Sturge-Weber syndrome (SWS) is a rare neurological and vascular disorder caused primarily by a specific genetic mutation that occurs after conception, meaning it is not inherited but arises spontaneously in the affected individual. The root cause is a **somatic mosaic mutation** in the gene called **GNAQ**, specifically a change known as **p.R183Q**. This mutation activates abnormal signaling pathways inside cells, particularly those involved in vascular development and function.
To understand this better, the GNAQ gene normally produces a protein that helps regulate signaling inside cells, especially in blood vessel cells. When the mutation p.R183Q occurs, it causes the protein to be constantly active. This leads to overactivation of pathways such as the **Gαq-PLCβ-PKC axis** and **Rho-ROCK signaling**, which are crucial for controlling how blood vessels grow and behave. Because these pathways are stuck in an “on” position, they cause abnormal proliferation and malformation of blood vessels, especially in the skin and brain coverings (leptomeninges). This abnormal blood vessel growth is what leads to the characteristic features of SWS, including the facial port-wine stain birthmark, neurological problems like seizures, and sometimes glaucoma in the eye.
The mutation happens in a mosaic pattern, meaning only some cells carry the mutation while others do not. This mosaicism explains why the symptoms can vary widely between individuals depending on which tissues and how many cells are affected. The mutation is not present in the sperm or egg cells, so it is not passed from parents to children but arises early in embryonic development.
The abnormal blood vessels in SWS are fragile and malformed, leading to impaired blood flow and oxygen delivery in the brain. This causes damage to the underlying brain tissue, contributing to neurological symptoms such as seizures, developmental delays, and weakness on one side of the body. The vascular malformations in the skin cause the port-wine stain, which is a flat, reddish to purplish birthmark often found on the face.
In addition to the GNAQ mutation, the disease process involves complex interactions of cellular signaling pathways that regulate blood vessel formation and brain development. These include pathways like **mTOR**, **Ras-MAPK**, and **PI3K-AKT**, which are also implicated in other neurocutaneous syndromes. The overactivation of these pathways leads to abnormal growth and function of endothelial cells (which line blood vessels) and other supporting cells, causing the vascular and neurological abnormalities seen in SWS.
Because the mutation affects blood vessel cells, the syndrome is classified as a neurocutaneous disorder, meaning it affects both the nervous system and the skin. The vascular abnormalities in the brain’s leptomeninges cause neurological symptoms, while the skin manifestations arise from similar vascular malformations in the facial skin.
Recent research is focused on understanding these molecular mechanisms in detail to develop targeted therapies. For example, drugs that inhibit the overactive signaling pathways or gene therapies that correct the mutation hold promise for future treatment. Early detection and intervention, sometimes even before seizures begin, are becoming possible thanks to advances in genetic testing and imaging.
In summary, Sturge-Weber syndrome is caused by a spontaneous somatic mutation in the GNAQ gene that leads to abnormal activation of signaling pathways controlling blood vessel growth. This results in malformed blood vessels in the skin and brain, causing the hallmark port-wine stain and neurological symptoms such as seizures and developmental issues. The mosaic nature of the mutation explains the variability in symptoms, and ongoing research aims to translate this genetic understanding into precise, effective treatments.
