A rare type of brain blood vessel malformation known as a cavernous angioma affects more than one million Americans and carries a lifetime risk of stroke and seizures. Only about a third of cases can be linked to inherited familial genetic mutations. The majority of cavernous angiomas are sporadic and – until now – their cause was unknown.
A new study by researchers from the University of Chicago Medicine, Duke University and the University of Pennsylvania has identified a set of sporadic genetic mutations that make it more likely that a person will develop these lesions, as well as additional mutations in the same area that fuel lesion growth. Understanding the underlying causes of these brain malformations will be key to identifying patients at risk for their development and finding effective treatments for the disease. The research was published March 14 in Nature Cardiovascular research.
“We have known for more than two decades that there is a familial form of cavernous angiomas inherited from genes passed down from generation to generation,” said Issam Awad, MD, John Harper Seeley Professor of Neurological Surgery and Director of Neurovascular Surgery at UChicago. Medical. “But in the majority of people with this type of brain bleed, the damage is not hereditary. And until now, we never knew why some people randomly end up with this lesion. »
The new research has identified a unique combination of mutations that occurs during brain development that results in a cavernous angioma. First, a mutation in the gene PIK3CA leads to an abnormal pattern of vessels in the brain, known as developmental venous abnormality, or VAD. DVA alone is generally harmless. But when a second mutation in one of several genes, like MAP3K3, KRIT1, CCM2, Where PDCD10occurs in the area of the abnormal vein, a cavernous angioma develops.
“We had previously observed that often these lesions develop near a pre-existing abnormal vein,” Awad said. “But these DVAs are actually very common – around 6% to 10% of people have one, and the vast majority of them never have any problems. Rarely, these veins develop a cavernous angioma and we never knew why. In this study, we were finally able to use mutation analysis on the vein itself, to see why the vein seems predisposed to these angiomas. »
Researchers were able to examine the genetics of the angioma and his connected DVA, thanks to the delicate surgical method used to repair bleeding lesions. This requires removing small portions of the veins to disentangle them from the cavernous angioma lesion. This led to the discovery of the mutation in PIK3CA in the vein, and the realization that the same mutation coexists with a second mutation in the angioma.
“It’s very new, because now we can explain why DVA forms in the first place,” Awad said. “With a second mutation, it is the genetic seed for the formation and growth of the cavernous angioma. »
Not only does this provide a genetic mechanism for DVA formation, but the Chicago team also discovered molecules circulating in the blood that are associated with the key brain mutation. This is the first time that a blood test for a focal somatic mutation in the brain has been described.
“Now we can develop blood tests that can identify these mutations in the brain, and in the future we can develop therapies that can inhibit the mechanisms that cause these lesions to form,” Awad said. “Some of the genes we have identified can be inhibited by drugs that are already on the market. »
The researchers hope to translate these findings into further research and ultimately into more treatments to prevent and cure cavernous angiomas. Next steps include finding biomarkers that could help distinguish benign VADs from those that are destined to develop a cavernous angioma.
“Ideally, we’ll be able to tell with a simple blood test if you have a benign vein abnormality, or if it has the seed that will lead to it developing an angioma,” Awad said. “In addition, we will test some of these pharmacological inhibitors of the mutations we have identified to see if they will stabilize or even reduce brain damage.
“A mechanism is not just a matter of scientific curiosity,” he continued. “This should motivate us to change patient care. If we don’t know the mechanism, we can’t have a truly rational therapy. »
The study, “Developmental venous abnormalities are a genetic primer for cerebral cavernous malformations,” was supported by the National Institutes of Health (P01NS092521 and F31HL152738). Other authors include Romuald Girard, Rhonda Lightle, Abhinav Srinath, Sharbel Romanos, Ying Li, and Chang Chen from the University of Chicago; Daniel A. Snellings and Douglas A. Marchuk of Duke University; and Aileen A. Ren and Mark L. Kahn of the University of Pennsylvania.