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).