Introduction

Sleep disorders, including insomnia, which is difficulty in falling asleep and/or staying asleep, can be quite common and frustrating for people of all ages.¹ Interestingly, fatal familial insomnia (FFI), despite its name, is not a sleep disorder but instead a prion disease, where abnormally folded proteins cause irreversible neuronal loss and dysfunction in the thalamus of the brain. It is a genetic condition caused by a mutation in a specific gene (PRNP gene), which can be inherited in an autosomal dominant way, meaning that one copy of this mutated gene from one parent is enough to cause the disease. FFI is a neurodegenerative disease, characterised by symptoms such as insomnia, memory loss, cognitive deficits, and autonomic dysfunction, which progressively worsen and eventually lead to death. Currently, an efficient treatment method does not exist, and the disease is managed only symptomatically, with palliative care and psychosocial support.²

FFI was initially identified in 1986, during an autopsy, but its diagnostic features were not suggested until 2014.³ It is an extremely rare condition with limited epidemiological data, suggesting only hundreds of cases worldwide, mostly documented in Europe and Asia. The significant and degenerative symptoms of FFI, including sleep disturbances, neurological impairments and mental health problems, can immensely affect the physical and psychological profiles of patients.²

The psychological impact of associated symptoms

The average FFI duration is approximately 13 months. During this time, clinical symptoms begin to appear that gradually deteriorate, worsening the quality of life and psychology of patients. Features of FFI include:²

• Sleep problems: insomnia, leg movement, central sleep apnoea
• Autonomic impairment: high blood pressure, increased sweating, lacrimation, sexual dysfunction, constipation, abnormally rapid breathing
• Neurological deficits: double vision, swallowing difficulties, hallucinations, walking and speaking problems, memory loss, disorientation, and vegetative state
• Mental health difficulties: The intellectual capacity of patients may remain intact even during late disease, but depression, apathy, and mood changes are common
• Systemic and endocrine alterations: weight loss, increased cortisol secretion, dysregulation in melatonin and prolactin levels

Disturbances related to the circadian rhythm of patients are common in FFI, initially manifesting as insomnia that progressively worsens. Vivid dreaming when sleeping and confusion, panic attacks and paranoia when awake have all been documented during the early stages of the disease. The psychological aspects of these disturbances, including various emotional, cognitive, and behavioural issues, are exacerbated as stages advance. Mental health problems like anxiety, stress, depression, irritability, and mood dysregulation often appear, which can further aggravate sleeping issues in a debilitating cycle. Feelings of frustration and fear due to the uncertainty regarding the progression of the disease are common. Behavioural changes like apathy, unresponsiveness, or slow responses are also prevalent during the daytime due to lack of sleep. Furthermore, cognitive impairment emerges, along with memory loss, confusion, and difficulty in carrying out daily activities. Hallucinations can also occur, with patients talking to themselves and showing perceptual distortions.^4,5

Social implications

FFI symptoms may appear in different stages of life; according to a specific study, the average age of disease onset was reported at 47.5 years from a range of 17 to 76 years.⁶ Naturally, people who already present symptoms have devastating social alterations, as their mind and body functions rapidly decay over the progressing stages of insomnia and the other effects of the disease. 

People with a family history of the disease are considered suspected carriers of the mutated gene and can choose to undergo molecular genetic testing. Because of the nature of the disease, genetic testing provides the probability of an unwanted outcome and a tragic certainty if the gene is indeed present. The knowledge of carrying a lethal gene can have extremely burdensome implications on the psychosocial life of individuals. People may experience heightened anxiety and emotional distress and completely alter the way they perceive their future. Relationships may be strained, family planning is heavily influenced due to considerations of potential genetic inheritance to children, and communication with other family members may become challenging. As people try to cope with this genetic information, social stigma also comes into play, with discrimination and social isolation often occurring. On the other hand, some individuals may be relieved from the uncertainty of not knowing whether they carry the gene or not, therefore, genetic testing can instead provide clarity, primarily when coupled with appropriate counselling and support through all stages.⁷

