Clinical manifestations

Presentation and course

The mean age at onset in fatal familial insomnia is 48 years (range: 19 to 72 years). Remarkably, onset in early youth is possible (93; 80), engendering differential diagnostic difficulties with variant Creutzfeldt-Jakob disease (31). The disease duration is significantly shorter (12 months ± 4 months) in homozygous than in heterozygous patients (21 months ± 15 months) (61; 95). Insomnia, autonomic signs related to sympathetic hyperactivity, motor signs, and rapidly progressive cognitive impairment represent the cardinal clinical features of the disease. However, although insomnia and autonomic dysfunction are prominent in patients homozygous for methionine at codon 129, motor signs and cognitive decline predominate in the codon 129 heterozygous. Moreover, the relative frequency of specific symptoms may also vary according to the genetic (Asian vs. non-Asians) background (95). The disease is ultimately fatal, with coma and akinetic mutism often preceding death.

Insomnia. Insomnia is an early sign that progresses in some months to a total or nearly total inability to sleep. The insomnia is not the trivial difficulty in initiating or maintaining sleep, but rather a severe, persistent, and complete disorganization of sleep cycles (50; 59). The inability to sleep is more prominent and rapidly progressive in the early part of the course in patients’ methionine homozygous at codon 129 than in the methionine and valine heterozygous patients. Indifference to surroundings, inability to express feelings or emotions, and prolonged episodes of stupor associated with automatic behavior, such as enacting dreams, are other prominent clinical features.

In some cases, the disease may present as psychosis with auditory and visual hallucinations with persecutory delusions and disorganized thinking associated with catatonia, alternating with brief periods of psychomotor excitement (20).

Dysautonomia. Difficulties in micturition, impotence, lacrimation, salivation, and sweating usually appear in the earlier stages of the disease (68). Body temperature, breathing and heart rates, and systemic blood pressure are persistently elevated with reduced circadian oscillations and sometimes with dissociated features (19). Cardiovascular balance is lost, with higher background and stimulated sympathetic activity (13). Epinephrine and norepinephrine plasma concentrations are persistently elevated. New evidence suggests that cardiovascular dysautonomia in fatal familial insomnia may be partly attributable to parasympathetic abnormalities, not just sympathetic activation (18).

Motor manifestations. Gait disturbances and dysarthria are usually the first motor disturbances and typically appear some months after insomnia and dysautonomia (12). Excessive saccadic intrusions and diplopia may also manifest early in the disease course (74; 53). The evolution of motor symptoms varies according to the codon 129 genotype. Homozygous patients develop only a cautious gait with some difficulties in turning and in tandem gait; heterozygous patients show a clear progressive worsening of equilibrium with lateropulsion or retropulsion ultimately preventing standing and walking unaided (12). Speech becomes progressively unintelligible. Segmental and diffuse, spontaneous and evoked myoclonus can appear transiently.

Generalized tonic-clonic seizures are occasional late signs and, like all motor signs, are more evident in 129 heterozygous patients.

Neuropsychological findings. Progressive impairment of vigilance, attention, and visuomotor performances associated with selective memory disturbances and behavioral features of a confusional state are seen in most patients (25).

Neurophysiological features. EEG background activity becomes progressively slow and less reactive. Transient periodic 1 to 2 Hz activities associated with myoclonus are observed only in the advanced stages and in patients with long evolution. Total sleep time decreases and sleep EEG activity shortens progressively up to a complete or nearly complete inability to generate deep sleep patterns. Sleep spindle activities disappear early and only brief episodes of REM sleep, or more seldom, slow-wave sleep arise abruptly and randomly during wakefulness (79).

Endocrine functions. Plasma cortisol concentration is abnormally high; corticotropin is constantly low. In addition, sleep-coupled (growth hormone, prolactin) and uncoupled (cortisol, corticotropin) hormones lack circadian oscillations. The nocturnal increase in melatonin secretion progressively subsides (69). CSF hypocretin-1 levels are normal (51). Insulin resistance to both glucose and amino acid metabolism was reported in a patient with fatal familial insomnia and attributed to the effects of slow-wave sleep loss (05).

Neuroimaging. Routine brain CT and MRI are unremarkable. However, Haik and associates emphasized how multi-sequences of magnetic resonance including spectroscopy and diffusion water coefficient of the thalamus can detect prion-induced gliosis in vivo, as confirmed by subsequent neuropathologic examination (29). Grau-Rivera and colleagues reported volumetric and diffusion tensor imaging changes in patients with fatal insomnia, primarily involving the thalamus and, to a lesser extent, the cerebellum (28).

