PubMed · 12557863
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Domenico Inzitari, Cristina Sarti. 2003. Screening for CADASIL mutations.. https://pubmed.ncbi.nlm.nih.gov/12557863/
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BACKGROUND AND PURPOSE: To report a unique case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy manifesting as a progressive supranuclear palsy phenotype, thereby expanding its recognized presentations. METHODS: Review of the pertinent literature from MEDLINE, cross-referencing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, progressive supranuclear palsy, and parkinsonism. Description of a 60-year-old woman who presented with a several year history of step-wise, progressive parkinsonism secondary to cerebral autosomal dominant arteriopathy. RESULTS: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy may present with a progressive supranuclear phenotype. CONCLUSION: Parkinsonism, including a progressive supranuclear palsy phenotype, is one of a growing number of recognized ways that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy may present.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease. The onset of clinical symptoms occurs with migraine with aura, transient ischemic attacks, recurrent subcortical ischemic infarcts, neuropsychiatric changes reaching subcortical dementia. Brain magnetic resonance images show multiple deep cerebral infarcts in white matter and basal ganglia and diffuse leukoencephalopathy. Neuropathologic hallmark consists of deposition of small electron dense granular patches related to the basement membrane of vascular smooth muscle cells with degeneration of smooth muscle cells and media and luminal obliteration. Recently, the genetic characteristics of this disorder have been reported. Missense mutations in notch3 gene localized in chromosome 19 are involved in its pathogenesis. Only three families from Spain have been reported. Here we describe a patient with typical clinical symptoms, neuroimaging and pathology of CADASIL. C406T (Arg110Cys) mutation in notch3 gene was found. We comment on the clinical symptoms of different members of the patient's family.
Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia.