I can’t say that I have heard of “Fatal Familial Insomnia.” So –– what I do in that case –– is go to the OMIM web site (Online Mendelian Inheritance in Man), created by my colleague and friend Victor McKusick. THIS [part of summary is pasted below] is what I found. FFI is a prion mutation disease, in which case, it qualifies as an environmental (infectious, much like “mad cow disease”) event. However, clinically — the phenotype (trait) appears as an (inherited) autosomal dominant trait, because the prion can be incorporated into the germline of future generations of an infected person.
“Prions” were discovered by Stanley Prusiner (Stanford) who was laughed at for more than a decade; eventually he won the Nobel Prize for “insisting he was right, and against the (misinformed) consensus was wrong.” Since then, it has been discovered that even YEAST cells have the prion gene.
A number sign (#) is used with this entry because fatal familial insomnia (FFI) is associated with mutation in the prion protein gene (PRNP; 176640).
Fatal familial insomnia is a prion disorder showing autosomal dominant inheritance. It is clinically characterized by insomnia with or without a diurnal dreaming state, hallucinations, delirium, and dysautonomia preceding motor and cognitive deterioration. FFI is specifically associated with the Asp178-to-Asn mutation of the PRNP gene (D178N; 176640.0010) when the amino acid at position 129 is methionine (M129V; 176640.0005). The D178N mutation and the val129 allele results in Creutzfeldt-Jacob disease (CJD; 123400) (see 176640.0007) (Goldfarb et al., 1992). CJD typically presents with dementia, ataxia, myoclonus, and other abnormal movements; however, there is considerable clinical and pathologic overlap between FFI and CJD, and some individuals with D178N and met129 may present with a phenotype suggestive of CJD. Thus, FFI and CJD may be viewed as extremes of a phenotypic spectrum (summary by Zarranz et al., 2005).
Manetto et al. (1992) presented the pedigree as well as the clinical and neuropathologic findings in 5 new cases. Men and women were affected in a pattern consistent with autosomal dominant inheritance. The age at onset varied between 37 and 61 years; the course averaged 13 months, with a range of 7 to 25 months.
Capellari et al. (2008) reported a family in which several members died of FFI associated with the PRNP D178N mutation, but a female family member with the disorder did not carry the D178N mutation and appeared to have sporadic onset of the disorder. Neuropathologic examination of the patient with sporadic disease confirmed the diagnosis, and she was found to be homozygous for the met129 allele. Capellari et al. (2008) commented on the uncertainty that still exists in the etiology of prion diseases.
In the study of fatal familial insomnia by Lugaresi et al. (1986), pathologic changes were distinguished from those seen in the thalamic form of Creutzfeldt-Jakob disease, in which there is always cortical spongiosis, and the gliosis is not confined to the thalamus. The well-defined location of the pathologic changes in FFI permitted more precise clinicopathologic correlations than had been possible in cases of tumors and vascular lesions. These correlations indicated that the anterior and dorsomedial thalamus has a role in integrating and expressing sleep, autonomic functions, and neuroendocrine circadian rhythm. The authors concluded that the kindred reported by Little et al. (1986) probably had the same disorder because of the identical pattern of inheritance, pathologic changes, and signs and symptoms.
Tateishi et al. (1995) succeeded in transmitting human fatal familial insomnia to mice, thus placing FFI within the group of infectious cerebral amyloidoses.
Useful information on the pathogenesis of fatal familial insomnia was provided by the descriptions of sporadic fatal insomnia by Mastrianni et al. (1999) and Parchi et al. (1999), which were reviewed by Gambetti and Parchi (1999). Mastrianni et al. (1999) described a 44-year-old man with insomnia, dysautonomia, and ataxia, followed toward the end of the fatal 16-month course by hallucinations and myoclonus. Histopathologic examination showed lesions that were indistinguishable in type and regional distribution from those of fatal familial insomnia; the amount, distribution, and molecular mass of the pathologic isoform of the prion protein (PrP(Sc)) in the brain were similar to those in fatal familial insomnia. However, a rigorous analysis of the PRNP gene failed to identify the mutation at codon 178 (D178N) that is associated with FFI. Mastrianni et al. (1999) argued that their patient had a sporadic form of fatal insomnia. This conclusion was supported by the description of 5 such patients by Parchi et al. (1999). Mastrianni et al. (1999) also demonstrated experimental transmission of sporadic fatal insomnia to mice. Mice inoculated with brain homogenates from subjects with fatal familial insomnia or sporadic fatal insomnia had lesions of similar types and distributions in their brains. In both familial and sporadic fatal insomnia, the molecular mass of the Prp(Sc) fragment was 19 kD (PrpSc type 2) in these mice. In contrast, these characteristics were different in the mice inoculated with homogenate from patients with typical sporadic or familial Creutzfeldt-Jakob disease, and the molecular mass of their PrP(Sc) was 21 kD (PrpSc type 1). These findings indicated that fatal familial insomnia can be generated in the absence of the D178N mutation. Gambetti and Parchi (1999) suggested that the repertoire of conformational changes of PrP(Sc) may be relatively limited–a factor that may facilitate the discovery of treatments.
▼ Molecular Genetics
Goldfarb et al. (1992) demonstrated that an Asp178-to-Asn (D178N) substitution in the PRNP gene, in conjunction with the met129 polymorphism on the same allele (176640.0010) was responsible for FFI. Creutzfeldt-Jakob disease was associated with val129 in all 15 affected members of 6 kindreds (see 176640.0007), whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.
Medori et al. (1992) identified the D178N mutation in all 4 affected persons and 11 of 29 unaffected persons from a kindred with FFI.
[You can read much more on the OMIM website.]