Researchers identified genetic variants linked to spontaneous CSF leaks in the spine. These findings may lead to earlier diagnosis and more targeted treatment.
Image credit:©iStock.com, Md Saiful Islam Khan
Spinal cerebrospinal fluid (CSF) leaks occur when tears develop in the protective membrane surrounding the brain and spinal cord, allowing fluid to escape. These leaks can result in severe headaches and neurological complications. While some patients develop spontaneous spinal CSF leaks without an identifiable connective tissue disorder, they often exhibit subtle or nonspecific signs of underlying tissue abnormalities. Researchers investigated whether these unexplained cases might have a genetic basis.
This hypothesis is supported by observations that spontaneous CSF leaks frequently occur in individuals with genetic connective tissue diseases such as Marfan syndrome and Loeys-Dietz syndrome, which weaken connective tissue and increase susceptibility to tears. Approximately two-thirds of patients with spinal CSF leaks demonstrate features of connective tissue disorders. “Since some patients with unexplained spinal CSF leaks show subtle signs of connective tissue disease despite lacking a formal diagnosis, we sought to identify a genetic cause,” explained Wouter Schievink, a neurosurgeon at Cedars-Sinai Health Sciences University.
Published in The Lancet Neurology, the study utilized whole-exome sequencing to examine 42 individuals with unexplained leaks and over 3,800 controls. The researchers focused on spontaneous spinal CSF leaks associated with connective tissue disorders and searched for rare functional variants in the dura mater—the outermost layer enveloping the brain and spinal cord. They identified 11 genes, with FBN2—which governs tissue development and structural integrity—showing the most frequent variants.
Testing dural fibroblasts and their ability to bind extracellular matrix components revealed impaired adhesion in cells carrying FBN2 variants compared to healthy controls. Using CRISPR-Cas9 gene editing, the team created mouse models with these variants and compared them to established Marfan syndrome models. All mice with Fbn2 variants developed CSF leaks, confirmed by pressure drops during dye infusion tests. “Future therapies could include medications that strengthen connective tissue or modulate biological pathways affected by the FBN2 gene,” Schievink noted.
