Study Identifies Genetic Cause of Some Spinal Fluid Leaks

Researchers at Cedars-Sinai Health Sciences University and Johns Hopkins University have identified genetic mutations that may explain why some people develop a spontaneous cerebrospinal fluid (CSF) leak in the spine. The findings, published in The Lancet Neurology, may lead to earlier diagnosis and more targeted treatments for the painful and often disabling condition.

"Spinal CSF leaks can be incredibly debilitating, and in many cases we haven't understood why they happen," said Wouter Schievink, MD, co-senior author of the study and professor of Neurosurgery at Cedars-Sinai.

The brain and spinal cord are bathed in protective cerebrospinal fluid. A tear or hole in the membrane that surrounds the spinal cord can allow this fluid to leak out, leading to nausea, neck stiffness and severe headaches that worsen when standing. Current treatments for spinal CSF leaks focus on sealing the leak after it occurs. Patients are often treated with epidural blood patches, which can provide temporary relief, or may require specialized surgery to repair the tear when symptoms persist.

Spinal CSF leaks are associated with genetic connective tissue diseases that affect tissues supporting the body's structure, but for many patients without a diagnosis of connective tissue disorder, the cause of the ruptured membrane is unknown.

"Because some patients with unexplained spinal CSF leak show subtle signs of connective tissue disease, even though they do not have a defined diagnosis, we sought to find a genetic cause," Schievink said.

Investigators, including lead author of the study Cassie Parks, MD, PhD, and co-senior author Hal Dietz, MD, analyzed whole-exome sequencing from 42 patients with unexplained spinal CSF leak and compared the results with more than 3,800 individuals without the condition. They tested how the genetic variants they detected behave in human cells and laboratory mice.

The study found that about 1 in 5 patients with this type of spinal CSF leak had changes in the FBN2 gene, and that these changes appeared significantly more often in patients with CSF leak than in those without the condition.

Additional experiments showed that these genetic changes disrupt the way cells attach to the supportive tissue surrounding the spinal cord, potentially weakening this protective layer. In laboratory mice carrying the same mutations, the spinal lining was more prone to tearing and leaking.

Together, these findings suggest that defects in connective tissue caused by FBN2 variants may increase a person's risk of developing spinal cerebrospinal fluid leaks.

"By identifying a genetic contributor, we now have the first understanding of cellular events that may be targetable for prevention or treatment of spontaneous CSF leaks," said Dietz, professor of Genetic Medicine at the Johns Hopkins University School of Medicine.

"Potential future treatments can include medications that strengthen connective tissue or target the biological pathways affected by the FBN2 gene," Schievink added.

Additional authors include Mukti Singh, Elizabeth Wohler, Renan Martin, Silke Peeters, Emily Juzwiak, Xinyi Sun, Bart Loeys, Nara Sobreira and Claire Baldock.

Funding: This work was supported by the Howard Hughes Medical Institute, the Marfan Foundation, the Pease/Scheeler Fund and the Biotechnology and Biological Sciences Research Council.

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