Fatal familial insomnia (FFI) is a rare degenerative brain disorder caused by a genetic mutation. It is characterized by a persistent inability to sleep (insomnia), which may begin mildly but gradually worsens, resulting in significant physical and mental deterioration. Affected individuals may also develop dysfunction of the autonomic nervous system, the portion of the nervous system that regulates involuntary or automatic body processes – those that occur automatically, such as body temperature regulation, sweating, breathing, or heart rate regulation. The specific symptoms observed vary according to the region of the autonomic nervous system affected by the disease. FFI is always caused by an abnormal variant in the prion-related protein (PRNP) gene, although it can occur randomly in the absence of a variant PRNP gene (sporadic fatal insomnia, or SFI). The PRNP gene is involved in the regulation of the human prion protein's production. Changes in this gene result in the production of an abnormally shaped (misfolded) prion protein, abbreviated "prion," which is toxic to the body. In FFI, abnormal prions accumulate primarily in the brain's thalamus. This results in the progressive loss of nerve cells (neurons) and the associated symptoms. Although there is no cure, researchers are investigating the most effective ways to treat and manage FFI.
Introduction
FFI is classified as a prion disease or a transmissible spongiform encephalopathy (TSE). The accumulation of misfolded prion proteins in the brain results in prion diseases. Two additional prion diseases, Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, may also be caused by PRNP gene variants, although some prion diseases occur in the absence of a genetic variant. In general, prion disorders have a long incubation period and a brief clinical duration, which means that abnormal prions can accumulate for many years without causing symptoms (a long incubation period), but the disorder rapidly worsens once symptoms manifest.
Symptoms & Signs
Progressive insomnia is a hallmark symptom of FFI. While insomnia most frequently begins in middle age, it can begin earlier or later in life. Insomnia may begin mildly, but gradually worsens until the affected individual sleeps very little. Insomnia typically begins abruptly and deteriorates rapidly over the next few months. When a person falls asleep, vivid dreams may occur. Sleep deprivation results in physical and mental decline, and the disease eventually progresses to coma and death.
Although insomnia is frequently the first symptom, some individuals may present with progressive dementia, characterized by deteriorating cognitive, memory, language, and behavioral abilities. At first, the symptoms may be subtle, such as unintentional weight loss, forgetfulness, inattentiveness, difficulty concentrating, or speech difficulties. Confusional or hallucinatory episodes may eventually occur.
Certain individuals who are affected may experience double vision (diplopia) or jerky, abnormal eye movements (nystagmus). There may be swallowing difficulties (dysphagia) or slurred speech (dysarthria). Certain individuals eventually experience difficulty coordinating voluntary movements (ataxia). Additionally, abnormal movements such as tremors or twitchy, jerking muscle spasms (myoclonus) may develop, as well as Parkinson's-like symptoms.
Additional symptoms involving autonomic nervous system dysfunction frequently develop. Specific symptoms vary according to the area of the autonomic nervous system affected. Fever, rapid heart rate (tachycardia), high blood pressure (hypertension), increased sweating (hyperhidrosis), increased tear production, constipation, body temperature variations, and sexual dysfunction, including erectile dysfunction, are all common symptoms. Anxiety and depression are also frequent findings.
Causes
FFI is caused by an abnormal variant of the PRNP gene (gene mutation). Genes encode instructions for the production of proteins that are required for the proper functioning of numerous bodily functions. When a gene is mutated, the resulting protein product may be defective, inefficient, absent, or excessively produced. Depending on the function of the specific protein, this can have a detrimental effect on a variety of organ systems throughout the body, including the brain.
In rare cases, individuals with FFI develop a change (variation) in the PRNP gene spontaneously, without a family history of the disease. This is referred to as a unique or de novo variant. The gene variation occurred during the egg or sperm formation process for that child alone; no other family members will be affected. Typically, the disorder is not inherited or "carried" by a healthy parent. However, an individual who acquires this de novo variant may pass it on to their offspring in an autosomal dominant manner.
Genetic diseases are determined by the combination of genes encoding a particular trait that are passed down from father to mother on the chromosomes. When a disorder is inherited in a dominant pattern, only one copy of an abnormal gene is required for the disorder to manifest. The abnormal gene may have been inherited from either parent or may have occurred as a result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene on to offspring from an affected parent is 50% for each pregnancy, regardless of the resulting child's sex.
