Fatal insomnia

Did You Know?

• The presence of prions causes reduced glucose use by the thalamus and mild hypometabolism of the cingulate cortex.
• The real-time quaking-induced conversion (RT-QuIC) assay detects PrP in cerebrospinal fluid with a sensitivity of 50% in FFI and sFI.
• Clonazepam may be prescribed for muscle spasms, and eszopiclone or zolpidem for insomnia, but these drugs do not work long term.

Signs and symptoms

The disease progresses through four stages. The first stage, lasting about four months, involves worsening insomnia that leads to panic attacks, paranoia, and phobias. In the second stage, hallucinations and panic attacks become noticeable and continue for about five months. The third stage, lasting about three months, is marked by a complete inability to sleep and rapid weight loss. The final stage, dementia, lasts about six months, during which the person becomes unresponsive or mute, followed by death. Other symptoms include profuse sweating, pinpoint pupils, sudden menopause or impotence, neck stiffness, elevated blood pressure and heart rate, and prolonged constipation. The sporadic form often presents with double vision. As the disease advances, the person enters a state of pre-sleep limbo (hypnagogia) and may repeatedly move limbs as if dreaming. Age of onset ranges from 13 to 60 years, averaging 50. Presentation varies considerably, even within families; in the sporadic form, sleep problems are not commonly reported early, with ataxia, cognitive impairment, and double vision being initial symptoms.

Cause

Fatal familial insomnia is a rare inherited prion disorder caused by a specific change in the PRNP gene on chromosome 20. This autosomal dominant condition involves a missense mutation at codon 178, where aspartic acid is replaced by asparagine. For FFI to occur, the mutant gene must also carry a methionine at position 129; if valine is present instead, the result is familial Creutzfeldt-Jakob disease. The disease primarily damages the thalamus, especially its medio-dorsal and anteroventral nuclei. A puzzling aspect of FFI is its variable symptoms among affected individuals.

Epidemiology and history

Fatal insomnia was first identified and named in 1986 by Elio Lugaresi and his team. By 1998, 40 families worldwide were known to carry the genetic mutation for the familial form (FFI): eight in Germany, five in Italy, four in the United States, two in France, two in Australia, two in Britain, one in Japan, and one in Austria. In Spain’s Basque Country, 16 cases of the 178N mutation appeared between 1993 and 2005, traced to two families sharing an 18th-century ancestor. In 2011, the first Dutch diagnosis occurred in a man of Egyptian descent who had lived in the Netherlands for 19 years. As of September 20, 2022, only 37 cases of sporadic fatal insomnia (sFI) had been recorded. Unlike FFI, sFI lacks the D178N mutation; instead, it involves a different mutation causing methionine homozygosity at codon 129. Researchers have suggested targeting this mutation as a possible treatment or cure. The original case that led to the 1986 description was a patient named Silvano, who arrived at the University of Bologna’s sleep institute in late 1983. Dr. Ignazio Roiter referred him to sleep expert Elio Lugaresi, who conducted advanced sleep analyses. Because no prion-related changes were found in tissue samples at the time, a prion disease was not suspected. Only after more cases emerged was FFI classified as a familial prion disease linked to the 178Asn mutation.

Research

A number of treatments, including pentosan polysulfate, mepacrine, and amphotericin B, have had tentative success in slowing disease progression in animal models, though benefit in humans remains unclear. As of 2016, a study investigating doxycycline was being carried out. In 2009, a mouse model expressing a humanized PrP protein with the D178N mutation was created; these mice showed progressively fewer and shorter periods of uninterrupted sleep, thalamic damage, and early deaths. The Prion Alliance, established by Eric Minikel and Sonia Vallabh after Vallabh's mother was diagnosed, conducts research at the Broad Institute to develop therapeutics, hypothesizing that lowering PrP levels may prevent onset. Other research interests include identifying biomarkers to track prion disease progression.