Fatal familial insomnia (FFI) is a very rare inherited neurodegenerative prion disease. A mutation in the prion protein gene (PRNP) can lead to the atrophy (decrease in size) of the thalamic nuclei (specialised areas in the thalamus of your brain), causing FFI.

With the thalamus having a central role in sleep-wake cycles and autonomic control, this irreversible degeneration (thalamic nuclei atrophy) has very serious downstream effects, including progressive insomnia, tachycardia (abnormal heart rhythm), hypertension, motor impairment (ability to move is affected), or endocrine dysfunction, among others.¹

Individuals with inherited PRNP mutation may become symptomatic between the ages of 20 and 60, with the mean age of onset being 50 years.¹

While the extent and appearance of specific symptoms and the progression of the condition may manifest differently from individual to individual, FFI is ultimately an incurable disease, with the mean expected survival time being around 18 months. Therefore, treatments for the disease are focused on palliative care (improving the quality of life) by making sure the individuals with FFI are as comfortable and pain-free as possible.¹

Understanding prion proteins

Prion proteins are cellular proteins most commonly found in the outer membrane of neurons (cells in your nerves). Due to their specific structure, prion proteins can interact with a wide range of targets.  These proteins play a role in maintaining and protecting your peripheral nerves (nerves branching out from the brain and spinal cord).

A genetic mutation (as in FFI), or other means cause misfolding of prion proteins. Misfolded prion proteins can give rise to prion diseases and have been shown to be involved in mediating neurotoxicity in Alzheimer’s and Parkinson’s disease.² 

Pathogenesis of fatal familial insomnia

Fatal familial insomnia is caused by a specific mutation (change) in the PRNP gene, located on chromosome 20 (of the 46 chromosomes) at position p13 (20p13). The mutation results in substituting specific amino acids, thereby altering the prion protein structure and function: aspartic acid (amino acid) is substituted for asparagine (amino acid) at codon 178 (D178N), accompanied by the abnormal presence of methionine at codon 129 (M129).¹

This alteration to the prion protein leads to a misfolding, which results in the accumulation of the mutant protein in specific areas of the brain, with the thalamus being the most affected. The accumulated mutant proteins can cause neuronal loss and gliosis, when the brain produces a larger number or larger-than-normal glial cells, leading to brain scarring and a reduction in brain function.¹

With the thalamus being so central to controlling the sleep-wake cycle and autonomic control, mutated prion protein-driven degeneration causes a wide array of symptoms, such as memory loss, balance difficulties, speech problems, and progressive insomnia. Other areas of the brain, such as the brainstem, are also affected by this degeneration, which can cause vision problems or hallucinations in the last stages of the disease.¹

Clinical manifestations 

Fatal familial insomnia has been described as having four stages, each with specific symptoms that progressively worsen, leading to the eventual death of the patient.

Stage 1

The first stage of the disease is characterised by the onset of insomnia, with the individual having difficulty falling asleep and maintaining a sleep state for long.¹ Vivid dreaming is common, and sleep apnoea has been detected in 40-60% of individuals at this stage. This lack of sleep can lead to psychiatric symptoms such as panic attacks or paranoia (fear or suspicion).³

Stage 2

In the next five-month period, insomnia symptoms worsen, and the individual often experiences hallucinations. This stage also involves the onset of autonomic dysfunction, such as hypertension and sudden changes in body temperature.¹

Stage 3

The third stage usually lasts around three months and is characterised by total insomnia and disruption of the circadian rhythms, worsening all aforementioned symptoms, such as paranoia, hallucinations, and hypertension, and the individual’s quality of life plummets.¹ 

Stage 4

The fourth stage of FFI usually lasts around six months, during which cognitive degeneration and dementia set in. Individuals with FFI experience ataxia (loss of muscle coordination) and walking difficulties, worsening their ability to perform everyday tasks.

Difficulties swallowing and speech impediments are also common, worsening during the six months to a stage where the patient is no longer able to speak. Short-term memory loss and delirium are commonly seen. Eventually, individuals with FFI lose their ability to move independently, which is quickly followed by coma and death.¹

Diagnostic approaches

Fatal Familial Insomnia is usually diagnosed clinically, with key symptoms being detected through a thorough evaluation by a medical professional. As the condition is inherited, medical professionals thoroughly examine the family history, as sleep-related issues and complications in family members could help diagnose FFI in an individual.

Researchers may also perform sleep studies like:¹

• Sleep latency, or the time taken to fall asleep
• Total sleep time
• Time spent in each phase of sleep, such as rapid eye movement (REM) and non-REM or deep sleep

The observed relationship between these factors may show a sleep disturbance pattern characteristic of FFI.

Clinical diagnoses and sleep studies are the most commonly used diagnostic approaches for FFI, as they are the easiest and most readily available methods that do not require any specialised facilities or equipment. However, there are other specialised tests that can be helpful in confirming an FFI diagnosis, but they often do require more advanced and niche testing equipment, making them more expensive and less available to the general public.

Molecular genetic testing is an option to detect the mutant variant of the PRNP gene, which is mutated in FFI and produces a misfolded prion protein that is prone to accumulate and cause damage.⁴

Positron emission tomography, or a PET scan, can be used to create three-dimensional images of the brain and analyse the levels of metabolic activity in specific areas. A positive clinical evaluation paired with a low metabolic rate in the thalamus in a PET scan may be suggestive of FFI, as the thalamus is selectively degenerated in the course of the disease.¹

Other imaging techniques, such as CT scans or MRI, are not useful in the diagnosis of FFI but are sometimes used in order to rule out other similar conditions, such as other prion diseases or forms of dementia.

Finally, the 14-3-3 protein is a marker of neuronal damage, and its presence in the cerebrospinal fluid (CSF) of the individual could be indicative of a prion disease such as FFI.⁵ However, this is also a method for diagnosing other prion diseases, such as Creutzfeldt-Jakob disease or other dementias, and a positive 14-3-3 CSF test would not be enough to diagnose FFI.

Treatment options and future directions

Currently, FFI does not have a cure, and any treatment options focus on managing the symptoms and palliative care. As the appearing symptoms may differ in each patient, an individual approach to treatment may be necessary in each case.

An important general rule is the discontinuation of any medications (e.g., antihistamines or antidepressants) that could exacerbate symptoms such as memory loss or insomnia.¹ Doing so could help lessen their symptoms or improve their quality of life.⁶

Movement aids may become necessary as the disease progresses. When swallowing problems arise, the individual with FFI may require feeding tubes to ensure appropriate feeding.

Psychosocial aids are also very common for individuals with FFI and their families, as FFI can be a very traumatic and difficult condition for all of them. Salvaging their mental health and well-being is important.¹

While current treatments focus on the management of symptoms and their consequences, active research is being done on modes of treatment, like immunotherapy, to selectively target misfolded prion proteins, which could address the cause of the disease and possibly alter its course and progression.¹

Summary

Fatal familial insomnia is a degenerative prion disease resulting from a genetic mutation that causes the production and aggregation of misfolded prion proteins in certain areas of the brain. The thalamus is heavily affected, as well as other areas like the brainstem. Individuals with the inherited genetic mutation could be affected by progressive insomnia, causing memory loss, hallucinations, and hypertension. Voluntary movement and speech will be progressively lost, often leading to coma and death. Average survival time in FFI patients is around 18 months, and there is currently no cure. While the treatments focus mostly on managing symptoms and palliative care, research is underway to discover ways to halt the progression of the disease and hopefully improve what is currently a very dire diagnosis.