Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) leading to inflammatory lesion in brain and spinal cord. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary NOTCH3-related vasculopathy causing ischemic white matter lesions. Magnetic Resonance Imaging (MRI) is the gold standard to evaluate CNS lesion in both diseases. However, achieving the correct diagnosis is not always easy. Indeed, several CADASIL cases were reported as MS misdiagnosis. Adding complexity is the co-occurrence of the two diseases in some cases. To date, a systematic investigation about frequency and clinical features of NOTCH3 mutation carriers among MS cases is still lacking. We will select a cohort of fifty MS patients with family history of MS, migraine, strokes or dementia or with MRI brain lesion compatible with MS and CADASIL. Each patient will undergo NOTCH3 molecular analysis. In those with variants of unknown significance or new mutations, deposits of granular osmophilic material on hypodermal vessels will be searched by electronic microscopy. Moreover, the impact of all detected mutations on the Notch3-receptor activity will be predicted by specific bioinformatics tools. Family history, neurologic and retinal evaluation, cerebrospinal fluid (CSF) profile and MRI features will be assessed, comparing NOTCH3 carriers and non-carriers among the above defined cohort.
This study aims at detecting the NOTCH3 mutations frequency in patients with MS and the clinical, MRI and CSF features able to discern MS-CADASIL co-occurrence from ¿inflammatory CADASIL¿. The results of this study would improve clinical management of our patients and their relatives at risk of developing the disease. DNA, plasma and fibroblasts from patients and carriers will be stored for further studies aimed at investigating the role of inflammation in the pathogenetic cascade related to specific NOTCH3 variants.
