Researchers find genetic link to cerebral hemorrhage and porencephaly

Researchers at The Jackson Laboratory have discovered a genetic link to porencephaly, a rare but devastating neurological condition.

Their research, published in the May 19 issue of the journal Science, may have significant implications for preventing the disease in humans.

Usually exhibited in infants shortly after birth, symptoms of porencephaly include mental retardation, cerebral palsy or epilepsy. The brains of porencephaly patients show degenerative cavities and lesions. Researchers have suspected that the damage is the consequence of fetal trauma and/or genes affecting blood clotting that predispose to hemorrhage.

An international team discovered a genetic defect that weakens blood vessels in the brain, making an infant much more vulnerable to hemorrhaging. The team was led by Dr. Douglas Gould a postdoctoral fellow at The Jackson Laboratory and Jackson Laboratory Staff Scientist and Howard Hughes Medical Institute Investigator Dr. Simon W.M. John.

The researchers identified a mouse model of porencephaly. They found that the mice had a mutation in a collagen gene, COL4A1, which controls production of a basement membrane protein. As the name suggests, basement membranes provide foundations for a variety of tissues, including forming a strong sheath around blood vessels. The scientists concluded that the mutant collagen protein cannot be secreted into the basement membrane of the blood vessels causing them to be weakened. Instead, mutant collagen proteins accumulate within the cells lining the blood vessels possibly damaging them. The combination of cells with accumulated mutant protein and the weak basement membrane around blood vessels predisposes to hemorrhage.

To determine whether humans with porencephaly also have COL4A1 mutations, the researchers studied two families with a history of the disease and found the mutations. Control families had neither the mutation nor any history of porencephaly.

Since not all mice with the mutation develop porencephaly and the human disease is also variable, the researchers suggest that the weakened blood vessels in the brain could be damaged by stress on the head during birth, resulting in cerebral hemorrhage and subsequent porencephaly.

“Our finding could have important implications for disease prevention,” said Dr. Gould. “For individuals who are at risk for vascular defects caused by mutations in COL4A1 genes, actions to reduce the stress on the weakened cerebral blood vessels could reduce the neurological damage. For example, Cesarean delivery of at-risk babies could increase the possibility of a healthy life,” he concluded.