Fatal Familial Insomnia: Unravelling the Mystery of a Rare and Devastating Disease

Fatal familial insomnia (FFI) is a rare condition that affects the central nervous system and brain. It is believed to affect between 1 and 2 people out of 1 million and is genetic, affecting between 50 and 70 families globally.

As neurological disorders go, few conditions evoke such fascination as this. First identified in the late 20th century, FFI belongs to a category of diseases known as prion diseases. These are characterised by the misfolding of proteins within the brain. What sets FFI apart from other conditions is its progression towards an inevitable end: total sleep deprivation followed by death. This can happen within months or years of symptom onset. This condition not only robs its victims of the ability to sleep but it also triggers a range of neurological symptoms that end up in a complete breakdown of mental and physical functions.

Understanding FFI

Understanding fatal familial insomnia (FFI) requires gaining an understanding of prion diseases—a group of rare, neurodegenerative disorders caused by the misfolding of prion proteins in the brain. Unlike many genetic diseases, FFI is inherited in an autosomal dominant pattern, which means you only need to inherit one mutated copy of the gene from either parent to develop the disease.

With FFI there is a specific gene mutation in the PRNP gene. This encodes the prion protein or PrP. The mutation is often denoted as D178N and leads to the production of an abnormal form of the protein. This then accumulates in the brain and disrupts normal neural function. Eventually, it causes the catastrophic symptoms of FFI.

The Genetic Link

Fatal familial insomnia (FFI) is genetic, specifically in a mutation within the PRNP gene located on chromosome 20. This gene plays a crucial role in various physiological functions, including neuronal protection and regulation of sleep. However, when the PRNP gene undergoes the D178N mutation, it results in the production of an abnormal prion protein.

As mentioned, the inheritance pattern of FFI is autosomal dominant, which means that a person who inherits even one copy of the mutated gene from either parent is at risk of developing the disease. Each child of an affected individual has a 50% chance of inheriting the mutated gene and consequently developing FFI later in life.

Symptoms of FFI typically manifest in mid-adulthood, although the age of onset can vary. The progression of the disease is rapid and relentless. Affected individuals experience severe insomnia that becomes progressively worse over months to years. Other neurological symptoms, such as hallucinations, delirium and involuntary movements, often accompany the sleep disturbances.

The discovery of the mutation has enabled genetic testing and counselling for individuals with a family history of FFI. It provides people with the opportunity to assess their risk of developing the disease and make informed decisions about family planning.

Symptoms and Disease Progression

Fatal familial insomnia (FFI) causes a range of symptoms besides sleeplessness. Initially, FFI symptoms are subtle. They often begin with mild insomnia that gradually escalates into a complete inability to sleep at all. This is the hallmark symptom that distinguishes it from other sleep disorders. It is the fact that affected individuals progressively lose the capacity for restorative sleep despite exhaustion, something absent in other sleep disorders.

As the disease progresses, typically over months to a few years, additional neurological symptoms emerge. This includes hallucinations becoming increasingly common. Individuals experience vivid and often disturbing sensory perceptions and it’s not clear what is real and what isn’t. Delirium also sets in. This becomes present as confusion, disorientation and impaired cognition and further erodes the affected person’s grasp on reality.

Another symptom is motor disturbances. This can range from involuntary movements like myoclonus (sudden, brief muscle jerks) to ataxia (loss of coordination). 

When FFI reaches its terminal stages, the progression of symptoms culminates in a complete breakdown of neurological function. Speech becomes unintelligible, swallowing becomes difficult and muscle control deteriorates to the point of immobility. The mind is ravaged by the absence of sleep and the accumulation of abnormal prion proteins and succumbs to a state of profound dementia. Ultimately, the brain ceases to function altogether.

Throughout the disease progression, those with FFI experience a decline in quality of life and end up requiring round-the-clock care. The course of the disease is tragic and predictable. Death typically occurs within 7 to 36 months after the first symptoms emerge.

Diagnosis and Differential Diagnosis

Diagnosing fatal familial insomnia (FFI) requires a combination of clinical evaluation, genetic testing and the exclusion of other potential causes of the symptoms. Given FFI’s rarity, an accurate diagnosis is essential to ensure appropriate management and support for affected individuals and their families.

