Dr. Susan White and her genetics team treated two triplets from a family who had an undiagnosed neurodegenerative disorder in 2014. After one year of age, the children’s developmental skills declined. They lost visual coordination. Feeding and swallowing food became impossible. The children developed intractable seizures.
Exactly what led to their neurodegeneration was a mystery.
“As you can imagine, that was just a horrendous experience for their family and we suspected a genetic condition because of that pattern of problems occurring in both children,” White, an associate professor at Murdoch Children’s Research Institute (MCRI) and Victorian Clinical Genetics Services (VCGS), said in an interview with Being Patient.
White and her research team launched a study and discovered that a variation in a gene—the NRROS gene—causes the rare childhood-onset neurodegenerative disorder. Their study opens up possibilities of treatments as there’s a window of opportunity to intervene before the children reach the age of one, said White.
The team studied the two triplets and four other children, administering genetic testing of genes that are known to be associated with neurodegenerative diseases. They compared the genetic codes of the affected children with the reference DNA. When that failed to yield any answers, they expanded the search to the rest of the genome.
The scientists found that the children had inherited the defective NRROS genes from both parents. Couples who are both carriers of the mutant gene have a one in four chance of giving birth to an affected child. The mutant gene impaired the signaling pathway of their brains called transforming growth factor beta-1 (TGF- β1) from anchoring in cells’ surfaces.
White hypothesizes that the NRROS mutant causes TGF- β1 to be overly active, leading to an unchecked activation of the microglia and causing inflammation in the brain. TGF- β1 regulates the brain’s microglia, cells that maintain immune responses in the central nervous system. Even though microglia can be a force of good by clearing toxic proteins from the brain and releasing cytokines—molecules that promote inflammation—this inflammatory response is over-activated in other neurodegenerative diseases like Alzheimer’s and traumatic brain injury (TBI).
The study may broaden researchers’ understanding of the link between the activation of the microglia and Alzheimer’s, an area of research that is relatively new and rapidly growing. Researchers found that a receptor in the brain can increase the risk of Alzheimer’s by putting the microglia into a dormant state. Another recent study showed that patients with Alzheimer’s have their first peak in microglial activation before they display other hallmarks of the pathology.
“It’s intriguing to me that there’s some overlap with the pathogenesis of more common neurodegenerative adult diseases like Alzheimer’s in [which] we see that inappropriate activation of the microglia,” White said. “And so maybe, just maybe, there’s something we can learn from this ultra-rare neurodegenerative disorder which can help us better understand the devastating disease that is Alzheimer’s.”
What’s certain is that children who are suffering from the rare neurodegenerative disorder can finally receive a diagnosis. The study provides an answer for doctors, the children and their loved ones, an answer that has eluded them until now.