Neonatal porencephaly and adult stroke related to mutations in collagen IV A1

Objective: The objective of this study was to describe leukoencephalopathy, lacunar infarcts, microbleeds and macrobleeds in the context of a collagen IV A1 mutation. Methods: We examined a family with autosomal dominant porencephaly, in whom a defect in collagen IV A1 was detected recently. The patients underwent neurological, ophthalmological, and cardiological examinations and magnetic resonance imaging of the brain. Electron microscopy of a skin biopsy was performed. Extensive laboratory screening was performed for thrombophilia and increased bleeding tendency. Results: The porencephaly was symptomatic in the infantile period in two patients, whereas it led to only minor neurological dysfunction in their affected mother. However, she experienced development of recurrent strokes in her 40s. In addition to the porencephaly, all patients had a leukoencephalopathy, which was most severe in the mother. Her magnetic resonance imaging results also showed lacunar infarcts, macrobleeds and a multitude of microbleeds. No other risk factors for recurrent stroke were found. Electron microscopy showed interruptions of the basement membrane of skin capillaries and inhomogeneous thickening of the basement membrane with pools of basement membrane fragments. Interpretation: Leukoencephalopathy, ischemic infarcts, microbleeds, and macrobleeds are indicative of an underlying microangiopathy, of which the best-known causes are hypertension, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and cerebral amyloid angiopathy. Mutations in collagen IV A1, a major component of the vascular basement membrane, appear to be another risk factor.