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 ... 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).
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 ... 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).
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 ... 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.
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 ... 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.