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 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.
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). 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 non-mutated 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.
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. 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.
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.
Patients with fatal familial insomnia (FFI) most commonly present between 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.
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.
Cerebrospinal fluid (CSF) Studies
Molecular Genetic Testing
Treatment is largely centered on symptomatic relief and palliative care.
When evaluating patients with FFI, it is important to consider other prion diseases due to overlap in symptomology.
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.
Neurodegenerative diseases including Alzheimer disease, Pick disease, corticobasal degeneration, multiple system atrophy, frontotemporal dementia and familial myoclonic dementia, irrespective of their slow progression, should be considered during evaluation.
FFI has been described to have 4 stages:
The disease course can last from 7 to 36 months, with an average duration of 18 months leading to eventual death. Patients with homozygous (Met-Met) mutation have a shorter mean survival time compared to heterozygous (Met-Val) patients.