Atypical CADASIL phenotypes and pathological findings in two new French families.

Atypical phenotypes of CADASIL and corresponding anatomical data in two cas es are described in 6 members of 2 new French families. In the first family , 4 cases in the same kindred were probably affected, two of them with a pr edominant psychiatric presentation, two others with dementia and a pseudo-b ulbar syndrome of progressive evolution. No history of migraine or ischemic event were documented in any. In the propositus, the diagnosis was documen ted by skin biopsy, Notch 3 gene mutation and autopsy after the patient had died when 67 years old, 8 years after onset. Brain examination showed a wi despread leukoencephalopathy with subcortical infarcts. Characteristic gran ular lesions of the small arteries of the brain and other organs were obser ved. In the second family, two cases are reported. One patient died when 63 years old after a subacute evolution mimicking intracranial hypertension. The anatomical diagnosis was retrospectively proven typical of CADASIL with Notch 3 immunostaining of arterial smooth muscle cells. The other case had a progressive evolution over 20 years of limb paresthesia with a mild spas ticity diagnosed as a progressive form of multiple sclerosis. It was follow ed by a pseudo-bulbar syndrome and a mild subcortical dementia without acut e ischemic attack. The diagnosis was confirmed by skin biopsy and mutation of the Notch 3 gene. This report illustrates 1) the intrafamilial and interfamilial phenotypic v ariability of CADASIL, 2) the significance of ischemic demyelinating lesion s of the white matter, without correlation with clinical ischemic symptoms and 3) the need for validated CADASIL diagnostic criteria which should cont ribute to genetic testing and epidemiological knowledge.