COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke

Objective: Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy and variable abnormalities of the anterior chamber of the eye. Methods: After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives. Results: Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld-Rieger type was observed in five individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, P.G720D, which cosegregates with the disease. Interpretation: Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld-Rieger anomaly and leukoencephalopathy and stroke.