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 PIK3CA in 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.”
Cerebral cavernous malformations (CCMs) are abnormally large collections of “low flow” vascular channels without brain parenchyma intervening between the sinusoidal vessels. McCormick (1966) recognized CCMs as one of the four classes of cerebral vascular malformations which include arteriovenous malformations (AVM), developmental venous anomalies (DVA), and capillary telangiectasia. Clinically, CCMs are highly variable in both symptomatic presentation and natural history. Adding to the confusion, CCM has assumed a variety of names in the medical literature including cavernomas, cavernous angiomas, and cavernous hemangiomas, though CCM is the preferred nomenclature. CCMs range in size from punctate to several centimeters in diameter and may occur anywhere in the central nervous system with up to 20% located in the brainstem.
CCM may be diagnosed in both young children and adults and may develop de novo or even regress spontaneously during a patient’s lifetime. A thorough understanding of the natural history of this entity is of paramount importance to avoid unnecessary and potentially morbid interventions. Given the heterogeneity of this condition, the ontogenesis, diagnosis, management strategies for CCMs are subjects of ongoing debate among neuroscientists and treatment paradigms continue to evolve.
Experts do not fully understand the pathogenesis of CCMs, but the genetic underpinnings have been clarified in recent years. The majority of CCMs are sporadic, but up to 20% follow a familial, autosomal dominant inheritance pattern characterized by the presence of multiple CCMs in a single patient. This has led to the identification of three homologically distinct genes responsible for CCM development: CCM1, CCM2, and CCM3. Mutations in any one of these genes can result in multifocal CCM and all three show relatively high genetic penetrance. Many authors have proposed a “two-hit” hypothesis of familial CCM wherein epigenetic or environmental exposure (the second hit) results in CCM gene loss-of-function and may account for the proclivity of these lesions to accumulate over time and with exposure to radiation. Studies of sporadic CCM support a common pathway involving de novo mutations of CCM genes.
CCM protein products interact with each other and other cellular machinery responsible for a range of functions including cell-cell communication and angiogenesis. The most critical dysfunction found in CCM mutants is endothelial junction permeability, an effect mediated by Notch1 and Rho kinase activity. This correlates with the characteristic histopathological appearance of CCM which lacks mature vessel wall architecture and mature blood-brain-barrier. CCMs are distinguished from other cerebral vascular malformations by the absence of direct arteriovenous communication and lack of intervening brain parenchyma.
CCMs are the second most common incidental vascular finding – after aneurysms – on brain magnetic resonance imaging (MRI), with a prevalence of 1 in 625 neurologically asymptomatic people. Clinical presentation is bimodal with a significant number of cases detected in both adolescents and middle-aged adults. There is no discernible sex difference in prevalence; however, there is conflicting research as to whether prognosis is different among men and women. Familial CCM is notably prevalent among persons of northern Mexican ancestry, an effect that has been traced to a common founder mutation. The incidence of incidentally detected CCM has increased substantially due to the widespread use of magnetic resonance imaging (MRI). The majority (approximately 75%) of CCMs are found in the supratentorial compartment in predictable proportion to the volume of neural tissue present.
The propensity for intra-lesional and extra-lesional hemorrhage is the chief mechanism underlying the clinical manifestations of CCM. Sluggish blood flow through dysplastic channels results in recurrent thrombosis, calcification, and deposition of hemosiderin along the margins of the lesion. Hemorrhage into adjacent brain parenchyma can produce focal neurologic deficits (FND), seizure, or a headache prompting the patient to present for evaluation. Clinical and lifestyle risk factors for a first symptomatic episode of CCM hemorrhage are unknown, but risk factors for re-hemorrhage are well-studied. The pathogenesis of CCM-related epilepsy has been attributed to peri-lesional reactive gliosis due to clinically silent micro-hemorrhages which alters conduction adjacent white matter pathways. The observation that seizure-free outcomes are improved when the entire lesion, including the surrounding hemosiderin rim, is resected, supports this.
rewference link :https://www.ncbi.nlm.nih.gov/books/NBK538144/
More information: Daniel A. Snellings et al, Developmental venous anomalies are a genetic primer for cerebral cavernous malformations, Nature Cardiovascular Research (2022). DOI: 10.1038/s44161-022-00035-7