The Diagnostic Process

• Clinical Evaluation: Typically, the path to diagnosis will begin with a thorough clinical assessment. Clinicians will take a detailed medical history and will focus on the onset and progression of symptoms present. They will ask about sleep patterns, cognitive changes and motor disturbances. They’ll also ask about whether there is any family history of similar symptoms. A neurological examination will help to identify abnormalities that are consistent with FFI.
• Genetic Testing: Since FFI is caused by a specific mutation in the PRNP gene, genetic testing is paramount for diagnosis. A blood sample is taken to analyse the PRNP gene for the presence of the D178N mutation. A positive test will confirm the diagnosis of FFI, especially in the context of compatible clinical symptoms and a family history of the disease.
• Polysomnography (Sleep Study): Polysomnography—in other words, a sleep study—may be conducted to document sleep patterns and disturbances. This comprehensive overnight test monitors brain activity, eye movements, heart rate, breathing and muscle activity during sleep. For individuals with FFI, polysomnography will typically reveal a severe reduction or complete absence of slow-wave and REM sleep.
• Neuroimaging: Advanced neuroimaging techniques like MRI and PET scans, can help visualise brain structure and function. Although these imaging studies may show atrophy or hypometabolism in certain areas of the brain, in FFI they are primarily used to rule out other neurological conditions.

Differential Diagnosis

The symptoms of FFI can mimic those of other sleep disorders and neurodegenerative diseases. This makes differential diagnosis essential to rule out alternative explanations. Conditions that need to be considered include:

• Insomnia Disorders: Common insomnia or other primary sleep disorders (e.g., sleep apnoea, restless legs syndrome) should be ruled out through sleep studies and clinical assessment.
• Prion Diseases: Other prion diseases, such as Creutzfeldt-Jakob disease (CJD) or Gerstmann-Sträussler-Scheinker syndrome (GSS), share overlapping features with FFI. Genetic testing and distinct clinical profiles help differentiate these conditions.
• Neurodegenerative Disorders: Diseases like Alzheimer’s, Lewy body dementia and frontotemporal dementia may present with cognitive and motor symptoms similar to FFI. Neuroimaging, genetic testing and clinical history are crucial for differentiation.
• Psychiatric Conditions: Severe psychiatric disorders, including psychosis, severe depression and certain anxiety disorders, can present with hallucinations, delirium and insomnia. Psychiatric evaluation helps exclude these diagnoses.
• Other Neurological Disorders: Conditions such as multiple system atrophy, progressive supranuclear palsy or Huntington’s disease may exhibit symptoms that overlap with FFI. Comprehensive neurological examinations and appropriate testing are necessary to distinguish these disorders.

Coping with FFI

There’s no doubt that FFI comes with huge challenges—both physical and emotional. It’s distressing and difficult for those diagnosed but their families are also affected. The progression of the disease is relentless and there’s an inevitable decline in quality of life. This requires comprehensive support and care to alleviate suffering and provide comfort.

Physical Challenges

FFI comes with physical challenges. These include:

• Progressive Insomnia: The hallmark of FFI is the inability to achieve restorative sleep. This leads to extreme fatigue and a range of cognitive impairments. As the condition progresses, patients may experience complete sleep deprivation. Sleep deprivation is known to cause a range of physical symptoms like headaches and hand tremors as well as other symptoms like nystagmus (uncontrollable eye movements), impaired judgement, impulsive behaviour, irritability, poor concentration and slowed reaction times.
• Neurological Decline: There is also a series of debilitating neurological symptoms, including hallucinations, delirium and motor disturbances such as involuntary movements and loss of coordination. These symptoms progressively worsen, contributing to a severe decline in physical function.
• Autonomic Dysfunction: FFI can affect the autonomic nervous system (ANS). This is part of the nervous system that controls and regulates internal organs. Autonomic dysfunction leads to problems such as high blood pressure, sweating and issues with body temperature regulation. These symptoms can complicate care and increase discomfort.

Emotional Challenges

Besides the physical symptoms, there are obvious emotional challenges too:

• Psychological Distress: The awareness of having a terminal, untreatable disease can cause significant psychological distress. Patients often experience anxiety, depression and fear as they confront the progressive loss of cognitive and physical abilities.
• Family Impact: The hereditary nature of FFI means that family members may also face the fear of developing the disease themselves. This can lead to heightened anxiety, stress and emotional turmoil.
• Caregiver Strain: Caring for a loved one with FFI is demanding and emotionally taxing. Caregivers must cope with the progressive deterioration of the patient, managing complex symptoms while dealing with their own emotional grief and exhaustion.

The Role of Palliative Care and Support

Given the severity and progressive nature of FFI, palliative care is used to manage symptoms and provide comfort. Palliative care focuses on improving the quality of life, alleviating suffering and supporting patients’ emotional, social and spiritual needs.

For symptom management, palliative care teams work to manage the varied symptoms of FFI, including sleep disturbances, pain and neurological symptoms. Medications and non-pharmacological interventions are used to enhance comfort and reduce distress.

Counselling and psychological support are essential for both patients and their families. Mental health professionals can help address anxiety, depression and other emotional challenges and provide strategies to cope with the psychological impact of FFI.

