Homozygosity and severity of phenotypic presentation in a CADASIL family.

[cadasil]

Most of causative mutations of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL ) are missense point mutations either creating or deleting one cysteine residue , inherited in a heterozygous state . Only few homozygous patients are reported to date and some of them showed phenotypic peculiarities . We here describe a CADASIL family in which a member showed homozygous mutation and compare its clinical profile with five subjects throughout three generation of the pedigree , carrying the same mutation in heterozygosity . The index patient was a 44 -year -old Italian man , born from consanguineous parents (first cousins ). Symptoms started at 23 years and progressing with recurrent ischemic stroke episode . Diffuse leukoencephalopathy and a severe cognitive impairment were evident , GOMs were detected in skin specimens and a homozygous p .C ys 183 S er mutation of the NOTCH 3 gene was found . Among the other five heterozygous relatives for the same mutation , both parents developed stroke in advanced age and all the others were clinically asymptomatic . We discuss these findings in relationship to previous data from the literature in CADASIL and in other dominant neurological disorders .