NORD gratefully acknowledges James A. Mastrianni, MD, PhD, Professor, Department of Neurology; Director, Center for Comprehensive Care and Research on Memory Disorders, Committee of Neurobiology, University of Chicago; The Helen McLoraine Neuroscience Investigator of the Brain Research Foundation, for assistance in the preparation of this report.
Fatal familial insomnia (FFI) is a rare genetic degenerative brain disorder. It is characterized by an inability to sleep (insomnia) that may be initially mild, but progressively worsens, leading to significant physical and mental deterioration. Affected individuals may also develop dysfunction of the autonomic nervous system, the part of the nervous system that controls involuntary or automatic body processes – which are things that happen without a person thinking about them, such as body temperature regulation, sweating, breathing or regulating the heart rate. Specific symptoms observed depend on the part of the autonomic nervous system that is affected by the disease. In all instances, FFI is caused by an abnormal variant in the prion-related protein (PRPN) gene, although sometimes, the disorder occurs randomly, without a variant PRPN gene (sporadic fatal insomnia, or SFI). The PRNP gene regulates the production of the human prion protein. Alterations in this gene lead to the generation of abnormally-shaped (misfolded) prion protein, also known simply as a “prion”, which is toxic to the body. In FFI, the abnormal prions build up primarily within the thalamus of the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. There is no cure, but investigators are researching ways to best treat and manage FFI.
FFI is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. Two other prion diseases, Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, may also occur as a result of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may accumulate for many years without causing symptoms (long incubation period), but once symptoms begin the disorder rapidly worsens.
The characteristic symptom in FFI is progressive insomnia. Insomnia often begins during middle age, but it can occur earlier or later in life. Insomnia may first be mild, but it then become progressively worse until an affected individual gets very little sleep. Insomnia usually begins suddenly and can rapidly worsen over the next few months. When sleep is achieved, vivid dreams may occur. The lack of sleep leads to physical and mental deterioration and the disease ultimately progresses to coma and death.
Although insomnia is usually the first symptom, some individuals may present with progressive dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating, or speech problems. Episodes of confusion or hallucinations can eventually occur.
Some affected individuals may experience double vision (diplopia) or abnormal, jerky eye movements (nystagmus). There may be problems with swallowing (dysphagia) or slurred speech (dysarthria). Some individuals eventually have trouble coordinating voluntary movements (ataxia). Abnormal movements including tremors or twitchy, jerking muscle spasms (myoclonus), or Parkinson’s-like symptoms may also develop.
Additional symptoms involving dysfunction of the autonomic nervous system often develop. Specific symptoms can vary from one person to another based on the specific part of the autonomic nervous system affected. Common symptoms can include fever, rapid heart rate (tachycardia), high blood pressure (hypertension), increased sweating (hyperhidrosis), increased production of tears, constipation, variations in body temperature, and sexual dysfunction including erectile dysfunction. Anxiety and depression are common findings as well.
FFI is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
In rare instances, the change (variation) in the PRPN gene in individuals with FFI occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their offspring in an autosomal dominant manner.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Some individuals have developed fatal insomnia (FI) without a variation in the PRPN gene. These individuals are said to have sporadic fatal insomnia (SFI) and although this is a non-genetic form of FFI, the underlying trigger for its development is unknown. Thus, SFI occurs randomly, by chance, with a much rarer occurrence than FFI.
The PRNP gene produces a protein called prion protein, or PrP. The exact function of PrP in the body is not fully understood. However, because of the variant gene, the PrP that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrP is toxic to the body, especially cells of the nervous system. In FFI, misfolded PrP is primarily found in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite, and body temperature. As the misfolded PrP builds up in the thalamus, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like holes or gaps when examined under a microscope, which is why prion diseases like FFI are called transmissible spongiform encephalopathies.
The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the transmissible nature of prion diseases. Extensive research has shown that a prion is essentially the misfolded PrP. However, it is important to know that FFI is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, perhaps by ingestion or injection. If a person without an underlying genetic defect develops a prion disease, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism).
FFI is an extremely rare disorder. The exact incidence and prevalence of the disorder is unknown. The sporadic form of FFI, known as sporadic fatal insomnia (SFI), is extremely rare and has only been described in the medical literature in about two dozen people. Collectively, prion disorders affect about 1 person per million people in the general population per year. Genetic prion diseases are believed to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. FFI affects men and women in equal numbers. The average age of onset is 45-50 years old, although the disorder has been described occurring in individuals in their teens and as late as their 70s. FFI has been described in populations around the world.
A diagnosis of FFI is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis in some instances. Molecular genetic testing can detect an abnormal variant in the PRPN gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories. In all cases of FFI, there will be an abnormal PRNP variant that is detectable, although negative genetic testing does not rule out SFI.
Polysomnography, also called a sleep study, may be performed on affected individuals to demonstrate a reduced amount of time sleeping and difficulties transitioning through the various sleep stages.
Positron emission tomography or PET scan is an advanced imaging technique that can be useful in diagnosing FFI. During a PET scan, three-dimensional images are produced that reflect the brain’s metabolic activity and can show reduced activity within the thalamus (thalamic hypometabolism), as a characteristic feature.
Other advanced imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). CT scanning is not useful in the diagnosis of FFI or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose FFI is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic FFI or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and body tissues.
Physicians may run tests to detect the presence of the 14-3-3 protein. This is a normal protein that is produced when nerve cells die. Sometimes, in individuals with FFI, levels of this protein increase substantially in the cerebrospinal fluid (CSF). CSF is the colorless fluid that surrounds the brain and spinal cord and provides protection and support. Elevated levels of 14-3-3 in the CSF does not always occur, and normal levels of this protein does not rule out FFI. The tau protein is also often elevated in the CSF of prion disease, although because of the rarity of FFI, the usefulness of testing for tau in FFI is not fully understood. More recently, a test called RTQuIC (real-time quaking induced conversion), that helps to detect low levels of prions in CSF, is now being used to assist in the diagnosis of prion disease and may be useful for FFI, but there is currently not enough data on that.
There is no cure for FFI. Treatment is directed toward management of the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with FFI.
Symptomatic treatments include anti-seizure (anti-epileptics) medications for seizures or clonazepam for myoclonus. Affected individuals may be advised to discontinue any medications that worsen confusion, memory or insomnia.
As of April 2018, there are currently no specific therapeutic trials for FFI. Only quinacrine, an antimalarial agent, was studied in a controlled clinical trial of prion disease, but failed.
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