Genetic Mutations Discovered to Be Accountable for the Occurrence of Brain Malformations That May Help Prevent, Heal ‘Cavernous Angiomas’

A new study recently identified sporadic genetic mutations that make it more likely an individual will develop a rare type of brain malformation known as the "cavernous angioma." As described in a EurekAlert! report, this condition affects over a million Americans and carries "a lifetime risk of seizures and stroke."

Only roughly one-third of cases can be associated with inherited familial genetic mutations. The report of cavernous angiomas is sporadic, and until now, this same report specified, their cause remains unknown.

This new research by scientists at the University of Chicago Medicine, Duke University, and the University of Pennsylvania has identified a set of sporadic genetic mutations that are making it more possible that a person is likely to develop such lesions, along with added mutations in the same site that fuel growth of that lesion.

Combinations of Mutations Resulting in Cavernous Angioma

Deciphering the underlying causes of these brain malformations will be the key to determining which patients are at risk of developing the condition and searching for effective treatments against it. The study was published earlier this month in Nature Cardiovascular Research.

According to Issam Awad, MD, Professor of Neurological Surgery at the John Harper Seeley and Director of Neurovascular Surgery at UChicago Medicine, they've known for over two decades that there is a "familial form of cavernous angiomas" that's inherited through genes passed on from generation to generation.

However, in most people who have this type of brain bleeding, explained Awad, the lesion is not inherited. This new study has identified a distinctive combination of mutations during the brain's development, resulting in a cavernous angioma.

Developmental Venous Anomaly

First, a mutation in the gene PIK3CA leads to an abnormal pattern of vessels in the brain called a developmental venous anomaly or DVA. This DVA alone is, in general, innocuous.

Nevertheless, when a second mutation in one of the numerous genes like MAP3K3, KRIT1, CCM2, or PDCD10, occurs in the site of the abnormal vein, a cavernous angioma develops.

Awad explained that they had previously observed that these lesions are frequently growing near a preexisting abnormal vein. However, he added that DVAs are quite common; roughly six to 10 percent of people have one, and the vast majority never encountered any problems.

Unusually, such veins grow a cavernous angioma, and the researchers have never known the reason. In this research, the professor said, they were finally able to use "mutation analysis on the vein itself" to determine why the vein appears predisposed in the angiomas.

Benign Vein Abnormality Occurrence Tested

The authors of this new study hope to translate their findings into additional research and, eventually, more treatments to prevent and heal cavernous angiomas. Their next steps include finding biomarkers that might help identify benign DVAs from those destined to develop a cavernous angioma.

Awad explained; ideally, they will be able to determine through a simple blood test, if an individual has a benign vein abnormality, or if it has the seed that will result in the growth of an angioma.

According to a similar ScienceDaily report, the professor also said, they will be testing some of these pharmacologic inhibitors of the mutations they have identified to determine if they will stabilize or even shrink the brain lesions.

Awad continued, a mechanism is not only about scientific curiosity. He elaborated that there should be a motivation for changing patient care that if there is no mechanism, there won't be a genuinely rational treatment.

Related information about brain malformation is shown on Mayo Clinic's YouTube video below:

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