PET scan shows an early severe hypometabolism of the thalamus associated with a milder impairment of the cingulate gyrus. The cerebral metabolic deficit is more widespread in heterozygous subjects, in whom the course of the disease is longer (15), and is present in presymptomatic carriers several months in advance of the appearance of the first clinical symptoms, thus, representing the metabolic signature of the disease (14), useful for differential diagnosis (89). Symmetrical hypometabolism in the frontal cortex, less intense also in the parietal and the posterior cingulate cortex, has been attributed to diaschisis because of cortical deafferentation caused by the thalamic pathology (92). Iaccarino and colleagues reported data of the first in vivo 11C‐(R)‐PK11195 PET study of microglia activation in fatal familial insomnia showing a lack of significant translocator protein (TSPO) overexpression in the homozygous presymptomatic carriers and a peculiar regional profile of activation in a single symptomatic patient (35).

CSF prion RT-QUIC assay and other biomarkers. It has been reported that the abnormal prion protein, PrPSc, can be detected in the CSF early during the clinical course in fatal familial insomnia patients and other genetic forms of human prion disease with a high sensitivity (83%) using the real-time quaking-induced conversion assay (RT-QUIC) (76). This is an ultrasensitive assay that monitors in vitro the conversion of recombinant PrP into protease-resistant, beta-sheeted, prion protein conformer, induced by prion-containing tissues and fluids. This assay can be useful as a diagnostic test in case of refusal of genetic testing or to confirm the diagnosis in the presence of a positive genetic test. However, the sensitivity of CSF prion real-time quacking-induced conversion assay (RT-QuiC) in fatal familial insomnia has been reported to be lower than in other prion disease subtypes (24; 72). Interestingly, prion-seeding activity by means of RT-QuIC has also been detected in the olfactory mucosa of patients with fatal familial insomnia (71). In contrast to Creutzfeldt-Jakob disease, CSF surrogate biomarkers of neurodegeneration (eg, 14-3-3, total-tau, neurofilament light protein) showed limited diagnostic value in fatal familial insomnia (34; 78). However, the measurement of plasma neurofilament light protein has been proposed as a prognostic marker and minimally invasive tool to monitor patients after clinical onset, given the stage-related increase and association with disease duration (34).

Diagnostic algorithm. Krasnianski and colleagues proposed an algorithm for the clinical diagnosis of fatal familial insomnia, which correctly identified at least 81% of patients, later confirmed to have fatal familial insomnia, during the early disease stages (42). Among diagnostic investigations in this study, only polysomnography and, to some extent, FDG-PET, contributed to the diagnosis before genetic testing. In another cohort study, polysomnography and genetic data showed the highest diagnostic value in fatal familial insomnia (39).

Prognosis and complications

Fatal familial insomnia has led to death in all affected subjects examined to date.

Clinical vignette

Case 1. Fatal familial insomnia short-lasting disease course (129 methionine/methionine). A 53-year-old man, who had been outgoing, cheerful, and sociable, became reserved and cold, even with relatives. A few weeks later he experienced difficulty in falling asleep and early awakenings. His insomnia worsened with time and he started to perform automatic gestures related to oneiric episodes (enacted dreams). Three months after the clinical onset he had impotence, hyperhidrosis, and myoclonic jerks. Somnolence and stupor episodes worsened and were associated with more intense enacted dreams, mild speech impairment, and uncertain gait. Six months after the onset, speech further deteriorated and gait was severely impaired. Muscle jerks and autonomic disturbances worsened. Stupor became persistent: verbal answers were in monosyllables and were only obtained after repeated stimulation. The patient died of respiratory failure 8 months after the first symptoms. A brother who was 129 M/M had died of the same disease after a 9-month clinical course.

Case 2. Fatal familial insomnia long-lasting disease course (129 methionine/valine). A 60-year-old woman presented with a life-long history of headache. At the age of 57 years, she first presented with marked reduction in nocturnal sleep, some speech difficulties, and uncertain gait. Three months later these disorders worsened and were accompanied by fever, hyperhidrosis, and lacrimation. Six months after onset speech was dysarthric and gait became increasingly impaired with retropulsion and difficulty in turning when asleep. Sleep was reduced to 3 to 4 hours per night. Nine months after onset, spontaneous and reflex muscle jerks appeared; gait retropulsion increased causing frequent falls. Three months later, somnolence or stupor states were characterized by hallucinations and mental confusion with sporadic grand mal seizures. At 15 months, stupor was more persistent with automatic gestures and enacted dreams; speech was incomprehensible and unaided gait impossible. Stupor progressively worsened and became permanent. Relatively calm periods alternated with agitation, and the patient died 32 months after the clinical onset.

