A Genetic Cause for Primary Intracerebral Hemorrhage?

Abstract & Commentary

By Matthew E. Fink, MD, Vice Chairman, Professor of Clinical Neurology, Weill Cornell Medical College, Chief, Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital. Dr. Fink reports no financial relationship relevant to this field of study.

Synopsis: An inherited defect in Type IV collagen, a basement membrane protein, may be a cause of small-vessel disease and primary intracerebral hemorrhage.

Source: Gould DB, et al. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke. N Engl J Med. 2006:354:1489-1496.

Intracerebral hemorrhage (ich) is the most devastating form of stroke, with a case mortality approaching 50%. While chronic hypertension and advanced age remain the most important risk factors, up to 40% of cases in people under the age of 50 have no definable etiology. Gould and colleagues have now shed light on a genetic disorder that affects the basement-membrane protein, type IV collagen (COL4A1), in mice and human families with porencephaly, which may predispose to small-vessel disease and intracerebral hemorrhage.

In a previous paper (Science. 2005;308:1167), the authors reported that the Col4a1 mutation in mice could cause perinatal hemorrhage and porencephaly in about 20% of newborn pups, and postulated that pressure on the head during birth, in the setting of abnormal small-vessels in the brain, accounted for ICH. In the present study, Gould et al delivered the mutant mice surgically to prevent birth trauma, and demonstrated that intracerebral hemorrhage was prevented at birth in that group compared with naturally born mutant pups, who all had cerebral hemorrhage visible through the skull and skin, with 50% of the pups dying on the day of birth. Among the surgically delivered mutant mice who were allowed to age, many had overt neurological episodes with seizures and hemiparesis, and all had pathological evidence of intracerebral or subarachnoid hemorrhage at autopsy. Hemosiderin-containing lesions were identified in the basal ganglia in 22 animals, and 1 lesion was found in the cortex. Other pathological evidence of small-vessel disease on the mutant mice were found, including retinal vascular tortuosity, defects in the glomerular basement membrane, and microalbuminuria.

In a striking similarity to the mutant mice, Gould et al also describe the phenotypic similarities between Col4a1-mutant mice and a French family with small-vessel disease. All 6 affected members of this family had retinal arterial tortuosity, 2 had infantile hemiparesis, 3 had migraine with aura, and all had neuroimaging that showed diffuse leukoencephalopathy with microbleeds. Two members of the family had fatal intracerebral hemorrhage, one after head trauma, and one while taking anticoagulant medications. DNA sequence analysis of the affected family members showed a G1769A transition in exon 25 of the COL4A1 gene.

Commentary

In a dramatic comparison between a mice-model and a human family, Gould et al have raised the possibility that a genetic disorder affecting basement-membrane collagen can predispose to small-vessel disease and, subsequently, to ICH. This discovery may be one of the missing links in our search for the cause of many cases of intracerebral hemorrhage, some familial, that have eluded diagnosis until now. It also raises the tantalizing idea of a genetic-environmental interaction that may result in ICH after minor trauma or use of anticoagulant medications, and may lead to new approaches for prevention and treatment for ICH.

It also sheds light on a larger group of people with ischemic cerebrovascular disease who are diagnosed with small-vessel disease as a cause of both clinical and silent strokes, as well as progressive dementia. In a companion editorial (N Engl J Med. 2006;354:1451), Dr. Greenberg points out that this large and important group of patients have eluded understanding and effective treatment. The traditional view has been that their small-vessel disease (lipohyalinosis) is the result of long-standing hypertension, yet effective treatment of blood pressure seems to do little to stop the progression of this disease, or reverse it. The work by Gould et al has now pointed to Type IV collagen as a new target for our focus and investigation into the causes, prevention, and treatment of small-vessel disease and ICH.

How does this information help us now to treat our patients? We should be more diligent in taking careful family histories, and refer patients for genetic studies when appropriate. We should recognize the attendant risks of minor head injury and use of anticoagulants in patients diagnosed with small-vessel disease, and be particularly aggressive in treating their high blood pressure, since the interaction between weak vessels and high blood pressure may be even more important in this group of patients than we previously thought.