Background. Although grey matter pathology is a relevant aspect of multiple sclerosis (MS) both with physical and cognitive rebounds, its pathogenesis is still under investigation. To what extent the familial and sporadic cases of MS differ in cortical pathology has not been elucidated yet. Here we present a multiple case report of four sisters affected by MS, all of them having a very high burden of cortical pathology. Methods. The clinical and grey matter MRI parameters of the patients were compared with those of twenty-five-aged matched healthy women and 25 women affected by sporadic MS (matched for age, disease duration, EDSS, and white matter lesion load). Results. Despite their short disease duration (<5 years), the four sisters showed a significant cortical thinning compared to healthy controls ( ) and sporadic MS ( ) and higher CLs number ( ) and volume ( ) compared to sporadic MS. Discussion. Although limited to a single family, our observation is worth of interest since it suggests that familial factors may account for a peculiar involvement of the cortex in MS pathology. This hypothesis should be further evaluated in a large number of multiplex MS families. 1. Introduction Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system whose etiopathogenesis is believed to be the result of a complex interaction of genetic and environmental factors [1, 2]. Beside the extensive inflammatory demyelination observed in the white matter (WM), the involvement of grey matter (GM), that is, focal lesions [3] and atrophy [4, 5], is a well-known feature of MS pathology [6]. Several magnetic resonance imaging (MRI) studies have demonstrated that a significant cortical damage is a frequent finding in all MS phenotypes [3] (including more than one-third of individuals at disease onset and also in patients with radiological isolated syndrome [7]), sometimes preceding the appearance of any WM lesion [8, 9]. Moreover, GM damage was found to have a significant impact on clinical [10–12] and cognitive [13, 14] disability as longitudinal studies have disclosed a more severe prognosis in patients having a high degree of cortical damage [10, 15]. Thus, cortical pathology has to be considered a further element of heterogeneity, and its use for a better clinical stratification of MS patients is currently under evaluation. Up to date, no study has been performed to evaluate the degree of cortical pathology in patients from multiplex MS families and to assess whether cortical pathology might be a “familial share factor” that could
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