Certain individuals have developed fatal insomnia (FI) in the absence of a PRNP gene variant. These individuals are said to have sporadic fatal insomnia (SFI), and while this is not a genetic form of FFI, the underlying cause is unknown. Thus, SFI occurs at random, by chance, and is much less common than FFI.
The PRNP gene is responsible for the production of a protein known as prion protein, or PrP. The precise function of PrP in the body is unknown. However, as a result of the variant gene, the PrP produced takes on an abnormal three-dimensional shape that is simply described as "misfolded." PrP that has been misfolded is toxic to the body, particularly to nervous system cells. In FFI, misfolded PrP is primarily found in the thalamus, a structure deep within the brain that is involved in the regulation of numerous bodily functions such as sleep, appetite, and body temperature. As misfolded PrP accumulates in the thalamus, it causes progressive destruction of nerve cells (neurons), resulting in the disorder's symptoms. When examined under a microscope, the damage to brain tissue may appear as sponge-like holes or gaps, which is why prion diseases such as FFI are referred to as transmissible spongiform encephalopathies.
The term "prion" was coined to refer to a "proteinaceous infectious agent" in order to explain how prion diseases are transmissible. Numerous studies have established that a prion is essentially a misfolded PrP. However, it is critical to understand that FFI is not contagious in the conventional sense, as the only way to transmit prion disease to a healthy individual is through direct contact with diseased brain tissue, possibly through ingestion or injection. If a person develops prion disease without having an underlying genetic defect, it is referred to as a 'acquired' form. For example, in the United Kingdom, people contracted variant Creutzfeldt-Jakob disease after eating prion-contaminated beef. Kuru is a lesser-known example. Kuru is a prion disease that was virtually eradicated from the Fore people of Papua New Guinea. Due to the villagers' practice of eating the brains of deceased kuru-affected tribesmen, the disease spread throughout this population (ritualistic cannibalism).
Populations Affected
FFI is a very uncommon disorder. The disorder's exact incidence and prevalence are unknown. The sporadic form of FFI, referred to as sporadic fatal insomnia (SFI), is extremely rare, having been reported in the medical literature in only about two dozen individuals. Prions disorders collectively affect approximately 1 person per million people in the general population each year. Genetic prion diseases are estimated to account for approximately 15% of all prion disease cases. Due to the fact that rare diseases frequently go undiagnosed or are misdiagnosed, determining their true prevalence in the general population is difficult. FFI affects both men and women equally. The average age of onset is 45-50 years old, but the disorder has been described in individuals as young as adolescents and as old as 70 years old. FFI has been identified in populations worldwide.
Disorders That Are Related
The following disorders may exhibit symptoms similar to those of FFI. Comparisons may be beneficial in establishing a differential diagnosis.
Other prion disorders may exhibit similar symptoms to FFI. There have been four additional major prion diseases identified in humans. Kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome are examples of these. These disorders are characterized by the death of nerve cells (neurons) and brain damage. Animals are also susceptible to prions diseases, such as bovine spongiform encephalopathy (mad cow disease) in cows and scrapie in sheep. Variant Creutzfeldt-Jakob disease was acquired through the consumption of beef contaminated with abnormal prions associated with bovine spongiform encephalopathy.
Frontotemporal degeneration is a collection of diverse disorders defined by neurodegenerative changes in the brain. Frontotemporal degeneration manifests clinically in a variety of ways. Individuals who are affected may exhibit gradual changes in their behavior and personality, as well as difficulty thinking and communicating effectively. The progression of the disease and the specific symptoms that develop vary from person to person. Clinical symptoms of these disorders can be broadly classified into three categories, depending on whether they involve changes in behavior, language, or motor function. Frontotemporal degeneration is a progressive loss and damage of nerve cells in the brain's frontal and temporal lobes. In the majority of people, this is accompanied by an accumulation of one of two proteins, tau or TDP-43. In FTD, these proteins are misfolded, resulting in their abnormal accumulation within brain cells and eventual disruption of these cells' normal function. Clinical subtypes of FTD can also be classified as 'tauopathies' or 'TDP43-opathies', depending on the misfolded protein that accumulates in the brain. Approximately 10% of the time, a third protein, FUS, accumulates in place of tau or TDP43. Other neurological disorders can also be associated with tau protein or TDP-43 protein accumulation. (To learn more about this disorder, use the Rare Disease Database search term "frontotemporal dementia.")
