A family curse
During the early 1980’s, an Italian physician was investigating a mysterious and dreadful disease that had long plagued his family.
“Fatal familial insomnia is extremely rare: The disease has only been reported in forty family groups worldwide. But for anyone afflicted, the disease is a death sentence.”
A warning to readers: The story that follows has no happy ending.
The Italian case study
In 1983, the physician brought a close relative to the Neurological Hospital at the University of Bologna when he noticed incipient symptoms of this familial disease. Upon admission to the hospital the patient was in fair general health, but suffered from nocturnal insomnia, managing to sleep only two or three hours nightly. The physician knew that this partial insomnia marked the beginning of a slow and steady decline, and he hoped that a close study in a neurological facility would elucidate the underlying cause of the condition and produce a badly needed cure, to free his family from the grip of the cursed affliction.
An examination of the patient revealed slurred speech, constricted pupils with diminished sensitivity to changes in lighting conditions, and tremor in both arms. When left to himself, the patient would lapse into a stupor, breathe irregularly, and enact dreamlike scenarios with complex and purposeful gestures. Gentle stimulation would dispel these waking dreams and call the patient back to attention. He was able to cooperate with the doctors and perform the tasks of the neurological assessment. Numerous treatment attempts all failed to alleviate symptoms and the patient’s condition continually worsened.
One month after the onset of the initial mild but worrisome neurological symptoms, the patient’s continual autonomic breakdown manifested as urinary difficulty and constipation, significant filling of the nasal cavity with mucous fluid, uncontrollable secretion of sweat and tears, and an elevated body temperature. By the time another month had passed, the patient’s sleep deteriorated to one hour per night and was often disturbed by seemingly vivid dreams that would be enacted physically and sometimes violently.
Another month later, and all normal sleep was completely gone. Electroencephalogram (La electroencefalografía, o EEG,) recordings from the patient’s scalp made during periods of alertness as well as during waking dreams were devoid of characteristic sleep signs.
“Despite the best efforts of all the doctors, nothing could put the patient to sleep.”
By eight months after the onset of symptoms, the doctors had tried almost every conceivable pharmacological option in an effort to alleviate some of the patient’s suffering, but none of the drugs allayed symptoms or produced sleep. Injecting the barbituate thiopental – one of the most reliable general anesthetics on the pharmacist’s arsenal – induced a coma-like state in the patient, to the doctors’ great relief. But when they inspected the EEG activity from the patient in this catatonic state, the doctors saw clearly that the patient was not sleeping but merely trapped in a wakeful stupor. Dismayed by failure after failure, the doctors were desperate for new options as the patient progressed through the final stages of autonomic malfunction. No such options came.
In the final stages of his disease, the patient suffered episodes of screaming, writhing, and widespread muscle spasm. He was incommunicable and ran a high fever. His lungs slowly filled with fluid and he died shortly therefrom, nine months after the onset of symptoms.
Fatal familial insomnia
To this day, fatal familial insomnia remains incurable, and each case tracks a stereotyped pattern of clinical and pathological symptoms, ending with the death of the patient. Clinical symptoms of the disease are a progression through untreatable insomnia in conjunction with severe autonomic disturbances and motor signs, culminating in dementia and vegetative stupor.
“…researchers have linked fatal familial insomnia with a class of conditions called prion diseases, and now believe that the disease is entirely genetically determined…”
The case of the Italian patient closely tracked this characteristic pattern of symptoms, and his demise followed the typical time course: His symptoms began at age 53, consistent with the average age of disease onset among observed cases – 49.3 years. And his disease progressed for nine months, consistent with the average duration of symptoms until death – 12.5 months.
Fatal familial insomnia is extremely rare: The disease has only been reported in forty family groups worldwide. But for anyone afflicted, the disease is a death sentence.
The link to prion diseases
Through post-mortem assessments of atrophied brain tissue and genetic sequencing within afflicted families, researchers have linked fatal familial insomnia with a class of conditions called prion diseases, and now believe that the disease is entirely genetically determined by a single mutation in the PrP protein gen on human chromosome 20, which transforms normally functioning PrP proteins into pathological evil twins called prions. Prions are proteins that can be infectious and self-replicate like viruses, but without any genetic component – instead, it is simply the protein’s shape that can induce other proteins to refold themselves into this same pathological form, thus becoming new prions and perpetuating the protein-reshaping cycle.
The discovery and study of such prion diseases predates the characterization of fatal familial insomnia. In 1957, 26 years before fatal familial insomnia was encountered for the first time in a modern clinic, Australian anthropologists in Papua New Guinea encountered Kuru – a widespread, debilitating disease endemic to the indigenous Fore people. Those afflicted by the disease would initially suffer bouts of weakness and tremors, followed by violent shivering, infection, or pneumonia. In 1961 a hospital was opened in Papua New Guinea to study the disease. Post-mortem assessments of the brains of Kuru patients revealed a peculiar pattern of atrophy riddling the neural tissue of the cerebral cortex with pocked, sponge-like formations. Although Kuru was widespread among the Fore people, it was never transmitted to the anthropologists or medical researchers who worked with the patients. On the basis of this clue, the researchers discovered that Kuru was transmitted directly between individuals by ritualistic cannibalism.
