Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)

Bugiani, M.; Kevelam, S.H.; Bakels, H.S.; Waisfisz, Q.; Ceuterick-de Groote, C.; Niessen, H.W.M.; ... ; Knaap, M.S. van der (2016)

Article / Letter to editor

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.

• All authors: Bugiani, M.; Kevelam, S.H.; Bakels, H.S.; Waisfisz, Q.; Ceuterick-de Groote, C.; Niessen, H.W.M.; Abbink, T.E.M.; Oberstein, S.A.M.J.L.; Knaap, M.S. van der
• Date: 2016-10-25
• Journal: Neurology
• Volume: 87
• Issue: 17
• Pages: 1777 - 1786
• DOI: doi:10.1212/WNL.0000000000003251
• Link: https://www.neurology.org/doi/10.1212/WNL.0000000000003251