Fatal familial insomnia (FFI) affects the thalamus, the part of the brain that controls the sleep-wake cycle. The most common symptoms are sleep disturbance, psychiatric problems, weight loss, and balance problems. Other symptoms include high blood pressure, excess sweating, and difficulty controlling body temperature. These symptoms tend to get worse over time. Almost all cases of FFI occur due to a specific variant in the PRNP gene and are inherited in an autosomal dominant pattern. Diagnosis is based on the symptoms, clinical exam, sleep study, and imaging studies. The results of genetic testing can help confirm the diagnosis.

Normal Function

The PRNP gene provides instructions for making a protein called prion protein (PrP), which is active in the brain and several other tissues. Although the precise function of this protein is unknown, researchers have proposed roles in several important processes. These include the transport of copper into cells and protection of brain cells (neurons) from injury (neuroprotection). Studies have also suggested a role for PrP in the formation of synapses, which are the junctions between nerve cells (neurons) where cell-to-cell communication occurs.

Different forms of PrP have been identified. The normal version is often designated PrPC to distinguish it from abnormal forms of the protein, which are generally designated PrPSc.

Health Conditions Related to Genetic Changes

Huntington's disease-like syndrome

A particular type of variant (also called a mutation) in the PRNP gene has been found to cause signs and symptoms that resemble those of Huntington's disease, including uncontrolled movements, emotional problems, and loss of thinking ability. Researchers have proposed that this condition be called Huntington's disease-like 1 (HDL1).

The PRNP gene variants associated with HDL1 involve a segment of DNA called an octapeptide repeat. This segment provides instructions for making eight protein building blocks (amino acids) that are linked to form a protein fragment called a peptide. The octapeptide repeat is normally repeated five times in the PRNP gene. In people with HDL1, this segment is repeated eleven or thirteen times. An increase in the size of the octapeptide repeat leads to the production of an abnormally long version of PrP. It is unclear how the abnormal protein damages and ultimately destroys neurons, leading to the characteristic features of HDL1.

Prion disease

Many variants in the PRNP gene have been identified in people with familial forms of prion disease, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). The major features of these diseases include changes in memory, personality, and behavior; a decline in intellectual function (dementia); and abnormal movements, particularly difficulty with coordinating movements (ataxia). The signs and symptoms worsen over time, ultimately leading to death.

Some of the PRNP gene variants that cause familial prion disease change single amino acids in PrP. Other variants insert additional amino acids into the protein or result in an unusually short version of the protein. These changes alter the structure of PrP, leading to the production of an abnormally shaped protein, known as PrPSc, from one copy of the PRNP gene. In a process that is not fully understood, PrPSc can attach (bind) to PrPC and promote its transformation into PrPSc. The abnormal protein builds up in the brain, forming clumps that damage or destroy neurons. The loss of these cells creates microscopic sponge-like holes (vacuoles) in the brain, which leads to the signs and symptoms of prion disease.

Researchers have identified several common variations (polymorphisms) in the PRNP gene that affect single amino acids in PrP. These polymorphisms do not cause prion disease, but they may affect a person's risk of developing these disorders. Studies have focused on the effects of a polymorphism at position 129 of PrP. At this position, people can have either the amino acid methionine (Met) or the amino acid valine (Val). This polymorphism is written as Met129Val or M129V. Because people inherit one copy of the PRNP gene from each parent, at position 129 an individual can receive methionine from both parents (Met/Met), valine from both parents (Val/Val), or methionine from one parent and valine from the other (Met/Val).

The Met129Val polymorphism appears to influence the risk of developing prion disease. Most affected individuals have the same amino acid at position 129 (Met/Met or Val/Val) instead of different amino acids (Met/Val). Having Met/Met at position 129 is also associated with an earlier age of onset and a more rapid worsening of the disease's signs and symptoms.

Wilson disease

The Met129Val polymorphism has been reported to influence the onset of Wilson disease, an inherited disorder in which excessive amounts of copper accumulate in the body. Wilson disease is caused by variants in the ATP7B gene, but studies suggest that symptoms of Wilson disease begin several years later in people who have Met/Met at position 129 in PrP compared with those who have Met/Val or Val/Val. Other research findings indicate that this polymorphism may also affect the type of symptoms that develop in people with Wilson disease. Having Met/Met at position 129 appears to be associated with an increased occurrence of symptoms that affect the nervous system, particularly tremors.

Other disorders

The Met129Val variation has been associated with differences in performance on long-term memory tasks among healthy young adults. In one study, people who had either Met/Met or Met/Val at position 129 performed better at long-term memory tasks than those who had Val/Val. It is unclear how these differences may be related to memory.

Other Names for This Gene

• AltPrP
• ASCR
• CD230 antigen
• CJD
• GSS
• MGC26679
• PRIO_HUMAN
• prion protein (p27-30) (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia)
• PRIP
• PrP
• PrP27-30
• PrP33-35C
• PrPc
• PrPSc

Genomic Location

• Inability to fall asleep or stay asleep (insomnia)
• Difficulty thinking and concentrating (cognitive impairment)
• Short-term memory loss
• Weight loss
• Difficulty coordinating movements
• High blood pressure
• Inability to maintain body temperature
• Excessive sweating and tearing

Fatal familial insomnia (FFI) is diagnosed based on the symptoms, clinical exam, a sleep study (polysomnography), and imaging tests. The results of genetic testing may be helpful to help confirm the diagnosis. A list of features for diagnosing FFI (diagnostic criteria) has been published.

The sleep study EEG of a person who has insomnia but not fatal familial insomnia (FFI) shows mainly delta wave activity (high-amplitude slow waves of sleep stage 3 or deep sleep) and episodes of “micro-sleep”. There are also brief bursts of K-complexes (large waves in sleep stage 2 or light sleep) and sleep spindles (small bursts of activity in sleep stage 2). Insomnia with this pattern is associated with perceiving something that isn't there (disturbed perception), moments of not being aware of self or surroundings (lapses of consciousness), and quickly changing and often extreme behavior or emotions (erratic behavior).

In people with FFI, sleep study EEGs contain a mixture of rhythms that are neither typical of wake nor of light sleep, and may be called “subwakefulness.” There is a clear absence of sleep spindles and K-complexes. Total sleep time is shorter and the sleep study shows only slow activity or desynchronization without rapid eye movements (REM).

• Neurologist
• Medical geneticist
• Social worker