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"The Worst Disease You Can Get"

"The Worst Disease You Can Get"

When Italian neurologist Pierluigi Gambetti characterised the condition known as Fatal Familial Insomnia (FFI), he described it as “the worst disease you can get”. Given the plethora of devastating diseases we can be afflicted with, that seems like a naive and inadvisable claim. However, a quick overview of the disease seems to suggest that he may not have been wrong.

FFI has been described in just 40 families worldwide; it is an autosomal dominant heritable disease, meaning that an affected parent has a 50% chance of passing it to their offspring. The disease has no known cure and involves progressively worse insomnia and the incredibly incapacitating symptoms that comes with that, such as hallucination, delirium and dementia. Unfortunately, given the devastating effects that no sleep has on the body, survival after the onset of symptoms is no longer than 18 months.

It is the complete inability to sleep that differentiates FFI from other neurodegenerative diseases, such as encephalitis, end-stage alcoholism and dementia. If you measure the electrical activity of the brain – in a technique known as electroencephalography (EEG) – in individuals affected with FFI, you find that those brain wave patterns vary wildly. They may show brain waves indicative of REM sleep – the ‘deepest’ type of sleep – but they neither go through the stages of brain activity that precede REM sleep, nor do they show any signs of sleep during this stage.

sleep-cycle
There are characteristic EEG patterns for each stage of sleep. Though FFI patients may show signs of REM sleep, they remain awake.

As well as spikes in brain activity, there are also unbelievable highs in pulse and blood pressure, excessive sweating and an eventual loss of coordination and other gross motor skills (including speech) before the victim finally falls into a coma-like state and dies. But, tragically, unlike other neuro-degenerative diseases, patients’ ability to think clearly remains throughout the disease – meaning that they remain completely aware of their growing loss of function and inevitable death.

The gene responsible for the disease is the PRNP gene, located on the short arm of chromosome 20 (its exact location is shown below). The mutation of the gene results in just a single change in the amino acid structure of the PrPC protein: an asparagine residue is found instead of an aspartic acid at position 178. When this is coupled with the presence of a methionine at position 129, the mutant gene produces the protein associated with the disease.

The exact location of the PRNP gene on chromosome 20.
The exact location of the PRNP gene on chromosome 20.

The mutated form of the PrPc gene is referred to as PrPsc and has a curious characteristic that remains a mystery. PrPscis essentially an infectious protein, known as a prion protein. In a process that is not well understood this mutated protein, which has folded up incorrectly, can bring about the same mis-folding in other, healthy proteins of this type. The body simply has no way of coping with such an ‘infection’, because the causative agents are the body’s own cells and so can’t be targeted by the immune system, which is designed to destroy foreign particles.

prions
Holes – denoted by the arrows – are characteristic in prion affected tissues.

Like all prion diseases, there is no cure for FFI. Gene therapy has yielded few results and the one existing animal model of the disease is not similar enough to the human disease to create an effective treatment. Thus far, the only hope for affected individuals is the tentative treatment of the symptoms, which can somewhat improve the patient’s quality of life.

‘Til next time…

Joe

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