Overview of Fatal Familial Insomnia

Fatal familial insomnia (FFI) is a form of prion disease that is characterised by abnormal protein folding in the brain leading to neurodegeneration (brain cell death).¹ The prion protein that induces this defect, in the case of FFI, results from a genetic mutation in the prion protein (PRNP) gene inherited from generation to generation.² Despite their rarity, prion diseases can be very destructive. 

FFI leads largely to sleep disturbances, ending in complete insomnia, while other defects such as blood pressure, heart rate, sweat release, balance, hormonal and cognitive (mental action) abnormalities. These cognitive defects include inhibition of memory, attention, and balance. Treatment only provides slight symptomatic relief since there is no current cure, therefore supportive care and appropriate management of patients is essential to reduce suffering. On average, death occurs 18 months from the onset of disease, with the average age for the onset of symptoms being 50 years.

As discussed, prion diseases are quite uncommon, particularly those that are inherited, with only hundreds of FFI cases reported historically. Despite this, it appears their occurrence is increasing in some regions of the world such as China.³ Additionally, the duration of disease can vary across global regions from 2 months to 2 years probably due to changes in genetics, while a similar effect is also seen with symptoms. For example, Asian patients are more likely to experience complications with movement and breathing while sleeping, while other ethnicities are more likely to experience excessive sweating and weight loss.

Cognitive decline is an important area of study as it may shine light on potential therapeutic therapies for FFI as well as prion disease in general. As quality of life is severely reduced due to these cognitive complications, it is a necessity that they are understood to alleviate their damage.

Pathophysiology 

During FFI, misfolded proteins resulting from the prion protein deposition lead to the death of cells within the brain called neurons, termed neurodegeneration, as well as scarring of brain tissue known as gliosis.¹ This commonly occurs in the thalamus (close to the center of the brain), which is necessary for receiving input information regarding the external environment, controlling output functions such as movement, and regulating sleep. Neuron cell death is also frequent in the brainstem in most cases of FFI, and it is found at the bottom of the brain.

As a result, neurodegeneration in these areas induces clinical symptoms such as sleep disruption, balance problems, and blood pressure changes. It is evident that most prion damage and neuron degeneration occurs in the thalamus, particularly during the early stages of disease progression, however there also appears to be consistent scarring and inflammation in the the outer layer of the brain called the cortex, although the reason for this pattern of damage is largely unknown.

Stages of FFI and cognitive change

Stage 1:

• Organic sleep disturbances, subacute onset (early stages) of insomnia (delayed sleep onset latency and total sleep time), and reduced quality of sleep. Potential for highly vivid dreams
• Subtle cognitive changes such as paranoia and panic attacks

Stage 2 (approximately 5 months): 

• Progressive insomnia and cognitive problems regarding memory and executive function (eg. attention, multitasking). Disrupted spatial orientation
• Psychiatric symptoms such as hallucinations
• Increased leg movements during sleep states. Sleep apnea (dysregulated breathing) is displayed in 50% of patients

Stage 3 (approximately 3 months): 

• Highly disrupted sleep/wake cycle characterised by total insomnia. leading to severe cognitive impairment during wakefulness e.g. confusion, psychosis. Slow thought processing and a very short attention span
• Complete insomnia can lead to severe autonomic dysfunction such as high blood pressure, increased heart rate, weight loss, and excessive sweating
• Mood changes such as depression and anxiety

Stage 4 (approximately 6 months): 

• Profound cognitive decline and vegetative symptoms with restricted ability to talk or be mobile
• The endpoint of coma is followed by death

Underlying mechanisms of cognitive impairment

Initial neuronal damage appears to begin in the thalamus and brainstem, leading to their dysfunction and manifesting in cognitive defects found in the early stages such as attentive difficulties.¹ Additionally, the thalamus is an essential integrator of hormonal chemicals and other messengers in the brain termed neurotransmitters, which are essential for cognition and mood.⁴ 

Therefore increasing lack of function of the thalamus as FFI develops is likely to explain various symptomatic effects throughout disease progression, such as depression. Cortical damage found during later stages appears to correlate well with an increased decline in thought processing and memory.

Moreover, the thalamus plays an important role in the regulation of sleep, notably through its influence on melatonin which is a key hormone necessary for sleep induction.⁵ Needless to say, cell death within the thalamus would therefore hinder melatonin production and its sleep-inducing effects. The brain stem also plays a role in reducing excitatory activity in the brain and therefore is an additional region that aids sleep, reflecting a further reason for sleep complications in FFI.

Clinical management and Future research

FFI is initially detected through a range of tests, largely targeted at sleep. Polysomnography for example can detect brain activity during sleep to analyse sleep time and transitions between sleep stages.¹ Genetic testing is also utilised due to the hereditary nature of the disease and can detect any variation in the PRNP gene. Once the diagnosis is finalised, treatment may begin for the relief of symptoms. 

Therapeutics are particularly limited, however, they can include gamma-hydroxybutyrate, a naturally occurring neurotransmitter that may help induce sleep. Substances that may worsen insomnia, memory, or other cognitive abilities are advised to be discontinued. In terms of future research, clinical trials are looking at the potential therapeutic effect of antibiotics during specific PRNP mutations to prevent the induction of prion disease by allowing prion proteins to be broken down more effectively.⁶ Further to this, immunotherapies may prove to be of benefit since vaccines could provide an opportunity for antibodies to bind specific targets on misfolded prion proteins to reduce their damaging effects.⁷

Summary

Fatal familial insomnia is a type of prion disease in which a genetic mutation results in increased protein folding in the brain due to the presence of a prion protein. Consequently, the damage is caused and the death of brain cells called neurons occurs in specific brain locations, notably the thalamus in the centre of the brain and the brain stem at the base of the brain.

The thalamus and brain stem are important for a variety of cognitive abilities including memory, attention, and mood, as well as induction and quality of sleep. Gradual degeneration of these brain areas therefore results in progressive sleep disturbances to the point of complete insomnia, along with slow thought processing, depression, anxiety, psychosis, hallucinations, and severe inhibition of memory to name a few cognitive-related symptoms.

Due to the lack of curative treatment, patient management and care is essential. The future, however, shows promise with the use of antibiotics to increase prion protein breakdown, in addition to antibodies with the ability to bind targets of prion proteins and overcome their effect.