Fatal familial insomnia (FFI) is a remarkably rare and invariably fatal inherited neurodegenerative prion disease. The mode of inheritance of this disease is autosomal dominant and involves the mutation of the prion protein (PRNP) gene. Aggressively progressive insomnia, with subsequent autonomic (tachycardia, hyperhidrosis, hypertension), cognitive (short-term memory and attentional deficits), motor system (balance problems), and endocrine dysfunction are a hallmark of the disease. The disease is currently incurable and has a mean course of 18 months, ultimately leading to death. The earliest description of the disease dates back to 1765 with a report of an Italian gentleman having symptoms suggestive of FFI.
The disease was formally identified and clinically described in 1986 by Lugaresi E. et al., followed by subsequent studies, further describing its pathophysiology, etiology, and clinical course.[1][2]
The cause of FFI has been identified as an autosomal dominant mutation at the codon 178 of the PRNP gene, located on the short (p) arm of chromosome 20 at position p13 responsible for making the prion protein PrPC.
The disease-causing mutation consists of substitution from the normal aspartic acid (Asp) to asparagine (Asn). The presence of methionine at codon 129 is distinct for FFI compared to valine at the same position in familial Creutzfeldt-Jakob disease (fCJD). Furthermore, an aggressive form of the disease has been linked to the configuration of the nonmutated allele (Met) at codon 129 of the disease-causing mutated gene. The more aggressive variant has methionine (Met-Met) on the nonmutated allele compared to when it has valine (Met-Val).
Evidence suggests that the onset of the disease depends on the critical amount of PrP conversion to the faulty prion protein.[2][3][4]
Genetic prion diseases are very rare. Annually, there are 1 to 1.5 new cases of genetic and non-genetic prion diseases per one million people. [5] Genetic forms of prion disease constitute approximately 10% of the total cases of prion diseases. FFI is exceptionally rare with the disease-causing mutation found in around 50 families worldwide.[4]
Fatal familial insomnia (FFI) remains neuropathologically ambiguous but is seen to manifest as a focal neuronal loss in the thalamus, inferior olivary nucleus, cerebellum, and varying degrees of spongiform changes in the cerebral cortex.
FFI is described to mainly affect the thalamus with a propensity for anterior ventral and mediodorsal thalamic nuclei. Other parts of the brain, including the inferior olives of the medulla oblongata and the cerebral cortex, have also been shown to be involved.
Parietal, temporal, and frontal lobes have shown higher degrees of involvement compared to the occipital lobe. Furthermore, the entorhinal cortex shows involvement in almost all cases, and the degree of spongiosis and astrogliosis is positively correlated to the duration of the disease. The prion protein’s deposition pattern favors the brainstem and thalamus earlier in the disease, but the thalamus is understood to be more vulnerable to subsequent degenerative changes. The reason for this involvement pattern is poorly understood but can explain the variety of symptoms seen in the disease.[2][4][5]
Patients with fatal familial insomnia (FFI) most commonly present between the ages of 20 and 61 years with a mean of 50 years and affects males and females equally. The disease leads to death eventually, and the course can range from 7 to 36 months, with a mean of 18 months. Patients with the homozygous Met-Met variant exhibit shorter mean survival time in comparison to heterozygous Met-Val.[6][4]
A detailed history and neurological examination are of paramount importance as FFI is largely a clinical diagnosis. When interviewing and examining a patient with possible FFI following points need to be considered:
A diagnostic criterion following the analysis of the frequency of presenting symptoms has been proposed.[7]
Labs
Polysomnography (PSG)
Electroencephalogram (EEG)
Cerebrospinal fluid (CSF) Studies
Imaging
Molecular Genetic Testing
Brain Biopsy
Treatment is largely centered on symptomatic relief and palliative care. Different treatment modalities mentioned in the literature are as follows. [8][9][10]
When evaluating patients with FFI, it is important to consider other prion diseases due to overlap in symptomology.[4][11]
Furthermore, ruling out other causes of dementia, which may be reversible, is necessary. Some of which include but are not limited to, herpes encephalitis, paraneoplastic syndromes (including limbic encephalitis), Hashimoto encephalitis, lithium poisoning, chronic meningitis, HIV encephalopathy, and hydrocephalus.[12][13]
Neurodegenerative diseases, including Alzheimer's disease, Pick disease, corticobasal degeneration, multiple system atrophy, frontotemporal dementia, and familial myoclonic dementia, irrespective of their slow progression, should be considered during evaluation.[14]
FFI has been described to have four stages:[15]
Fatal familial insomnia is best managed by an interprofessional team, including palliative nurses and hospice care. The disorder has no cure and is managed by first making the patient comfortable and improving the quality of life. Hospice should be involved early in the care.
