It's Raspberry Day!
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By Joshua Seid
Senior, Biomedical Engineering
Mississippi State University
September 16, 2022
Today is Raspberry Day, and we’re not talking about the sweet and tart fruit you get from your local grocery store! The Cavernoma Society has designated the third Friday of September as the annual Cavernoma Awareness Day. Why a raspberry, you may ask? A cavernoma is a clump of abnormal growing blood vessels on the brain or spinal cord that resemble a raspberry! These rare blood vessels are like caverns and contain blood that flows slowly through them. An estimated 16 to 50 per 10,000 people are affected by cavernomas worldwide. Cavernomas are also known as cavernous angioma, cavernous hemangiomas, intracranial cavernous vascular malformation, and cavernous cerebral malformation. More about Cavernoma Cavernomas appear as a cluster of small swollen blood vessels with aberrant underdeveloped vessel walls. Hence, the blood vessels are susceptible to leakage, leading to health conditions such as cerebral hemorrhage and stroke. Cavernomas can form anywhere in the body. However, they are detrimental only when they form in the brain and spinal cord. They appear similar to raspberry and may range from a few millimeters to several centimeters in diameter. Cavernomas are non-neoplastic or non-cancerous, although some may exhibit cancer-like qualities. What Causes Cavernoma? The first literature citing cavernous angioma dates back to the late 1940s. It was not until the late 1990s and early 2000s that early treatment methods and clinical trials began. Today, we know that cavernomas can be either inherited, the familial form, or acquired, the sporadic form. Compared to the sporadic form, individuals affected with the familial form are at higher risk of developing multiple cerebral cavernous malformations. Sporadic or acquired cavernomas results from cranial irradiation, viral infections, hormonal imbalance, and immature blood vessel development. Loss-of-function mutations cause the inherited or familial form of cavernoma. Mutations in either CCM1/KRIT1, CCM2/Malcavernin, or CCM3/PDCD10 can lead to brain and spinal cord lesions. Among the three, the CCM3 gene mutations pose the most severe threat. Individuals with the CCM3 gene mutations have a higher risk of developing an increased number of abnormal blood vessels, scoliosis, and cognitive disability. According to the National Health Service, less than 50% of cavernoma cases are inherited. What are the symptoms? According to the rare disease database, 40% of individuals affected are asymptomatic. These individuals tend to have no history of familial cavernomas. While most cavernomas are benign and go undetected, about 25% of cases may become symptomatic. Often reported mild symptoms include headaches, weakness, tremors, numbness, tiredness, and difficulty concentrating. More severe symptoms range from hemorrhagic stroke, epilepsy, migraine, slurred speech or dysarthria, double vision or diplopia, dizziness, and decreased coordination and mobility. Severity depends on the type, number, location, and size of the cavernoma. Most people with symptoms are between the ages of 20 and 50. What do we know about the disease mechanism? The CCM, or cerebral cavernous malformation family of proteins, CCM1/KRIT1 - Krev-interaction trapped 1, CCM2/Malcavernin, and CCM 3/PDCD10- Programmed Cell Death 10 regulate endothelial cell-cell contact and vascular homeostasis. Hence, mutations in these proteins often lead to abnormal blood vessel formation and thin blood vessel walls. The CCM 1 gene encodes for the largest CCM protein, KRIT 1. It strengthens the interactions between cells that form blood vessels and inhibits blood leakage from these vessels. In a normal cell, KRIT 1 aid in the suppression of the signaling molecule RhoA GTPase, which weakens the junctions between cells and stimulates the leakage of blood from vessels When the KRIT1 function is lost, the cell junctions' stability is compromised. Mutations in CCM1 are estimated to account for around 40% of familial cases. CCM2/malcavernin is a scaffold protein that connects KRIT1 and PDCD10 proteins to form a complex. Malcavernin is involved in angiogenesis, the process of migration, growth, and differentiation of endothelial cells to form new blood vessels. CCM2 is localized to the endothelial cell junctions by KRIT1 protein. When the KRIT1 function is lost, CCM2 recruitment to the endothelial cell junction is compromised, leading to reduced stability of cell junctions. An estimated 20% of the patients diagnosed with symptomatic cerebral cavernous malformation have a mutation in the CCM2 gene. As the name suggests, CCM 3/PDCD10- Programmed Cell Death 10 plays a role in regulating cell death. PDCD10 is hypothesized to have a role in structuring blood vessels. The primary function of the protein is unknown. However, studies suggest that PDCD10 strengthens interactions between cells and limits leakage from blood vessels, just as KRIT1 and malcavernin. One study shows that maintaining endothelial junctional stability requires blocking the function of Rho-associated protein kinase (ROCK) by the CCM family of proteins. For more information: Listed below are websites and organizations with a brief description for our readers: National Health Service (NHS) – A brief overview of the disorder, including symptoms, causes, diagnosis, and treatment Alliance to Cure Cavernous Malformation – A United States-based nonprofit charity organization created individuals affected by cavernoma for those affected by cavernoma. The Cavernoma Society – A United Kingdom-based charity supporting those affected by cavernoma. ClinicalTrials.gov – Lists current and completed studies along with progress made on studies related to cavernoma NCBI, Brain Cavernous Angiomas – A complete study published to the National Library of Medicine that aims to summarize steps to be taken post-diagnosis and to model a well-coordinated interprofessional team approach to provide adequate care to a patient affected by a cavernous angioma. NLM, MedlinePlus – Provides general information about the condition, including an overview, frequency, causes, inheritance, and other names. Uniquely, additional information and resources provided include the genetic testing registry. |
Histopathology of cavernous hemangioma of the liver. KGH / Wikimedia Commons / CC-BY-SA-3.0
Cavernoma Awareness
CCM 1 Protein Structure. Image from the RCSB PDB (rcsb.org) of PDB ID 3U7D (Gingras, A.R., Liu, J.J., Ginsberg, M.H (2012) J Cell Biol 199: 39-48).
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