Diseases with similar phenotypic sponge-like patterns of neural degeneration and transmissibility, such as scrapie in goats and sheep, and chronic wasting disease in deer and elk, were soon characterized as Transmissible Spongiform Encephalopathies. Once they recognized similar patterns of brain decay across these disparate conditions, researchers realized they were grappling with a new class of disease and began searching for the mysterious causative agents. The possibility of a viral agent was ruled out; the long time course of incubation and symptom manifestation was inconsistent with viral mechanisms, and furthermore no viruses linked to the diseases were ever isolated experimentally. A self-replicating protein hypothesis was proposed, and the agents were termed “prions” as an abbreviation for the term “proteinaceous infectious particles”. The notion of proliferating biological material devoid of nucleic acids initially caused skeptical reactions in the scientific community because it seemingly stood in contradiction to the central dogma of biology – that nucleic acid behavior is the essential mechanism by which living organisms transmit genetic information across generations. However, possible replicative mechanisms were devised and published, and the prion hypothesis gained traction.
Transmissible spongiform encephalopathies are now accepted to be prion diseases. These diseases cause neuronal death, and the large-scale transformation of healthy neural tissue into a useless, spongy mass. Prions do not elicit an immune response and are not susceptible to the body’s normal methods for breaking down errant proteins. They can be transmitted between individuals, as in Papua New Guinea’s endemic Kuru, or between species, as in the case of bovine spongiform encephalopathy, known more commonly as Mad Cow Disease.
The precise mechanism of tissue damage by pathological prions is unknown. And just as puzzling is the fact that healthy mammalian neurons are rife with non-pathological versions of these proteins called cellular prions, whose physiological importance is also mysterious. Cellular prion proteins are structurally distinct from their pathological counterparts, right down to the building blocks that constitute the proteins, and they are not infectious.
It is unclear whether the accumulation of the misfolded, infectious prions damages tissue directly, or by indirect means – for example, if cellular prions normally act to protect neurons from damage, diminishing the functional form would render a cell susceptible to extraneous neurodegenerative processes.
Most of the encountered cases of spongiform encephalopathies, such as Mad Cow Disease, are infectious and spread by direct transmission of the misfolded proteins between hosts. However, the existence of spontaneous and familial forms of spongiform encephalopathies imply that these diseases can also have genetic etiologies by which the host’s genes encode a misfolded form of prion protein. The expression of this misfolded genotype either produces all of the misfolded proteins, or induces normally-folded proteins expressed by other means to change their conformation to the diseased form.
Vexing mysteries and unanswered questions
Despite prion characterization, numerous detailed case studies, post-mortem tissue dissections, and plausible theories, we still know frustratingly little about fatal familial insomnia. The symptoms of the disease raise many beguiling questions. To name a few: Are the autonomic malfunctions caused directly by the loss of sleep? What is the role of the thalamus in normal sleep, and why does degeneration of the thalamus disrupt sleep? What is the role of sleep in homeostasis? What are the qualities of the waking dreams observed in those who suffer from this disease? Unfortunately, even answering these basic questions would leave us far from reliable treatments for the symptoms of this tragic disease. The precise role of sleep for an organism’s homeostasis is a matter of ongoing debate and speculation in the scientific and medical communities, and until more complete knowledge is uncovered, fatal familial insomnia will remain a nightmarish reminder of how little we understand some of the most basic neural phenomena.
Belay, E. (1999). Transmissible Spongiform Encephalopathies in Humans. Ann. Rev. Microbiol. 53, 283-314.
Belay, E. and Schonberger, L. (2005). The Public Health Impact of Prion Diseases. Ann. Rev. Public Health 26, 191-212.
Chakrabarti, O. and Hegde, R. (2009). Functional Depletion of Mahogunin by Cytosolically Exposed Prion Protein Contribute to Neurodegeneration. Cell Vol 137, Issue 6 994-996
Chakrabarti, O., Ashok, A., and Hegde, R. (2009). Prion Protein Biosynthesis and its Emerging Role in Neurodegeneration. Trends in Biochemical Sciences, Vol 34, Issue 6, 287-295.
Gajdusek DC. (1977). Unconventional viruses and the origin and disappearance
of kuru. Science 197, 943–6053
Goldfarb, LG et al. (1992). Fatal Familial Insomnia and Familial Creutzfeldt-Jakob disease: Disease Phenotype Determined by DNA Polymorphism. Science 258, 806-808.
Grifﬁth JS. (1967). Self-replication and scrapie. Nature 215, 1043–44.
Jan, J. et al. (2008). The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders. Journal of Pineal Research, 46, 1-7.
Kristiansen, M. et al. (2007). Disease-Associated Prion Protein Oligomers Inhibit the 26S Proteasome. Cell 26, 175-188.
Lewis, P. et al. (2006). Codon 129 Polymorphism of the Human Prion Protein Influences the Kinetics of Amyloid Formation. Journal of General Virology, 87, 2443-2449.
Lugaresi, E. et al. (1986). Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei. New England Journal of Medicine 315, 997-1003.
Medori, R. et al. (1992). Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon 178 of the Prion Protein La terapia génica. New England Journal of Medicine 326, 444-449
Sforza, E. et al. (1995). Sleep-wake cycle abnormalities in Fatal Familial Insomnia. Evidence of the role of the thalamus in sleep regulation. Electroencephalography and Clinical Neurophysiology, Vol 94, Issue 6, 398–405.