Introduction

Fatal familial insomnia (FFI) is a rare genetic condition caused by a mutation in the prion-related protein gene (PRNP). It causes a progressive decline in the ability to sleep, as well as physical and mental health deterioration.¹

FFI follows an autosomal dominant pattern of inheritance. Autosomal refers to the location of the PRNP gene on a non-sex chromosome. It is dominant because only one copy of the gene is required for the expression of the disorder.

Typically the disease presents in adults, but it has been observed in a wide range of ages. FFI has poor outcomes, with a lack of sleep ultimately leading to death in affected individuals. 

FFI is distinguished from sporadic fatal insomnia, although it shares some similarities in its presentation.

This article will explore the features of FFI as well as how it manifests clinically. Identifying the disease early can help optimise management of the condition. 

What causes FFI?

Genetic mutation

Proteins are molecules in our body that help us to function normally. They take on very specific shapes in order to perform this function.

Misfolded proteins are usually unable to carry out their designated roles. A prion is a misfolded protein that can induce otherwise healthy proteins to become the wrong shape, resulting in a variety of negative effects. 

The PRNP gene is central to the onset of FFI and encodes a major prion protein (PrP).² It is involved in several biological processes, like making new nerve cells and nerve signalling.

Mutated PRNP makes a prion (PrPˢᶜ) that induces the formation of new prions from adjacent proteins. These deposits accumulate in the brain, causing damage and thus disrupting its normal activity.³

Impact on the thalamus

Our sleep-wake cycle is controlled by a region in the midbrain called the thalamus.⁴ In FFI, there is notable degeneration of the thalamus, which results in sleep disturbances. 

The loss of nerve cells in the thalamus, and other areas of the brain where prions have accumulated, leads to the onset of other clinical features noted in FFI.¹

The cerebellar and cerebral cortex may also be involved.⁵ Coordination of movement is controlled by the cerebellar cortex, while the cerebral cortex governs memory and learning.

When these regions of the brain become damaged, it can lead to the behavioural changes demonstrated in those affected by FFI. 

Clinical stages

Four clinical stages of FFI have been outlined, based on the severity of the condition.⁶

Stage 1: Progressive insomnia

The first stage of FFI is the onset of insomnia. Psychiatric symptoms may also occur, such as:

• Panic attacks, especially at night
• Phobia (irrational fear)
• Paranoia (irrational anxiety, which may include delusional thoughts and feelings)
• Vivid dreams
• Hallucinations

Stage one lasts approximately 3-6 months. 

Stage 2: Aggravated insomnia and autonomic dysfunction

The second stage of FFI is characterised by an intractable insomnia, as well as the activation of the autonomic system. This governs involuntary bodily functions, such as pupil dilation, muscle contraction and sweating.

• Agrypnia excitata, describing overactivity, activation of involuntary bodily functions and persistent insomnia⁷
• Hyperhidrosis (excessive sweating)
• Tachycardia (an abnormally fast heartbeat)
• Hypertension (high blood pressure)
• Fluctuations in body temperature including hyperthermia (increased temperature) 
• Changes to breathing
• Hormone dysregulation
• Mood changes
• Changes in gait or difficulty moving
• Lack of appetite, resulting in weight loss

This stage can last from 5-9 months.

Stage 3: Cognitive and motor dysfunction

Stage three denotes the onset of cognitive decline, leading to memory loss and confusion. Symptoms include:

• Ataxia: disorders that affect coordination, balance and speech. Writing, vision and swallowing may also be impaired
• Muscle twitching and other motor disturbances
• Anxiety 
• Depression

The duration of this stage is approximately 3 months. At this point, sleep becomes severely disrupted for individuals affected by FFI. 

Stage 4: Advanced dementia and coma

The final stage of FFI involves severe cognitive impairments, and dementia:

• Dementia, or profound confusion
• Trouble speaking
• Unresponsiveness
• Coma

Stage four results in a coma that, within 12-18 months of symptom onset, progresses to death. This stage can last up to six months in total.⁸

Common symptoms across stages

Symptoms can overlap at multiple stages and affect a wide variety of body systems. 

