Fatal Familial Insomnia

A number sign (#) is used with this entry because fatal familial insomnia (FFI) is associated with mutation in the prion protein gene (PRNP; 176640).

Description

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).

Clinical Features

Lugaresi et al. (1986) reported a 53-year-old man who presented with progressive insomnia and signs of dysautonomia, including pyrexia, diaphoresis, myosis, and sphincter disturbances. Dreamlike status, dysarthria, tremor, and myoclonus subsequently developed and led to coma and death after 9 months. Two sisters of the patient and many relatives over 3 generations had died of a similar disease. Pathologic studies of the brains of the patient and 1 of his sisters showed severe neuronal degeneration, with reactive astrocytosis limited to the anterior and dorsomedial thalamic nuclei and without spongiosis or vascular or inflammatory changes. Although diffuse degenerative processes of the nervous system often affect the thalamus, this disorder appeared to be a genetically determined degenerative disease limited to selected thalamic nuclei.

Parchi et al. (1995) found protease-resistant prion protein in gray matter but not white matter of peripheral organs from 9 autopsied subjects with fatal familial insomnia. In general, the degree of histopathologic change correlated with the amount of the abnormal protein. However, the mediodorsal thalamic nucleus showed severe neuronal loss and astrogliosis in association with relatively modest amounts of abnormal prion protein, suggesting to the authors a higher vulnerability of this region.

Medori (1990) reported that despite a thorough search for similar cases in the literature and through neurologists and neuropathologists, the only additional cases they found were members of the same kindred: 4 in a branch of the family that emigrated from Italy to Belgium and France and 1 from the Italian branch of the family.

Harder et al. (1999) presented a large German kindred with fatal familial insomnia. Molecular genetic analysis of the PRNP gene confirmed that the D178N mutation segregated with methionine at the polymorphic codon 129 in all 7 affected patients examined. The authors noted a wide spectrum of clinical presentations and emphasized the difficulty in establishing the diagnosis of fatal familial insomnia on clinical and pathologic grounds alone. They were unable to confirm the previously reported relationship between the status of the M/V polymorphism at codon 129 and age at onset of this disease.

Spacey et al. (2004) described a family of Chinese descent in which at least 6 members spanning 4 generations were affected with autosomal dominant fatal familial insomnia. At age 36 years, the proband presented with myoclonus and refractory insomnia with somniloquism and dream enactment. He later developed intermittent diplopia, dysphagia, dysarthria, ataxia, dementia, and dysautonomia, and died 12 months after onset. Neuropathologic examination showed severe neuronal loss and gliosis in the thalamus, primarily in the ventral anterior, medial dorsal, lateral dorsal, and pulvinar nuclei. PrP(Sc) was widely distributed throughout the brain. Molecular analysis of the PRNP gene identified the D178N mutation and homozygosity for met129.

Dauvilliers et al. (2004) reported a French man with genetically confirmed FFI and heterozygosity for the met/val129 polymorphism (176640.0005) who reported pseudohypersomnia behavior instead of insomnia. He presented at age 41 years with progressive fatigue, severe depression, and episodes of vertical diplopia. Eighteen months later, he developed severe gait ataxia and dysautonomia, including hyperthermia, hyperhidrosis, dysuria, and sexual impotence without changes in blood pressure. He reported hypersomnia with frequent night hallucinations and agitation. Sleep and actigraphy studies performed 2.5 years after disease onset showed total disruption of physiologic sleep structure with dramatic reduction of total sleep, NREM sleep, and REM sleep, and normal rest activity. Neuroendocrine studies showed disruption of the circadian rhythms of plasma melatonin, growth hormone, and cortisol. CSF hypocretin-1 (HCRT; 602358) levels were normal. However, the patient's 24-hour temperature oscillation, sleep-wake cycle, and rest activity conserved a circadian distribution, suggesting normal functioning of the biologic clock, the suprachiasmatic nuclei. Dauvilliers et al. (2004) suggested a central lesion that functionally disrupted the neuroendrocrine rhythms with respect to the suprachiasmatic nuclei.

Dimitri et al. (2006) reported an 18-year-old man with FFI who presented with psychotic mood disturbances with catatonic features. He developed total insomnia, showed rapid progressive neurologic deterioration, and died 7 months after onset of insomnia. The authors emphasized the unusual and early presentation, and they noted that psychiatric treatments, including medications and electroconvulsive therapy (ECT), worsened the disease course in this patient.

