Genetic disorders are a rare but devastating phenomenon that can affect multiple generations in a family.

Familial Fatal Insomnia (FFI) is one such rare genetic disorder that results in total sleep deprivation, leading to a wide range of neurological symptoms, and eventually death.

FFI – A brief overview

FFI is a prion disease, meaning it is caused by abnormal proteins called prions, which can bind to normal proteins and convert them to misfolded proteins.

Misfolded proteins then start clumping in the brain, forming plaques and causing damage to brain cells. FFI affects the thalamus, a region of the brain that regulates sleep and other vital functions.

As a result, individuals with FFI experience progressive sleep loss, accompanied by a range of neurological symptoms, such as cognitive impairment, hallucinations, and muscle stiffness. The disease is always fatal, with patients typically surviving for only 6-18 months after the onset of symptoms.

The case in question

In 2001, a report was published describing a rare case of FFI that affected two brothers in Italy. The report described the clinical and genetic findings of the case, shedding light on the possible mechanisms of FFI and its genetic transmission.

The two brothers were in their early fifties when they started experiencing symptoms of FFI. The initial symptoms were insomnia, followed by vivid hallucinations, autonomic dysfunction, and delirium.

Despite treatment with sedatives and antipsychotics, their condition deteriorated rapidly, with multiple organ failure eventually leading to death within 12-24 months of the onset of symptoms.

Genetic testing

The autopsy of the two brothers revealed that they had the typical brain damage associated with FFI, as well as characteristic genetic mutations in the prion protein gene (PRNP).

Specifically, they both had a substitution of methionine for valine at codon 129 (V129M) in the PRNP gene. This mutation has been previously described in other cases of FFI and is thought to increase the susceptibility to prion misfolding and aggregation.

Interestingly, the father of the two brothers had died at the age of 72 from an unknown cause that was suspected to be a result of FFI.

Genetic testing of the father’s brain tissues revealed the presence of V129M mutation, confirming that he had indeed had FFI.

Transmission of FFI

The case of the two brothers provides evidence for the genetic transmission of FFI, in which the disease is passed down from one generation to the next in an autosomal dominant pattern.

Autosomal dominant disorders are caused by mutations in a single gene that results in an abnormal protein, which is sufficient for disease manifestation. In this case, the V129M mutation in the PRNP gene is the pathogenic mutation that causes FFI.

The transmission of FFI is unusual in that the disease is caused by prions, which are not technically living organisms and cannot reproduce like other pathogens.

However, prions can convert normal proteins into their misfolded form and spread throughout the brain, causing progressive damage and ultimately leading to death.

Treatment and future directions

Currently, there is no cure for FFI, and treatment is mainly palliative, aiming to alleviate symptoms and improve the quality of life of affected individuals.

Various drugs, such as benzodiazepines and antipsychotics, have been tried with limited success. However, a pharmaceutical approach that targets the prion protein or the mechanisms of prion propagation is still under investigation, offering hope for future therapeutic interventions.