A 'perfect storm' of genetic mutations is behind rare sporadic brain malformations that cause stroke, seizures

Date:
March 30, 2022
Source:
University of Chicago Medical Center
Summary:
A new study found that specific genetic mutations occurring in
just the right locations in the brain are behind the formation of
cavernous angiomas, which can bleed and cause strokes and seizures.



FULL STORY ==========================================================================
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 around one-third of cases can be
connected to inherited familial genetic mutations. The majority of
cavernous angiomas are sporadic and -- until now -- their cause was
unknown.


==========================================================================
A new study by researchers at 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 a person will
develop these lesions, along with additional mutations in the same area
that fuel the lesion's growth.

Understanding the underlying causes of these brain malformations will be
the key to identifying which patients are at risk for their development
and finding effective treatments against the condition. The research
was published March 14 in Nature Cardiovascular Research.

"We've known for more than two decades that there is a familial form of cavernous angiomas that is inherited via genes passed on from generation
to generation," said Issam Awad, MD, the John Harper Seeley Professor of Neurological Surgery and Director of Neurovascular Surgery at UChicago Medicine. "But in the majority of people with this type of brain bleeding,
the lesion is not inherited. And until now, we've never known why some
people randomly end up with this lesion." The new research has identified
a unique combination of mutations that occurs during the development of
the brain 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 a developmental venous anomaly, or DVA. The DVA alone is generally innocuous. But when a second mutation in one of several genes, such as
MAP3K3, KRIT1, CCM2,or PDCD10, occurs in the area of the abnormal vein,
a cavernous angioma develops.

"We'd previously observed that often these lesions grow near a preexisting abnormal vein," said Awad. "But these DVAs are actually very common --
about 6% to 10% of people have one, and the vast majority of them never
have any problems. Rarely, those veins grow a cavernous angioma and we've
never known 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." The researchers were able to examine the genetics
of both the angioma and its connected DVA, thanks to the delicate
surgical method used to repair bleeding lesions. It requires removing
small portions of the veins to detangle them from the cavernous angioma
lesion. This led to the discovery of the mutation in PIK3CAin the vein,
and the realization that the same mutation co-occurs with a second
mutation within the angioma.



========================================================================== "This is very novel, because we can now explain why the DVA forms in the
first place," said Awad. "Along 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 the formation of the DVA, 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've identified can be inhibited by drugs that are already
on the market." The researchers hope to translate these findings into additional research and, ultimately, more treatments to prevent and heal cavernous angiomas. The next steps include searching for biomarkers that
might help distinguish benign DVAs from the ones that are destined to
grow 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 it to grow
an angioma," said Awad. "In addition, we'll be testing some of these pharmacologic inhibitors of the mutations we've identified to see if
they will stabilize or even shrink the brain lesions.

"A mechanism is not just about scientific curiosity," he continued. "It
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 anomalies are a genetic primer for cerebral cavernous malformations,"
was supported by the National Institutes of Health (P01NS092521 and F31HL152738). Additional authors include Romuald Girard, Rhonda Lightle, Abhinav Srinath, Sharbel Romanos, Ying Li and Chang Chen of 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.


========================================================================== Story Source: Materials provided by
University_of_Chicago_Medical_Center. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Daniel A. Snellings, Romuald Girard, Rhonda Lightle, Abhinav
Srinath,
Sharbel Romanos, Ying Li, Chang Chen, Aileen A. Ren, Mark
L. Kahn, Issam A. Awad, Douglas A. Marchuk. Developmental
venous anomalies are a genetic primer for cerebral cavernous
malformations. Nature Cardiovascular Research, 2022; 1 (3): 246
DOI: 10.1038/s44161-022-00035-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220330130522.htm

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