Running head : FATAL FAMILIAL INSOMNIA : AN OVERVIEW 1 Fatal Familial Insomnia A Summary of Its Nature and the Major Studies Eric Schools

Fatal Familial Insomnia (FFI) is an insidious prion disorder that tends to manifest itself as a patient reaches middle age following a pattern consistent with autosomal dominance. A wide range of symptoms are represented, many related to motor function and autonomic regulation, but degeneration of certain areas of the thalamus is present in every case. Genetically, the condition is transmitted only within families, but it has been demonstrated by Jackson et al. (2009) that FFI can be transmitted by exposure to/ingestion of infected material. A number of groundbreaking studies are discussed. These include the initial documentation of FFI as a prion disorder by Medori et al. (1992), the identification of codon 129 on PRNP as a locus for prion disease susceptibility by Palmer et al. (1991), the discovery that the aberrant isoform PrP sc requires the normal PrP protein in order to produce infectivity by Mallucci et al. (2003), and others. There are no effective treatments for FFI as of yet; scientists are still searching for all the pieces to the puzzle. FATAL FAMILIAL INSOMNIA: AN OVERVIEW 4 Fatal Familial Insomnia A Summary of Its Nature and the Major Studies Introduction Fatal familial insomnia (FFI) is one of the more horrifying illnesses one may contract, but it is also one of the least known. It has been termed “familial” because it is passed down genetically within very few families worldwide and fatal because it inevitably causes the unfortunate victim’s demise (Gistau, Pintor, Matrai, & Saiz, 2006). Its pattern of occurrence within families shows that it propagates following the principle of autosomal dominance; that is, a person with the condition has a 50% chance of passing the trait in question on to the offspring regardless of the offspring’s gender. Some believe that the very first instance of the mutation for FFI was an Italian physician who passed the “curse” on to his family before his death in 1765 (Schadler and Viddy, 2008). FFI is a prion disease which refers to the fact that its underlying cause is actually prions or “altered isoform[s] of a protein that become resistant to treatment with proteases” (Medori et al., 1992). The name prion is actually derived from the fact that the mutated proteins are protease-resistant (PrP) (Medori et al., 1992). Prions were originally thought to be “proteinaceous infectious particles”; however, more recent studies have shown that they are actually protease resistant proteins that were somehow misfolded (Jackson et al., 2009, p. 438). The proteins alone can still produce prion infection if they are introduced into a host as demonstrated by Jackson et al. by injecting healthy mice with a brain homogenate taken from FFI-infected mice. Their findings and the implications, thereof, will be discussed in greater detail later. Prions are currently defined as FATAL FAMILIAL INSOMNIA: AN OVERVIEW 5 infectious proteins that are abnormal forms of normal cellular proteins, that proliferate by inducing the normal protein to convert to the abnormal form, and that in mammals include pathogenic forms which arise sporadically, as a result of genetic mutation, or by transmission (as by ingestion of infected tissue and which upon accumulation in the brain cause a prion disease. (“prion,” 2007). The lethal nature of prion diseases in general and specifically FFI is quite welldocumented. However, in FFI patients, the precise cause of death is still somewhat nebulous (Scheinken & Montagna, 2006). Some FFI patients have not shown enough neural damage postmortem to point to it as the cause of death. Some insomnia studies using rats have noted degeneration in the supraoptic nuclei (SON) in the anterior portion of the hypothalamus, which is involved in the regulation of many homeostatic operations. It has been posited that, if the proper function of this area of the hypothalamus is adversely affected, it could explain some of FFI’s symptoms (Scheinker & Montagna, 2006). Discovery FFI was first documented in 1986. Since then there have been a total of twentytwo families reported to suffer from this “curse” (Harder et al., 2004). The initial documentation resulted from the study of two similar cases within a particular family in 1986; twenty-nine cases were subsequently confirmed within that family in a study conducted by Medori et al. (1992). The fairly wide variation of symptoms centering upon the apparently untreatable insomnia suggested that the condition might be propagated by prions. Scientists confirmed this hypothesis by running analyses upon tissues from FATAL FAMILIAL INSOMNIA: AN OVERVIEW 6 patients suffering from FFI and Creutzfeldt-Jakob disease as well as some other family members and non-family subjects who were not afflicted with any such disease. The analyses indicated that FFI is in fact a prion disease that comes about through a point mutation at codon 178 of the prion protein. At this location on the gene, aspartic acid is replaced with asparagine which produces the FFI phenotype, but only in some cases. It was noted in this same study that all four of the members who were FFI-symptomatic tested positive for the codon 178 point mutation, but there were also eleven test subjects in which the mutation was found who were asymptomatic and well past the median age of onset, which “indicates that the penetrance of fatal familial insomnia is incomplete” (p. 447). The discovery of other determinant factors of the FFI phenotype is a topic that will be discussed later in the paper. It was also in these studies that the autosomal dominant nature of the disease was discovered (Medori et al., 1992). The purpose of this paper is to provide a literature review of some of the major studies that have been conducted on FFI and issues closely related to it. For the sake of simplicity, the studies and their findings will generally be presented in chronological order. The discussion of the aforementioned items will commence after the initial discussion upon the nature of prions themselves and the relationships between the diseases they cause. FATAL FAMILIAL INSOMNIA: AN OVERVIEW 7