Fatal Familial Insomnia

Fatal familial insomnia (FFI) is a rare genetic neurodegenerative disorder that is typically caused by a mutation in the prion protein (PRNP) gene thereby affecting the central nervous system. FFI was first described in 1765 and it is estimated that FFI affects 1 to 2 out of every 1 million individuals. Hallmark features of FFI include motor, cognitive, and endocrine abnormalities. As the disease progresses, individuals experience severe and progressive insomnia that does not respond to treatment, resulting in neuropsychiatric symptoms and ultimately, death. 

FFI is typically caused by a mutation in the prion protein (PRNP) gene inherited in an autosomal dominant fashion, meaning only one copy of the mutated gene is required to cause the disease. The disease-causing mutation involves a substitution of one amino acid, aspartic acid, to an incorrect one, asparagine. The PRNP gene controls the production of the human prion protein, therefore mutations in the PRNP gene, as seen in FFI, lead to the production of misfolded prion proteins. These abnormally shaped prion proteins are toxic to the body and accumulate within certain regions of the brain. FFI primarily affects the thalamus, a part of the brain responsible for relaying motor and sensory signals to the cerebral cortex, regulating body temperature and the sleep-wake cycle. Other affected regions such as the parietal, temporal, and frontal lobes have also been reported. The onset of disease depends on the extent of accumulated prion proteins in the brain. FFI most commonly presents between the ages of 20 to 60 years and it affects all sexes equally. On the other hand, sporadic fatal insomnia (SFI) is the acquired form of FFI, meaning that it occurs spontaneously in individuals without any known family history.

Signs and symptoms of fatal familial insomnia and sporadic fatal insomnia progress rapidly over several months to years, and consist of a combination of motor, cognitive, and neuropsychiatric abnormalities. Early symptoms include sleep problems like difficulty falling asleep or disrupted sleep; heightened anxiety; agitation; and minor cognitive problems such as mild memory impairment and changes in mood and behavior. Late symptoms include insomnia that leads to a complete inability to fall asleep, resulting in a severely sleep-deprived state. Sleep deprivation leads to weight loss; neuropsychiatric symptoms such as visual and auditory hallucinations; progressive cognitive decline such as memory loss; and loss of critical thinking and reasoning abilities. Since FFI affects the thalamus, individuals may develop autonomic dysfunction, resulting in tachycardia, extremely low or high blood pressure, and difficulties regulating body temperature. Late motor symptoms include ataxia (i.e., difficulty coordinating movement and balance), myoclonus (i.e., brief muscle twitching), dysarthria (i.e., impaired control over muscles used for speech), and dystonia (i.e., abnormal muscle tone such as sustained muscle contractions). Individuals eventually experience difficulties moving or speaking voluntarily and will likely succumb to coma or death.

Diagnosis of FFI is mainly clinical and begins with a thorough review of symptoms and medical history. Measurement of vital signs may be suggestive of autonomic dysfunction, especially if high blood pressure, tachypnea, and variations in body temperature are present. A neurologic and musculoskeletal exam which assesses the cranial nerves, gait, and muscle tone may reveal neuromuscular involvement. Reversible causes of cognitive decline can be investigated through laboratory testing (e.g., thyroid function tests, vitamin B12 and folate levels, and syphilis testing). A sleep study using polysomnography can help confirm a reduction in total sleep duration and abnormalities in the transition between sleep stages. While an electroencephalogram (EEG) is not necessary for diagnosis, it may reveal generalized slowing with or without periodic sharp-wave complexes that suggest prion disease. Finally, individuals with high suspicion of FFI may undergo genetic testing to identify the pathogenic PRNP gene variant through DNA testing or sequencing.

There is currently no cure for FFI, therefore, treatment consists of supportive and palliative care measures to improve the individual’s quality of life. Individuals with FFI generally do not respond to sedatives (e.g., barbiturates, benzodiazepines) but one report demonstrated the effectiveness of gamma-hydroxybutyrate, a benzodiazepine, in inducing slow-wave sleep. Additionally, medications that worsen memory and exacerbate confusion (e.g., anticholinergics and benzodiazepines) should be avoided. Supportive care measures include nutritional support, adequate hydration with fluids, and pain management. Physical and occupational therapy may be helpful to maintain or prolong functional status and to manage motor symptoms. 

Since FFI is fatal, a palliative care discussion should be integrated at the time of diagnosis. Ongoing goals of care discussions can be beneficial in optimizing symptomatic relief and ensuring comfort care measures. The disease course of FFI has been reported to last anywhere from as short as 7 months to up to 3 years. The average life expectancy is 18 months after diagnosis.

Fatal familial insomnia (FFI) is a rare autosomal dominant neurodegenerative disorder caused by a mutation in the prion protein (PRNP) gene. The resulting genetic mutation leads to the production of misfolded prion proteins that are toxic to the body and eventually accumulate in the thalamus, a part of the brain that is responsible for relaying motor and sensory signals to the cerebral cortex, regulating body temperature, and the sleep-wake cycle. Early symptoms include sleep problems like difficulty falling asleep or disrupted sleep, heightened anxiety, and minor cognitive problems. Late symptoms include insomnia that leads to a complete inability to fall asleep, resulting in a severely sleep-deprived state. FFI is a clinical diagnosis and a sleep study can help confirm abnormalities in sleep architecture. There is currently no cure for FFI, therefore, treatment consists of supportive and palliative care measures including nutritional support, hydration, and pain management. The life expectancy of individuals with FFI is 18 months following a diagnosis, although there are reports of individuals living up to 3 years.