Biological basis

Etiology and pathogenesis

Fatal familial insomnia is a prion disease linked to: (1) the presence of a mutation at codon 178 of the prion protein gene (PRNP) resulting in the substitution of aspartic acid (D) with asparagine (N) (D178N); and (2) a methionine codon at position 129 of the mutated allele (D178N, 129M haplotype) of the PRNP (27; 55). The probabilities of linkage between fatal familial insomnia and the haplotype D178N, 129M gave a combined maximum logarithm of odds score of 6.5 for three fatal familial insomnia kindreds; this is consistent with the mutation being the cause of the disease. However, the possibility that the mutation acts as a strong susceptibility factor that requires an additional cofactor to cause the disease cannot be completely ruled out. According to one study, other genetic risk factors, besides PRNP, involved in programmed cell death, caspase-mediated cleavage of cytoskeletal proteins, and apoptotic cleavage of cellular proteins may influence the age of onset of fatal familial insomnia (90).

Neuropathology. The neuropathology in both familial and sporadic cases is dominated by thalamic and olivary atrophy (26; 63; 64; 62; 85). The anterior-ventral and medial dorsal thalamic nuclei are consistently and severely affected. The other thalamic nuclei present variable and less consistent atrophy. Among them, the centromedian and pulvinar nuclei are more frequently affected. The cortex may show minimal to moderate astrogliosis and spongiosis that are often focal. Overall, the extent of cortical changes depends on the total duration of clinical disease and are, therefore, more prominent in the 129 heterozygous subjects or in sporadic cases, who generally have a longer clinical course. Severe atrophy of the inferior olives is also common, whereas atrophy of the cerebellar cortex is minimal to moderate (63). In fatal familial insomnia, a relative increase in 5HT synthesizing neurons occurs in the median raphe system (91). This corresponds to a demonstration that a 4- to 5-fold increase in the 5HIIA catabolite occurs in cerebrospinal fluid compared with normal subjects (16). Some observations suggest that neuronal loss in fatal familial insomnia is caused by apoptosis (22). Tubulovesicular virion-like structures, a consistent and still unexplained finding in the brains of humans with prion diseases, are also found in brains from fatal familial insomnia patients (46). According to Massignan and colleagues, mutant prion protein (PrP) induces overexpression of glycosyl-phosphatidyl-inositol, activating a cytotoxic feedback loop that leads to protein accumulation in the secretory pathway (52). Other evidence suggests that the same mutation and PRNP haplotype may be occasionally found associated with a distinct atypical neuropathological phenotype, characterized by spongiform changes in cerebral cortex in the absence of significant thalamic and olivary degeneration (85).

Protein molecular pathology. The protease-resistant PrPSc core fragment associated with fatal familial insomnia migrates on gel at about 19kDa. In contrast, the PrPSc core fragment associated with Creutzfeldt-Jakob disease linked to the D178N mutation in PRNP (CJD178) migrates at 21 kDa (58). The basis for the different migration profiles between the PrPSc protease-resistant fragments associated with fatal familial insomnia and CJD178 has been definitely established by amino acid sequencing (65). The N-terminus of the PrPSc protease-resistant fragment associated with fatal familial insomnia starts at amino acid 97, whereas the corresponding PrPSc fragment associated with CJD178 starts at amino acid 82. Furthermore, both PrPSc associated with fatal familial insomnia and CJD178 are also characterized by the under-representation of the unglycosylated form of PrPSc (58). The distribution and amount of PrPSc accumulation in fatal familial insomnia-affected brains largely match those of the pathology and are a function of the disease duration, which in turn is often a function of the 129 polymorphism; therefore, like the pathology, PrPSc has generally a more widespread distribution and is more abundant in 129 heterozygous than in homozygous subjects (63). Contrary to other familial prion diseases, in fatal familial insomnia the PrPSc derives only from the mutant PRNP, whereas the PRNP expressed by the normal (nonmutated) allele is never converted to the PrPSc (10). Other polymorphisms in the prion protein gene may also regulate the disease phenotype (08). The Japanese patient with atypical fatal familial insomnia showed the same PrPSc fragment and glycosylation profile as the typical fatal familial insomnia cases by Western blotting (85).