Alzheimer's disease is a progressive brain disease that impairs memory, cognition, and language. Alzheimer's disease's degenerative changes result in the formation of plaques or clumps of misfolded protein in the brain, as well as the accumulation of misfolded protein within the neuron (neurofibrillary tangles). As a result of these protein accumulations in brain tissue, memory loss and behavioral changes occur. Alzheimer's disease is typically a slow-progressing illness that occurs more frequently in people over the age of 65, as opposed to frontotemporal degeneration, which occurs more frequently in midlife and younger people. Short-term memory impairment is frequently the first symptom, and early behavioral changes may go unnoticed. As the disease progresses, memory loss worsens and personality, mood, and behavior changes. There are difficulties with judgment and concentration, as well as confusion and restlessness. Mental changes vary significantly in their nature, severity, sequence, and progression. Long periods of little change are common, although the disease can occasionally progress rapidly. (To learn more about this disorder, use the Rare Disease Database's search term "Alzheimer.")
Additional disorders, such as Huntington disease, progressive supranuclear palsy, dementia with Lewy bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes, and multiple system atrophy, can cause signs and symptoms similar to those seen in prion diseases such as FFI. (To obtain additional information about these disorders, enter the disorder's name as a search term in the Rare Disease Database.)
Diagnosis
FFI is diagnosed based on the presence of specific symptoms, a thorough patient history, a thorough clinical examination, and a battery of specialized tests.
Clinical Examinations and Workups
In some cases, molecular genetic testing can confirm a diagnosis. Although molecular genetic testing is capable of detecting an abnormal variant in the PRNP gene known to cause the disorder, such testing is only available as a diagnostic service at specialized laboratories. All cases of FFI will have a detectable abnormal PRNP variant, although negative genetic testing does not rule out SFI.
Polysomnography, also known as a sleep study, may be used on affected individuals to demonstrate decreased sleep duration and difficulty transitioning between sleep stages.
PET scanning, or positron emission tomography, is a sophisticated imaging technique that may be helpful in diagnosing FFI. PET scans produce three-dimensional images of the brain's metabolic activity and, as a characteristic feature, can reveal decreased activity within the thalamus (thalamic hypometabolism).
Additionally, computerized tomography (CT) scanning and magnetic resonance imaging are advanced imaging techniques (MRI). CT scanning is ineffective for diagnosing FFI or prion disease, whereas MRI can detect some abnormalities in the scan that are consistent with prion disease, although its use to diagnose FFI is not well defined. MRI and CT scans, on the other hand, may be helpful in ruling out other conditions that mimic FFI or prion disease. CT scanning utilizes a computer and x-rays to create a film that depicts cross-sectional images of specific tissue structures. A magnetic field and radio waves are used in an MRI to create cross-sectional images of specific organs and body tissues.
Tests for the presence of the 14-3-3 protein may be performed by physicians. This is a normal protein produced by dying nerve cells. Occasionally, in individuals with FFI, the level of this protein in the cerebrospinal fluid increases significantly (CSF). CSF is a colorless fluid that surrounds and protects the brain and spinal cord. Elevated 14-3-3 levels in the CSF are not always present, and normal levels of this protein do not exclude FFI. The tau protein is also frequently elevated in the CSF of patients with prion disease, although the utility of tau testing in FFI is not fully understood due to the disease's rarity. Recently, a test called RTQuIC (real-time quaking induced conversion) has been developed to aid in the diagnosis of prion disease and may be useful for FFI, but there is currently insufficient data.
Conventional Therapies
FFI is incurable. Treatment focuses on the management of the individual's distinct symptoms. Treatment may necessitate the coordination of the efforts of a multidisciplinary team. Neurologists, psychiatrists, psychologists, pain specialists, social workers, and other healthcare professionals may be required to develop a treatment plan that is systematic and comprehensive. Psychosocial support is also critical for the entire family. Genetic counseling is recommended for individuals who are affected and their families.
For affected individuals, there are no standardized treatment protocols or guidelines. Due to the disease's rarity, there are no large-scale treatment trials. Numerous treatments have been described in the medical literature as case reports or small series of patients. Trials of specific medications and treatments for individuals with FFI would be extremely beneficial in determining their long-term safety and effectiveness.
Anti-seizure (anti-epileptic) medications are used to treat seizures, while clonazepam is used to treat myoclonus. Individuals who are affected may be advised to discontinue any medications that exacerbate confusion, memory loss, or insomnia.
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