Clinical Features of Fatal Familial Insomnia: Phenotypic Variability in Relation to a Polymorphism at Codon 129 of the Prion Protein Gene

Abstract

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake-sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio-dorsal and anterior-ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mal seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion proteingene.

Fatal familial insomnia: Clinical features and early identification

“…As in sCJD, the M129V genotype was shown to influence age at onset, disease duration, and frequency and time of occurrence of clinical symptoms and signs. 3,5,6 MM patients were younger than MV patients, but both groups were younger than those with sCJD.…”

“…Ataxia occurred in heterozygous FFI patients as early as after a median duration of 4 weeks, similarly to MV sCJD often presenting with prominent ataxia. 5,6,11 Although the exact mechanism of the influence of the codon 129 genotype on the disease phenotype is not entirely clear, it has been proposed that phenotypic differences between MM and MV FFI patients may be caused by different rates of PrP c -to-PrP res conversion. 17 Although established criteria may fail to diagnose atypical subtypes of sCJD, some diagnostic tests, such as magnetic resonance imaging in the MV2 subtype and detection of 14-3-3 proteins in the MM2 and VV1 subtypes, are helpful in the diagnosis of CJD.…”

“…The diagnostic importance of polysomnography in FFI noted in our study has been emphasized by other authors. 2,6,12,14 [ 18 F]FDG-PET studies were reported to support FFI diagnosis. 9 Selective thalamic changes were seen on PET in only two of our patients, whereas widespread cortical hypometabolism without clear preference for a particular cortical region was found in five patients.…”

“…However, only limited data on this subject have been reported. 2,6 Although diagnostic criteria for FFI have been proposed, 7 The aim of this study was to develop a detailed clinical description of FFI in a larger group of patients with respect to the M129V genotype to improve clinical diagnosis.…”

Anti-NMDA receptor encephalitis presenting with total insomnia — A case report

“…However, FI characteristically has a slower progression, with about five months of progressive sleep decrease and behavioral and psychiatric changes before the patient presents with total insomnia [1,[9][10][11][12] and usually other motor abnormalities develop with disease progression including myoclonus, ataxia, pyramidal signs, dysarthria and dysphagia [7]. Seizures may occur in both conditions [4,5,13].…”