Abstract Body

Genetic ischemic cerebral subcortical small vessel diseases (SSVD) are rare, usually autosomal dominant conditions related to impairment of proteins mainly involved in small vessel functions. Symptoms are characterized by combinations of migraine with aura, ischemic events (transient ischemic attacks, lacunar strokes) and progressively worsening ischemic lesion load in brain imaging, vascular cognitive impairment (usually of the frontal-subcortical type) with behavioral-psychiatric symptoms and bilateral pyramidal and pseudobulbar signs leading to severe disability and premature death. In some patients, microbleeds and hemorrhagic strokes may be evident. A large clinical heterogeneity is usually present.

Between the different forms the most frequent is CADASIL, due to mutations of the NOTCH3 gene, followed by COL4A1/A2-related disease, autosomal dominant forms of HTRA1-related disease and leucoencephalopathies with calcifications and cysts. CARASIL, with an autosomal recessive HTRA1 mutation, is less frequent. A new form has been recently described, named CARASAL.

In this presentation we will report our experience with these patients describing recent data on their pathogenesis and some guideline on the diagnosis and therapeutic options.

Abstract Body

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is now recognized as the most frequent cerebrovascular disease of genetic origin. The disease is caused by mutations of the NOTCH3 gene and is now easily diagnosed worldwide.

Over the last decades, multiple studies and observations at clinical and preclinical level allowed to understand the natural history of the disease, progression of clinical manifestations, development of cerebral tissue lesions, phenotypic variability as well as some key molecular players at vascular level and their potential relationships with accumulating white matter lesions in the mouse model.

CADASIL mutations lead to a complex process of Notch3^ECD aggregation into multimeric species that complex with binding partners (TIMP3 and vitronectin, among others). These processes will eventually form GOM deposits visible by electron microscopy in the vascular wall of arterioles and capillaries. Notch3 agregation may also have multiple consequences at long term on the life and function of smooth muscle cells and pericytes in the cerebral micocasculature which could ultimately result in alterations of cerebral tissue integrity.

We propose to examine some key lessons from research in animals and humans which must now necessarily converge to enable therapeutic development in CADASIL patients.