Transmissibility. Fatal familial insomnia has been transmitted to experimental animals (87; 88). In affected mice inoculated with fatal familial insomnia brain homogenate, PrPSc deposition is more prominent in the thalamus than in other brain locations. Inoculation of fatal familial insomnia human PrPSc to transgenic chimera mice expressing a mouse or human PRNP carrying the methionine codon at position 129 gives rise to a PrPSc of the same type (and size) as the human PrPSc associated with fatal familial insomnia; however, the PrPSc formed in the transgenic mice does not show underrepresentation of the unglycosylated form (88). Spontaneous generation of prion infectivity has been reported in one animal model of fatal familial insomnia knock-in mice (37).

Interestingly, brain tissue from typical and atypical fatal familial insomnia cases showed a distinct transmission profile, suggesting the existence of two distinct FFI-related prion strains. Specifically, typical fatal familial insomnia showed successful transmission only to knock-in mice expressing a human-mouse chimeric PrP, whereas the atypical variant demonstrated successful transmission only using knock-in mice expressing bank vole PrP (85).

Epidemiology

Currently, at least 70 kindreds, apparently unrelated, have been published in Europe, Australia, the United States, Japan, and more recently, in China and Brazil (82; 93; 80; 66; 17; 95).

Sporadic fatal insomnia. Although Kawasaki and colleagues described a probable case of sporadic fatal insomnia in 1997, the sporadic form of fatal insomnia was definitively established in 1999 by both Mastrianni and colleagues and Parchi and colleagues. Parchi and colleagues, in particular, reported five cases of a prion disease that was clinically and histopathologically indistinguishable from fatal familial insomnia, but lacked the D178N mutation in the PRNP gene (62). Abu-Rumeileh and colleagues collected a large series of patients (n=13), representing the result of 20 years of prion disease surveillance in Europe (01). With this addition, to date, the number of cases of sporadic fatal insomnia reported in literature worldwide raises above 40 (01; 17). Sporadic fatal insomnia is a disease of young or middle-aged adults (about 40 years old), rather than of the elderly, which is intriguing because this is difficult to reconcile with the current leading hypothesis of an age-related “stochastic” origin of sporadic prion disease (01). Further, sporadic fatal insomnia was also confirmed in a 13-year-old adolescent (07). Mean disease duration is about 24 to 30 months, which is longer compared to fatal familial insomnia (01; 17; 11). Early peculiar clinical features include psychiatric, sleep (ie, insomnia), and oculomotor disturbances, followed by cognitive decline and postural instability (01). In the full-blown disease patients may also develop myoclonus, dysarthria, motor overactivity and extrapyramidal, cerebellar, and pyramidal signs. Moreover, in sporadic fatal insomnia autonomic and neurohormonal alterations may be present but are less prevalent than in fatal familial insomnia (01). As for fatal familial insomnia, EEG, conventional MRI, and CSF biomarkers, such as 14-3-3 and t-tau lack diagnostic sensitivity in sFI (60; 44; 01). Prion real-time quacking-induced conversion assay (RT-QuIC) showed 50% to 60% sensitivity for sporadic fatal insomnia (01; 17); the CSF concentration of neurofilament light protein was significantly increased in all tested cases (01). FDG-PET or CBF-SPECT may reveal thalamic hypometabolism or an altered thalamic perfusion (54; 30; 60; 57; 33; 01). Moreover, proton MR spectroscopy was shown to be useful for the demonstration of thalamic degenerative pathology in both familial and sporadic fatal insomnia (47). In all tested patients, video-polysomnography demonstrated a severe reduction of total sleep time, or a disorganized sleep mimicking the pattern reported in fatal familial insomnia, or both (77; 09; 28; 01). Some cases showing the coexistence of sporadic fatal insomnia and sporadic Creutzfeldt-Jakob disease MM2C subtype features have also been reported (62; 30; 28). Ethnicity seems to influence sporadic fatal insomnia features: Asian sporadic fatal insomnia patients had a higher proportion of males and positivity for cerebrospinal fluid 14-3-3 protein and fewer sleep-related symptoms than Caucasian sporadic fatal insomnia patients (11).

