval encompassing the CTSA variant on chromosome 20q13.12, suggesting a common ancestor. Brain autopsy of 3 patients showed a leukoencephalopathy that was disproportionately extensive compared to the vascular abnormalities. CTSA encodes cathepsin A. Recessive CTSA mutations cause galactosialidosis. One of the numerous cathepsin A functions is to degrade endothelin-1. In the patients, striking endothelin-1 immunoreactivity was found in white matter astrocytes, correlating with increased numbers of premyelinating oligodendrocyte progenitors. This finding supports a role for endothelin-1 in the leukoencephalopathy through inhibition of oligodendrocyte progenitor maturation.
Conclusions:
CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy) is a novel hereditary adult-onset cerebral small vessel disease. It is of interest that, next to the cerebral vascular abnormalities, endothelin-1 may have a role in the pathogenesis of the extensive leukoencephalopathy.
