A Novel TREX1 Frameshift Variant (c.802del p. (Arg268Glyfs*9) Associated with Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations: a Case Report

The human body relies on a delicate balance of repair and maintenance to keep its cells functioning correctly. Among the many molecular tools that perform this upkeep is a protein called TREX1, which acts like a specialized editor, scanning DNA for errors and removing damaged sections to prevent genetic chaos. Normally, this protein stays safely anchored outside the cell's command center, the nucleus, where it handles its specific tasks without interfering with the genetic blueprint. However, when the instructions for building this protein are slightly altered, the editor can become misdirected. Instead of staying put, it slips into the nucleus and begins damaging the very DNA it is meant to protect. This specific type of error triggers a cascade of inflammation and weakens the tiny blood vessels throughout the body, leading to a rare and severe condition known as retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. While the disease affects the eyes, the brain, and various organs, it remains poorly understood, and for decades, doctors have struggled to identify the precise genetic triggers that cause it in different families.

In a recent case report, researchers describe a 42-year-old man whose confusing and worsening symptoms finally led to a breakthrough in understanding this condition. The man arrived at the emergency room in a state of confusion, suffering from severe headaches and nausea after a minor head injury. Initial scans of his brain revealed a large, alarming mass in the left side of his head that was pushing against surrounding structures, a finding that typically suggests a tumor or a severe infection. Doctors performed a biopsy, removing a piece of the tissue to examine it under a microscope, but the results were inconclusive, showing only inflammation and dead tissue rather than a clear cancer or bacteria. Despite treatment with broad-spectrum antibiotics, his condition did not improve, and the medical team was left without a definitive answer. The situation seemed to be a medical mystery, with the patient's brain lesions and a history of substance abuse complicating the picture.

The turning point came when doctors looked beyond the brain and examined the patient's eyes. An ophthalmic examination revealed a distinct pattern of damage in the blood vessels at the back of the eye, specifically a lack of blood flow in the peripheral retina and the growth of new, fragile vessels that required laser treatment to prevent blindness. This specific eye condition, combined with the brain lesions, pointed toward a rare genetic disorder rather than an infection or a tumor. Further investigation into the patient's family history revealed a tragic pattern: his father had died at age 38 from what was diagnosed as "brain cancer," and other relatives, including a grandmother and cousins, had suffered from similar eye and brain issues. This family history provided the crucial clue that the problem was inherited.

Genetic testing on a sample from the patient's cheek confirmed the diagnosis. The researchers found a new, previously unknown error in the gene that codes for the TREX1 protein. This specific mistake, a small deletion in the genetic code, causes the protein to be built incorrectly. Instead of the full-length protein that stays in its proper place, the body produces a shortened version that lacks the anchor needed to keep it outside the nucleus. Consequently, this faulty protein enters the nucleus and damages DNA, triggering the inflammation and blood vessel weakness seen in the patient's brain and eyes. This discovery is significant because it identifies a new genetic cause for the disease, expanding the list of known mutations that can lead to this devastating condition.

The patient's case also highlighted the broader impact of the disease on the body. Beyond the brain and eyes, he suffered from avascular necrosis, a condition where bone tissue dies due to a lack of blood supply, specifically affecting the hip joint. He also exhibited signs of systemic inflammation, including elevated levels of certain proteins in the blood that are often associated with autoimmune disorders. The researchers noted that recognizing this genetic condition early could have spared the patient from unnecessary brain surgery, as the symptoms often mimic tumors or abscesses. Currently, there is no cure for the disease, and treatments focus on managing symptoms, such as using steroids to reduce brain swelling or laser therapy for the eyes. While some experimental drugs have been tested to slow the progression of the disease, results have been mixed, and patients often face a shortened lifespan.

This report serves as a vital reminder of the importance of genetic testing when patients present with a combination of eye and brain problems that do not fit standard diagnoses. By identifying the specific genetic error, doctors can provide a clear explanation for the patient's suffering and avoid invasive procedures that offer no benefit. The discovery of this new variant in the TREX1 gene adds another piece to the puzzle of how genetic errors can lead to complex, multi-system diseases. It underscores the need for continued research into how these misdirected proteins cause damage and how new therapies might one day stop the process before irreversible harm occurs. For families affected by this rare condition, the identification of the genetic cause offers a path to understanding, even if a complete cure remains out of reach.