Iriarte et al. (2007) reported the polysomnographic findings of a 49-year-old man with FFI. His sleep structure was severely altered, with loss of spindles and REM without atonia. During sleep, the patient was moving, talking, had periodic limb movements, and produced noises such as stridor, nocturnal groaning, and snoring. The results were consistent with the term 'agrypnia excitata,' meaning a peculiar type of lack of sleep associated with generalized overactivity and sympathetic activation.

Krasnianski et al. (2008) evaluated 41 German patients with FFI. The median age at onset was 56 years, and the median disease duration was 11 months. There were some phenotypic differences as determined by M129V genotype. Hallucinations and myoclonus were more common in patients with the MM genotype, whereas vegetative disturbances, bulbar signs, nystagmus, and ataxia were more common with the MV genotype. Those with the homozygous MM genotype had significantly shorter disease duration. Polysomnographic studies in 5 patients showed decreased rapid eye movement, reduction in deep sleep and efficiency, periodic limb movements, and central apnea.

Clinical Variability

Zarranz et al. (2005) reported 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were found to be genetically related by haplotype analysis. There were a total of 23 affected individuals. The largest family had 5 affected individuals. The genotype in all was D178N and met129 homozygous, but only 2 presented with FFI. The 3 other family members presented with CJD, 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and homozygous met129 had a clinical and neuropathologic profile compatible with CJD. In addition, 2 patients who were D178N and val/met129 heterozygous had FFI. PrPSc isotype analysis was not informative. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities.

Saitoh et al. (2010) reported a Japanese mother and son who were D178N and met129 homozygous. He developed a sleep disorder at age 54 years, consistent with FFI, but her phenotype was more consistent with CJD. Both patients had PrPSc type 2. The authors noted the similarities to the report of Zarranz et al. (2005).

Inheritance

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.

Pathogenesis

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 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.

Scaravilli et al. (2000) reported another case of sporadic fatal insomnia, confirmed by polysomnography and neuropathologic findings, in which there was no mutation detected in the prion gene. The patient was homozygous for methionine at codon 129.

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.

Genotype/Phenotype Correlations

In an analysis of 14 patients with FFI from 5 unrelated families, Montagna et al. (1998) found that patients who were homozygous for the met129 polymorphism had more prominent oneiric episodes, insomnia, and dysautonomia at disease onset, whereas patients heterozygous for met/val129 showed ataxia and dysarthria at disease onset, earlier sphincter loss, and seizures.

Dauvilliers et al. (2004) stated that FFI patients with met129 homozygosity tended to have a clinical course of less than 1 year, severe insomnia, recurrent oneiric episodes, continuous motor overactivity, and severe dysautonomia. In contrast, FFI patients with met/val129 heterozygosity tended to have a clinical course of greater than 2 years, insomnia or pseudohypersomnia, severe ataxia and dysarthria at disease onset, normal rest activity, and mild dysautonomia.

Animal Model

Tobler et al. (1996) reported alterations in circadian rhythm and sleep in PrP null mice. They stressed that the changes in these mice show intriguing similarities with the sleep alterations in FFI.

Jackson et al. (2009) found that mice expressing a mutant murine D177N Prnp protein, which is equivalent to the FFI-associated D178N mutation in humans, developed biochemical, physiologic, behavioral, and neuropathologic abnormalities that were similar to FFI in humans and different from other animal prion diseases. Pathologic brain changes in homozygous mice included atrophy of neural nuclei, enlarged ventricles, vacuolization and reactive gliosis in the deep cerebellar white matter, and neuronal loss and gliosis of the thalamus. There were very low amounts of proteinase K-resistant PrP, as seen in human FFI. Mutant mice showed age-related changes in behavior reflecting sleep interruption. Injection of a brain homogenate from mutant animals into wildtype animals resulted in a similar pathology in serial recipients, indicating that the disorder was transmissible and that a single amino acid change in Prnp is sufficient for the spontaneous generation of prion infectivity. Prnp-null mice who were injected remained normal, indicating that physiologic amounts of Prnp protein are required for disease transmission. The disease induced by the D177N mutant protein was distinct from scrapie, indicating that the FFI-associated mutant represents a unique strain of prion infectivity.