More Than Pipes

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More Than Pipes

Evidence of an association between a mutation in type IV collagen and cerebral hemorrhage could lead to new insights about small-vessel disease.

Small-vessel disease is a seemingly ubiquitous proclamation on CT and MRI reports, despite a virtually universal inability to substantiate this diagnosis with vessel pathology or any form of angiography. Indirect evidence of this common and often-devastating disorder comes from the distribution of parenchymal lesions. These researchers describe a mutation in the COL4A1 gene, in diminutive cerebral vessels of mice and men, that leads to an inherent susceptibility to environmental stress and resultant hemorrhage.

In genetically engineered mice, the mutation was associated with microvascular abnormalities and abnormalities of type IV collagen, a basement-membrane protein. Many of the mice died of cerebral hemorrhages shortly after birth; the rest had either neurologic deficits and subarachnoid hemorrhage or clinically silent intracerebral hemorrhage.

Separately, affected members of a family with porencephaly had a pattern of retinal tortuosity, white matter lesions, and intracerebral hemorrhage, with clinical features strikingly similar to those in the mice. Leukoencephalopathy and scattered microbleeds were apparent on MRI brain scans. The authors found a mutation in COL4A1 in the patients but not in 196 healthy controls. They suggest that future studies of small-vessel ischemic disease and intracerebral hemorrhage in humans should consider the role of genetic mutations that precipitate collagen disorders.

Comment: This intriguing and unusual mechanistic explanation links vessel fragility in mutant mice with clinical disease in humans. The findings suggest that molecular heterogeneity exists in the arterial wall, revising the concept of the perforating arterioles as mere pipes. Consideration of unique molecular features at such distal reaches of the cerebral circulation may provide insight into the links between small-vessel ischemia and hemorrhage. Environmental or mechanical stressors such as hypertension may promote injury in genetically predisposed individuals. Future molecular and neuroimaging investigations are required to elucidate the diverse nature of the vessel wall and to move beyond the established cult of luminology in cerebrovascular disease.

— David S. Liebeskind, MD

Dr. Liebeskind is Assistant Professor of Neurology, University of California, Los Angeles.

Published in Journal Watch Neurology October 3, 2006