Sleep disturbances

• Persistent insomnia
• Interrupted sleep
• Absence of slow-wave and REM sleep on polysomnography

Autonomic nervous system dysfunction

• Excessive sweating
• Rapid heartbeat
• High blood pressure
• Elevated body temperature

Neuropsychiatric symptoms

• Anxiety
• Panic attacks
• Hallucinations
• Progressive memory loss
• Confusion
• Disorientation
• Depression
• Mood swings

Motor symptoms

• Loss of coordination
• Muscle jerking
• Speaking difficulties

Diagnosis of FFI

A diagnosis of FFI may be suggested using a variety of tests including genetic analysis, polysomnography (PSG), electroencephalogram (EEG), brain magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission tomography (SPECT) scans, biochemical cerebrospinal fluid (CSF) analysis, and autopsy.⁹

Many researchers have attempted to create diagnostic criteria that feature clusters of symptoms, with a higher score indicating a greater risk of FFI. 

Genetic testing

Genetic testing may be offered when there is suspicion of FFI, or as a confirmatory tool for diagnosis. The PRNP gene is analysed after taking a DNA sample from the blood of a suspected individual.

If a PRNP mutation is found, other relatives may be advised to undergo genetic testing as the mutation can be inherited. On the other hand, if the individual is found to have no mutation then it is unnecessary for other family members to take part. 

Information on family history can aid diagnosis, so investigating the potential disease history of other relatives is beneficial.¹⁰

Polysomnography

Polysomnography is a technique used to study sleep, measuring electrical activity in the brain, eyes and muscles – as well as breathing patterns.¹¹ This has been a useful diagnostic tool in other disorders, producing a physiological blueprint of what happens during sleep.

For the diagnosis of FFI, the following features may be demonstrated on a polysomnogram:¹²

• Reduced sleep time, or sleep fragmentation
• Abnormal short non-rapid eye movement (REM) cycling
• REM sleep loss

Brain imaging

Neuroimaging is a powerful way to visualise abnormalities and to map areas of disease in the brain. Thalamic degeneration is the hallmark of FFI which can be shown as an abnormal signal on MRI scans. PET scans may show reduced metabolic activity in the region of the thalamus.

Clinical assessment

A specialised doctor will comprehensively evaluate the symptoms and progression of the disease against set criteria, which have evolved over the years. Clinical evaluation will include examination of the nerves and assessment of cognitive status in patients.

Management and prognosis

As FFI has no cure, as yet, current treatments focus on improving quality of life for individuals with the condition. Increasing comfort for the patient is the primary goal and involves a multidisciplinary approach including neurologists, psychiatrists and palliative care specialists.

Symptom management

Medications can be prescribed to alleviate certain symptoms. Sleep aids like melatonin can be used to combat insomnia, for example, and anxiolytics can be prescribed to reduce anxiety.

Supportive care can ease symptoms of autonomic dysfunction and this can be improved with nutritional support. A case study suggested that diet, vitamin supplements, exercise and light therapy together may have helped in prolonging the lifespan of a patient with FFI.¹³ 

Prognosis

Unfortunately, the disease progresses rapidly, with an average survival time of 12-18 months from the onset of symptoms. With no cure, the accumulation of sleep disturbances on the mental and physical wellbeing of patients results in a coma and, ultimately, death. 

Summary

Fatal familial insomnia is a devastating prion disorder with poor outcomes. Disease progression occurs in four stages, with the symptoms of each having significant overlap.

The genetic basis of FFI leads to a myriad of clinical features that occur as a result of thalamic degeneration, and damage to other areas of the brain.

Recognising the symptoms early can aid in getting an affected individual the care they need. Diagnosis and timely management can improve the lifespan of a patient with FFI.

More research is needed on this rare disease to provide better ways to support patients and families affected by FFI. For further enquiries and information, the Creutzfeld-Jakob disease foundation is an organisation that specialises in helping those with prion-related disorders.