Marianna Bugiani1, Sietske H Kevelam1, Hannah S Bakels1, Quinten Waisfisz1, Chantal Ceuterick-de Groote1, Hans W M Niessen1, Truus E M Abbink1, Saskia A M J Lesnik Oberstein1, Marjo S van der Knaap2. 1. From 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. 2. From 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. ms.vanderknaap@vumc.nl.
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.
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.
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