Ultimately, individuals who are potential carriers of FFI, just like other lethal genes, should have the liberty of choosing between entering or opting out of genetic testing at any time. Educational and psychological support and reproductive counselling are a few essential steps they must follow throughout the process.⁷

Impact on families and caregivers

Apart from people with FFI, their families and caregivers may also experience extreme emotional burden. A wide range of professionals are typically involved in the management of FFI, with the necessity of psychosocial counselling for family members. An effective approach to discussing the diagnosis and analysing end-of-life care is harsh but inevitable. Such a traumatic experience would lead to long-term emotional trauma, with emotions of grief and undeniable anticipatory loss. Loneliness and role shifts among family members are also possible, with children becoming isolated and losing their childhood in the case of an affected parent and non-affected parents becoming emotionally distressed. Furthermore, there are practical and financial challenges for relatives to support their loved ones and planning future decisions proves difficult.⁷

Ethical dilemmas

In cases of fatal outcomes, a great number of ethical considerations may arise. Social, moral, and legal aspects complicate end-of-life situations and care. Euthanasia and assisted suicide are conflicting matters that have been historically misused but are currently under bioethical evaluation. The legal framework of such acts varies between different locations, making it possible for people who are terminally ill or those with fatal genetic conditions to undergo the procedure in a few countries worldwide. The patient’s autonomous right to choose a dignified death is pivotal in the euthanasia debate and should be discussed in-depth with professionals offering continuous psychological support.⁸

Current research includes a few advancing methods involving genetic engineering, suggesting significant alternatives in reproductive medicine. Particularly, people carrying fatal genes who decide to reproduce can resort to pre-implantation genetic diagnosis (PGD). The process of PGD involves screening embryos created with in-vitro fertilisation for genetic mutations and the selection only of embryos without the lethal gene for implantation. It is an effective method for preventing the transmission of genetic disorders, including FFI, and is established in some countries worldwide. However, PGD may be limited only to those with significant resources, although efforts to increase its accessibility are currently ongoing.

Moreover, gene editing technologies, such as CRISPR/Cas9, are one of the latest, most functional, and accurate methods of DNA modification. Nevertheless, this approach is highly controversial, with numerous ethical implications and legal concerns. Conducting essential clinical research on such a technique is either illegal in most countries or subjected to strict regulations, raising profound ethical questions. Specifically, germline editing, which involves editing genes in embryos and passing the changes onto future generations, can have unpredictable effects on human genetics, resulting in potential undesired consequences and uncertainty regarding long-term impacts. Research is currently ongoing to address the safety, efficacy, and ethics of this technology, but further discussions with a global consensus on the matter are crucial to ensure responsible applications for health needs.^9,10

Summary

FFI is a rare genetic disease caused by a mutation in a specific gene that leads to inevitable damage to the brain. It is a deadly neurodegenerative condition, which can pass down from affected parents in an autosomal dominant way. It is characterised by progressive, worsening insomnia, autonomic problems, neurologic deficits, and other systemic and endocrine alterations. The mental health of patients is tremendously affected by this fatal condition, with depression, anxiety, paranoia, and apathy often being observed. Social relations are also inevitably changed in such cases, with both patients and relatives carrying a great burden and trauma. Caregivers and family members are also under extreme psychosocial stress as they cope with end-of-life care and loss.

There is no current treatment option for FFI, and potential carriers of the defective gene can choose to learn their genetic profile through testing. The mental burden may be lessened for some of those who decide to know their fate, while for others, it can be unbearable. A few ethically complex choices may be considered for the life of patients, including euthanasia or assisted suicide, where legal. Other approaches regarding the choice of reproduction for affected individuals include PGD and gene editing technologies. However, gene editing, particularly germline editing, is mostly illegal or subject to strict regulations in many countries. Multiple ethical issues, such as inconsistent regulations, accessibility concerns(the risk of favouring some individuals over others), safety assessments, potential misuse of the technology, eugenic practices, and the inability of embryos or future generations to consent, naturally halt the adoption of these techniques.