Fatal Familial Insomnia: Silvano's Brain, Codon 178 and the Prion Alliance

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In late 1983 an Italian man known as Silvano arrived at a sleep institute at the University of Bologna, unable to sleep and aware that two of his sisters had died the same way. Under neurologist Ignazio Roiter he let doctors record his decline and arranged to donate his brain. Roiter, sleep expert Elio Lugaresi, and neuropathologist Pierluigi Gambetti found none of the spongy damage of Creutzfeldt-Jakob disease, but the family kept tracing its history, and a 1986 paper named fatal familial insomnia. This episode follows the disease's four stages over roughly 18 months, from panic and paranoia to agrypnia excitata, dream enactment while awake, severe weight loss, and dementia.

The cause is a prion disease from a mutation at codon 178 of the PRNP gene on chromosome 20, swapping aspartic acid for asparagine, paired with methionine at codon 129; valine there produces familial Creutzfeldt-Jakob disease instead. The misfolded prions starve the thalamus of glucose, so sedatives have nothing to act on. A 52 year old American in 2001 used vitamins, meditation, stimulants, and sensory deprivation tanks to outlive the average by nearly a year. Sonia Vallabh, who carries the mutation that killed her mother, and her husband Eric Minikel left their careers and now pursue gene silencing at the Broad Institute.

• About 70 families worldwide, including 16 Basque cases traced to one 18th century ancestor
• A 57 year old Egyptian man in the Netherlands whose 2011 case began with double vision and paranoia
• Sporadic fatal insomnia, with 37 confirmed cases by late 2022 and no family history
• Why the RT-QuIC spinal fluid test misses the disease about half the time, and PET scans of a starving thalamus
• 2009 mice carrying the human mutation, and evidence that the normal prion protein may be dispensable