All subjects affected by sporadic fatal insomnia reported to date were homozygous for methionine at codon 129. All of the subjects examined had PrPSc type 2 as the familial cases (62; 60; 57; 01), but none showed the under-representation of the unglycosylated form (62). The neuropathological hallmarks of sFI also resemble those of fatal familial insomnia (62; 01). One case of sporadic fatal insomnia transmitted to transgenic mice led to the same intense PRNP deposition in the thalamus as fatal familial insomnia (54), suggesting that both disorders are linked to the same prion strain. Two additional cases were able to transmit the disease to transgenic mice expressing 129MM human PrP (57). The pathological and molecular features in the affected mice indicate that sporadic fatal insomnia (also known as MM2-thalamic sCJD) is caused by a specific prion strain that is distinct from those associated with other sporadic Creutzfeldt-Jakob disease subtypes (57).

Prevention

The haplotype of fatal familial insomnia has been well established and, thus, prenatal diagnosis and genetic counseling can be provided. A founder effect has been described in European families (73). A founder effect is what happens when a population is descended from a small number of ancestral individuals, the so-called original founders; at a population level this means that, when only a small part of a population moves to a new locale, the genes of these founders are disproportionately frequent in the resulting population. The interpretation of these findings is, however, still contentious, and recurrent new mutational events have been argued for (45; 67).

Differential diagnosis

The differential diagnosis involves other subtypes of familial prion disease. Fatal familial insomnia itself displays a certain degree of interfamilial and even intrafamilial phenotypic variability, ranging from classical Creutzfeldt-Jakob disease presentation to cerebellar ataxia to a Gerstmann-Straussler-Scheinker phenotype, with marked variability of disease onset (94; 56; 83; 75). The clinical characteristics, especially the sleep and behavioral features, are, however, substantially distinctive even at presentation (41; 70). CJD178 differs from fatal familial insomnia clinically by the lack of early, severe sleep disorder with oneiric stupor and dysautonomia, and pathologically by the marked and widespread cortical spongiform changes of the cerebral cortex and the lack of severe atrophy of thalamic nuclei. Genetically, fatal familial insomnia and CJD178 are distinguished by the different haplotype: D178N, 129V in CJD178 and D179N, and 129M in fatal familial insomnia. Furthermore, fatal familial insomnia is associated with PrPSc type 2; CJD178 is associated with PrPSc type 1 (58). Some overlap in clinical features is, however, possible (94).

Other familial prion diseases, similar to the typical sporadic Creutzfeldt-Jakob disease and the Gerstmann-Straussler-Scheinker syndrome, which is characterized by cerebellar ataxia, are easier to distinguish from fatal familial insomnia. One reported case of CJD200 had a total lack of sleep due to the fact that the thalamus was severely affected in this particular case (86). Sporadic fatal insomnia can be distinguished from fatal familial insomnia by the lack of the D178N mutation and the normal representation of the unglycosylated form of PrPSc (62). Arguably, most of the cases reported in the literature under the label of thalamic atrophy or thalamic dementia belonged to fatal familial insomnia or to sporadic fatal insomnia (62). Sleep abnormalities consisting of loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep have also been reported in sporadic Creutzfeldt-Jakob disease (43).

Behavioral and polysomnographic features similar to those of fatal familial insomnia characterize alcohol withdrawal syndrome, Morvan fibrillary chorea (an autoimmune condition clinically characterized by neuromyotonia, hyperhidrosis, and CNS dysfunction in the form of limbic encephalitis with insomnia, hallucinations, and disorientation, and often associated to thymoma and serum antibodies vs. K+ channels), Mulvihill-Smith syndrome (a progeroid disorder with dwarfism, mental retardation, striking multiple pigmented nevi, and lack of facial subcutaneous fat, causing a somewhat bird-like face), and other diseases (23). In fact, similarities among all these diseases led to the concept of “agrypnia excitata” as a clinical syndrome due to dysfunction within the thalamo-limbic circuits (36; 49). Increased muscle sympathetic activity has been demonstrated by means of microneurographic recordings in cases of agrypnia excitata (21).

Diagnostic workup

In the International Classification of Sleep Disorders (03), fatal familial insomnia is currently listed within Appendix A, which lists the sleep disorders associated with conditions classifiable elsewhere. The American Sleep Disorders Association lists the following diagnostic criteria for fatal familial insomnia (03):

In the International Classification of Sleep Disorders, 3rd edition (ICSD-3), fatal familial insomnia is also listed in “Appendix A: sleep related medical and neurological disorders;” however, diagnostic criteria are not given (02).

Management

No treatment is currently available. Administration of barbiturates and other sleep-inducing drugs appears to have only a transient beneficial effect. Quinacrine and chlorpromazine, reported as helpful for the treatment of prion diseases (40), were ultimately ineffective in two patients with fatal familial insomnia (06).