Palliative care also includes support for family members to help them navigate the complexities of caregiving and the emotional burden of watching a loved one deteriorate. Support groups and counselling can offer a sense of community and shared experience.

In terms of advance care planning, palliative care teams can ensure that the patient’s wishes regarding end-of-life care are documented and respected. This planning can provide clarity and comfort to families during difficult times.

Research and Treatment

Due to how rare the disease is, research has been limited. While there is currently no cure for FFI, research aims to uncover the underlying mechanisms of the disease and explore potential treatment options that could alleviate symptoms and improve the quality of life for those affected.

The Institute of Prion Diseases and Research

The Faculty of Brain Sciences at University College London created the Institute of Prion Diseases back in 2017. Research has been ongoing. Central to FFI is the misfolding of the prion protein (PrP). Research into the structural and functional aspects of PrP can help with the understanding of how mutations in the PRNP gene lead to abnormal folding and accumulation in the brain. 

Genetic research is critical for identifying and understanding the specific mutations associated with FFI. Advances in genetic sequencing technologies have enabled more detailed analysis of the PRNP gene, facilitating earlier and more accurate diagnosis. 

Advances in neuroimaging techniques, such as MRI and PET scans, are enhancing our understanding of the structural and functional changes in the brains of FFI patients. Research to identify biomarkers—biological indicators that can be measured to diagnose or monitor disease progression—could improve early detection and intervention strategies. Currently, there are no specific biomarkers for prion disease.

Treatment for FFI

There is no cure for FFI and treatment focuses on managing symptoms and improving the quality of life for patients. This includes the use of medications to manage sleep disturbances, anxiety, depression and other neurological symptoms. Benzodiazepines and other sleep aids may provide temporary relief from insomnia, although their effectiveness is limited as the disease progresses.

• Gene Therapy Potential: Gene therapy is a burgeoning field with the potential to correct the underlying genetic mutation causing FFI. Techniques such as CRISPR-Cas9—a technique used to edit the DNA—could, in theory, be used to edit the PRNP gene and prevent the production of abnormal prion proteins. However, this approach is still in its infancy and faces significant technical and ethical challenges.
• Neuroprotective Agents: Drugs that protect neurons from damage and support brain health are also being explored. Neuroprotective agents could help slow the progression of neurological symptoms and maintain cognitive and motor function for a longer period. Research in this area includes the investigation of antioxidants, anti-inflammatory drugs and compounds that promote neural repair.
• Supportive Therapies: In addition to medical treatments, lifestyle modifications and supportive therapies have a role to play in managing FFI. This includes maintaining a structured daily routine, engaging in cognitive and physical activities and therapies such as occupational therapy, physiotherapy and counselling to support overall well-being.

Raising Awareness

There is little awareness surrounding fatal familial insomnia. This rarity often means that the disorder is not widely known, even within the medical community. Increased awareness can lead to better understanding and earlier diagnosis. It also helps support those dealing with the disease. With more awareness, there are more opportunities to fund and advance research in this area too so that effective treatments and perhaps even a cure can be sought.

Increased awareness can educate both the public and healthcare professionals about the symptoms, progression and genetic basis of FFI. This knowledge can lead to earlier diagnosis and more accurate differentiation from other neurodegenerative diseases and sleep disorders, enabling timely and appropriate interventions.

Supporting Research and Resources

Awareness campaigns have power. Here’s how raising awareness can support research and resources around FFI:

• Funding for Research: Raising awareness can drive funding and resources towards FFI research. Increased financial support can accelerate studies on the underlying mechanisms of the disease, the development of animal models and the testing of potential treatments. Public and private funding initiatives, alongside advocacy efforts, can help bridge the gap in research needs.
• Support Networks for Affected Families: Families affected by FFI often experience isolation due to the rarity of the condition. Awareness campaigns can help develop support networks and communities where families can share experiences, resources and emotional support. Organisations dedicated to rare diseases can play a role in connecting affected individuals and their caregivers.
• Public Policy and Advocacy: Advocacy efforts can influence public policy to ensure that rare diseases like FFI receive the attention they deserve. Policies that promote funding for rare disease research, provide support for affected families and ensure access to genetic testing and counselling are essential components of a comprehensive approach to tackling FFI.
• Collaborative Research Initiatives: Awareness can stimulate collaborative efforts among researchers, clinicians and institutions worldwide. International collaborations and data-sharing initiatives can enhance the understanding of FFI and expedite the development of effective treatments.

Final Thoughts

It’s clear that fatal familial insomnia is a challenging illness—and one without a happy ending. Although rare, it’s important that continued research and funding be poured into prion diseases so that those who suffer (and their families) can be supported and have hope.