Curious case of a genetic typo

In the early 1980's, Italian neurologists found a prevalent sign among individuals of the same extended family who presented signs of sleeplessness. It was not temporary and not related to any physical or psychological factors. They just stopped sleeping and never recovered.

Welcome to the world of medical case mysteries, where diagnosis feels more like detective work than science.

The familial pattern

A familiar familial pattern of symptoms was found throughout a predominant number of members of an Italian family residing in Venice. The disease seemed to be hereditary affected individuals aged 30-40. The signs and symptoms included

• Gradual loss of sleep

• Anxiety

• Hallucinations

• Cognitive decline

• Ataxia

• Death within months to a few years

The closest they get to normal sleep is a kind of mindless stupor ; not quite asleep, but not quite aware

The lab reports failed to detect any signs of depression or psychosis

The revelation of the brain autopsy

A 12 hour postmorterm finally revealed the mystery

• Loss of neurons and reactive astrocytosis - Degeneration of the thalamus

• Minimal damage to other brain regions

• A pattern unlike Alzheimer’s, Parkinson’s, or Huntington’s disease

In 1986, neurologist Dr. Elio Lugaresi described and named the condition as Fatal Familial Insomnia ( Fatal - 100% mortality, Familial - Hereditary, Insomnia - Sleeplessness)

The size and shape of a walnut, in Silvano's brain the thalamus appeared to have been riddled with boring worms - Cortelli

Mystery solved

The mystery remained unsolved for many years ws scientists were still unable to identify the exact cause of the disease until the discovery of prion

There’s this one protein that’s sort of at the heart of this disease, the prion protein,This is a protein that we all have. We’re all producing it all the time, and it’s part of normal biology, but it’s capable of undergoing … a change in shape. As these prions spread, they’re killing brain cells in their wake - Vallabh

Later, it was found to be caused by a mutation, a typo in the coding of the DNA sequence of the prion protein (PRPN) gene. It caused accumulation of toxic misfolded prion protein in the thalamus, causing disruption of the sleep-wake cycle as the thalamus is the primary sleep center of the body.

Legacy of the First Case

Today, Fatal Familial Insomnia remains:

• Incurable

• Extremely rare

• A critical window into sleep, consciousness, and neurodegeneration