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

Abstract

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.

• Authors: Marianna Bugiani, Sietske H Kevelam, Hannah S Bakels, Quinten Waisfisz, Chantal Ceuterick-de Groote, Hans W M Niessen, Truus E M Abbink, Saskia A M J Lesnik Oberstein, Marjo S van der Knaap
• Journal: Neurology (Neurology) Vol. 87 Issue 17 Pg. 1777-1786 (Oct 25 2016) ISSN: 1526-632X [Electronic] United States
• PMID: 27664989 (Publication Type: Journal Article)
• Copyright: © 2016 American Academy of Neurology.

Chemical References

• Endothelins
• CTSA protein, human
• Cathepsin A

Topics

• Adult
• Aged
• Brain (diagnostic imaging, metabolism, ultrastructure)
• Cathepsin A (genetics)
• Endothelins (metabolism)
• Family Health
• Female
• Genome-Wide Association Study
• Hemorrhage (complications, diagnostic imaging, genetics)
• Humans
• Leukoencephalopathies (complications, diagnostic imaging, genetics)
• Magnetic Resonance Imaging
• Male
• Microsatellite Repeats
• Middle Aged
• Mutation (genetics)
• Neurologic Examination
• Stroke (complications, diagnostic imaging, genetics)
• Vascular Malformations (complications, diagnostic imaging, genetics)