[1] | Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178., Medori R,Montagna P,Tritschler HJ,LeBlanc A,Cortelli P,Tinuper P,Lugaresi E,Gambetti P,, Neurology, 1992 Mar [PubMed PMID: 1347910] |
[2] | Self management of fatal familial insomnia. Part 1: what is FFI?, Schenkein J,Montagna P,, MedGenMed : Medscape general medicine, 2006 Sep 14 [PubMed PMID: 17406188] |
[3] | Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene., Montagna P,Cortelli P,Avoni P,Tinuper P,Plazzi G,Gallassi R,Portaluppi F,Julien J,Vital C,Delisle MB,Gambetti P,Lugaresi E,, Brain pathology (Zurich, Switzerland), 1998 Jul [PubMed PMID: 9669701] |
[4] | Genetic Prion Diseases, Mastrianni JA,,, 1993 [PubMed PMID: 20301407] |
[5] | Tinuper P,Montagna P,Medori R,Cortelli P,Zucconi M,Baruzzi A,Lugaresi E, The thalamus participates in the regulation of the sleep-waking cycle. A clinico-pathological study in fatal familial thalamic degeneration. Electroencephalography and clinical neurophysiology. 1989 Aug; [PubMed PMID: 2473878] |
[6] | Geschwind MD, Prion Diseases. Continuum (Minneapolis, Minn.). 2015 Dec; [PubMed PMID: 26633779] |
[7] | Krasnianski A,Sanchez Juan P,Ponto C,Bartl M,Heinemann U,Varges D,Schulz-Schaeffer WJ,Kretzschmar HA,Zerr I, A proposal of new diagnostic pathway for fatal familial insomnia. Journal of neurology, neurosurgery, and psychiatry. 2014 Jun; [PubMed PMID: 24249784] |
[8] | Burchell JT,Panegyres PK, Prion diseases: immunotargets and therapy. ImmunoTargets and therapy. 2016; [PubMed PMID: 27529062] |
[9] | Forloni G,Tettamanti M,Lucca U,Albanese Y,Quaglio E,Chiesa R,Erbetta A,Villani F,Redaelli V,Tagliavini F,Artuso V,Roiter I, Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases. Prion. 2015; [PubMed PMID: 25996399] |
[10] | Reder AT,Mednick AS,Brown P,Spire JP,Van Cauter E,Wollmann RL,Cervenàkovà L,Goldfarb LG,Garay A,Ovsiew F, Clinical and genetic studies of fatal familial insomnia. Neurology. 1995 Jun; [PubMed PMID: 7783865] |
[11] | Medori R,Tritschler HJ,LeBlanc A,Villare F,Manetto V,Chen HY,Xue R,Leal S,Montagna P,Cortelli P, Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. The New England journal of medicine. 1992 Feb 13; [PubMed PMID: 1346338] |
[12] | Yang TW,Park B,Kim KT,Jun JS,Kim YS,Lee ST,Jung KH,Chu K,Lee SK,Jung KY, Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review. Medicine. 2018 May [PubMed PMID: 29718878] |
[13] | Gaudino S,Gangemi E,Colantonio R,Botto A,Ruberto E,Calandrelli R,Martucci M,Vita MG,Masullo C,Cerase A,Colosimo C, Neuroradiology of human prion diseases, diagnosis and differential diagnosis. La Radiologia medica. 2017 May [PubMed PMID: 28110369] |
[14] | Manix M,Kalakoti P,Henry M,Thakur J,Menger R,Guthikonda B,Nanda A, Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurgical focus. 2015 Nov [PubMed PMID: 26646926] |
[15] | Lindsley CW, Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI). ACS chemical neuroscience. 2017 Dec 20; [PubMed PMID: 29258312] |
[16] | Parchi P,Petersen RB,Chen SG,Autilio-Gambetti L,Capellari S,Monari L,Cortelli P,Montagna P,Lugaresi E,Gambetti P, Molecular pathology of fatal familial insomnia. Brain pathology (Zurich, Switzerland). 1998 Jul; [PubMed PMID: 9669705] |
[17] | Montagna P,Gambetti P,Cortelli P,Lugaresi E, Familial and sporadic fatal insomnia. The Lancet. Neurology. 2003 Mar; [PubMed PMID: 12849238] |