By Ava Williams
Leaf peeping, costumes, and a whole grocery aisle of pumpkin spice flavored goods mark the beginning of the Halloween season. But, if you look deeper into the night’s shadows, you’ll notice creatures lurking in the dark trying to keep you up at night. Thankfully, home provides a haven, where you can lock the door, forget the day's worries, and fade off to sleep. Now imagine the creature creeping in the night not only had the power to invade your home but was strong enough to permanently steal your sleep. This is precisely the bone chilling reality of Fatal Familial Insomnia (FFI).
FFI is a genetic neurodegenerative disease that is transmitted through family members in an autosomal dominant pattern of inheritance. Simply put, this means that a parent with the mutated gene has a 50% chance of passing on the disease to their child. While there are lots of functioning parts to the human body, proteins can be thought of as the building blocks of all life. Enzymes, hormones, antibodies, pH, healing properties, and energy are all possible because of properly folded and functioning proteins. That being said, you can imagine the devastating effects misfolded proteins would have on the body. In FFI, there is a mutation in the DNA where the prion protein PrP is synthesized. This mutated PrP protein leads to prominent cell death in the brain and accumulation of PrPSc, a toxic misfolded protein.
While the disease is extremely rare, those that are diagnosed with FFI experience a slew of symptoms that follow distinct stages. First, the affected individual experiences insomnia, categorized by increased anxiety and panic attacks. This then progresses to hallucinations and a worsening of anxious behaviors. Next, rapid weight loss, accompanied by a complete loss of the ability to sleep occurs. Finally, dementia kicks in. As though the progression of the disease isn’t startling enough, there is no cure. Once symptoms are present, death within 2 years is the most reported prognosis. Given the inevitable fate of those with FFI, research leans more toward understanding hallmark signs that can then be used as a biomarker to track disease progression.
In this experiment researchers sought to determine whether the presence of PrPSc was associated with FFI by using two different assaying methods, an analysis that allows for the presence and amount of a substance to be quantified. Assays measuring the toxic PrPSc protein were completed for urine, blood, and cerebrospinal fluid (CSF) samples. For the first time, prion protein concentrations were also measured in samples taken from the olfactory mucosa (OM), the tissue that lines the nasal cavity. Together, the two assay methods were used in analysis of 2 patients with FFI, 16 patients suffering from other neurodegenerative disorders, and 10 healthy controls.
The assays successfully documented the presence of PrPSc in urine, CSF, blood, and OM of patients with FFI. PrPSc was not detected in patients impacted by other neurodegenerative disorders. The aggregation of PrPSc in OM samples is thought to be a result of prions migrating from the central nervous system into the olfactory system. This pattern of prion distribution is similar to what happens in patients with Creutzfeldt-Jakob disease, another rapid-onset invariably fatal neurodegenerative disease. The nasal cavity, which is constantly exposed to stress, could promote PrPc, a normal protein, to take on less stable conformations, leading to the formation and aggregation of PrPSc.
While the data may seem small in its relevance, this new knowledge about PrPSc present in OM samples of FFI patients can be implemented as a quantifiable biomarker used to monitor disease progression. There is currently a well-studied Italian family with FFI who are now on a preventive clinical trial using doxycycline. This new knowledge of where exactly the misfolded prion protein aggregates in patients with FFI can be used to monitor if the clinical trial drug has any impact on toxic PrP replication. As the specifics of this elusive disease are uncovered, perhaps there will come a day when the fatal familial curse is broken and affected families can finally rest easy knowing that they are safe from the sleep-stealing monster that resides in the shadows.
Redaelli, V., Bistaffa, E., Zanusso, G. et al. Detection of prion seeding activity in the olfactory mucosa of patients with Fatal Familial Insomnia. Sci Rep 7, 46269 (2017). https://doi.org/10.1038/srep46269
U.S. Department of Health and Human Services. (n.d.). Fatal familial insomnia. Genetic and Rare Diseases Information Center. Retrieved November 3, 2021, from https://rarediseases.info.nih.gov/diseases/6429/fatal-familial-insomnia#:~:text=The%20first%20symptoms%20of%20FFI,and%20trouble%20controlling%20body%20temperature.