What are Prion diseases? Around 1-2 million people worldwide are affected by a group of fatal diseases with no known cure each year. This group of devastating diseases aren't caused by a bacteria, virus, or other pathogen, but by misfolded proteins called prions. When prion proteins misfold, they cause other prions to misfold. This leads to the formation of aggregates that the body can not naturally clear out. These toxic aggregates build up in neurons, eventually causing cell death and fatal neurodegeneration. Without specific therapies and treatments, prion diseases are always fatal. The cause of these diseases are mutations of the PRNP gene. The specific gene and mutation in the PRNP gene determines the specific prion disease.
What is Fatal Familial Insomnia
One kind of Prion disease is Fatal Familial Insomnia (FFI). The mutation associated with FFI is located at codon 178, where aspartic acid is replaced by asparagine(D178N mutation). FFI is one of the most rare and devastating prion diseases, and is characterized by incurable insomnia. The disease follows an autosomal dominant pattern of inheritance, but only around 1 to 2 people out of every 1 million are affected by the disease, meaning around 50 to 70 families worldwide carry the mutation that causes the condition. FFI affects the thalamus of the brain, which is responsible for sleep, regulating body temperature, and other motor functions. FFI shares the same prion based mechanisms as other diseases such as Creutzfeldt-Jakob Disease (CJD). However, FFI is distinguished by its primary impact on sleep and the thalamus, setting it apart from other prion disorders.
Symptoms, Progression, and Diagnosis of FFI
As stated FFI primarily affects the thalamus of the brain, thus most of its symptoms are related to insomnia and autonomic disturbances. These disturbances include an abnormally fast heart rate (tachycardia), excessive sweating (hyperhidrosis), hypertension. Other symptoms include cognitive disturbances like issues with short term memory, endocrine dysfunction, and balance problems. Symptoms of FFI typically begin between 20 and 70 years of age with the average disease onset being 47.5 years. The disease progresses in four stages. The first stage is identified by the onset of worsening insomnia and psychiatric symptoms such as paranoia and panic attacks. After four months, the second stage begins during which the insomnia becomes more severe, and mood disturbances like anxiety and depression worsen. Autonomic dysfunction begins, resulting in symptoms like tachycardia, hyperhidrosis, and hypertension. Stage three is around 3 months long, and by this stage, patients experience severe disruptions to their sleep-wake cycle, often with little to no sleep. In the final stage, the inability to sleep leads to dementia, complete loss of motor functions, and eventually, a coma. Death typically follows due to complications like infections. FFI is incurable and has an average duration of 18 months before death. Diagnosis of FFI can involve polysomnography (sleep tests), electroencephalogram, cerebrospinal fluid analysis, genetic testing, imaging testing (MRI, CT scan, etc), and lab tests like blood cultures, complete blood counts, and liver function tests. Treatment of FFI Current treatments of FFI revolve around managing symptoms and delaying progression. Treatments involve medicines that activate deep sleep (phenothiazines), clonazepam to treat muscle spasms, vitamins, and psychosocial therapy. Current researchers are investigating small molecules and antibodies that can prevent or reverse prion misfolding. These compounds aim to stabilize the normal prion protein (PrPC) and inhibit its conversion to the misfolded prion form (PrPSc). Research in this area includes screening potential drugs and developing compounds that can cross the blood-brain barrier to target the brain, where prion aggregates form. Efforts are also underway to develop treatments that protect neurons from the toxic effects of prion aggregates. This includes researching compounds that enhance cellular repair mechanisms, boost autophagy (the process by which cells clear out damaged proteins), or protect brain cells from oxidative stress.
Conclusion Prion diseases are an incredibly unique and fatal group of diseases that are caused by the aggregation of misfolded proteins. Of the many Prion diseases, FFI is one of the rarest; FFI affects a small number of families globally, but is devastating in its effects. Common symptoms of FFI are insomnia and autonomic disturbances, caused by FFI affecting the thalamus of the brain. Currently, there are no cures for prion diseases, including FFI, and current treatments are only palliative. Future research into potential therapies will be key in preventing the misfolding of prions and neurodegeneration. With a growing understanding of prion biology, there remains the potential for breakthroughs that could one day alter the devastating course of these diseases.
Citations
Karagianni K, Pettas S, Kanata E, Lioulia E, Thune K, Schmitz M, Tsamesidis I, Lymperaki E, Xanthopoulos K, Sklaviadis T, et al. Carnosic Acid and Carnosol Display Antioxidant and Anti-Prion Properties in In Vitro and Cell-Free Models of Prion Diseases. Antioxidants. 2022; 11(4):726. https://doi.org/10.3390/antiox11040726
Cieślik, M., Czapska, A., Wieczorek, M., & Wiśniewska, A. (2021). The role of molecular chaperones in prion diseases. Cell and Tissue Research, 385(2), 321–336. https://doi.org/10.1007/s00441-021-03573-x
Khan, Z., Sankari, A., & Bollu, P. C. (2024). Fatal familial insomnia. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482208/
Chen, C., & Dong, X. P. (2016). Epidemiological characteristics of human prion diseases. Infectious diseases of poverty, 5(1), 47. https://doi.org/10.1186/s40249-016-0143-8
Cleveland Clinic. (2023). Fatal familial insomnia (FFI). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/25001-fatal-familial-insomnia Image: https://www.mcgill.ca/oss/article/health-you-asked/what-are-prions Assessed and Endorsed by the MedReport Medical Review Board
Komentarze