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Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review.

ABSTRACT: Fatal familial insomnia (FFI) is a human prion disease that is characterized by sleep-wake cycle deterioration, loss of slow-wave sleep, and motor overactivation over the daily 24-hour period.Here, we report the case of a 57-year-old man who had an irregular sleep-wake cycle and exhibited frequent movements and vocalizations during sleep.Video-polysomnography showed disrupted sleep structure, rapid alternation between sleep stages, and an absence of sleep spindles and slow-wave sleep. Moreover, body movements persisted throughout the entire sleep period, including rapid eye movement (REM) sleep. The atonia index was very low (<0.025) during REM sleep. Genetic testing revealed a prion protein gene mutation at codon 178, and the patient was diagnosed with FFI.We tried to treat with amantadine, doxycycline, and immunotherapies, but the disease progressed.Sleep disturbance is the most frequent and essential symptom of FFI.FFI is difficult to diagnose due to the low sensitivity of diagnostic tools. Diagnoses can be further supported by better knowledge of typical polysomnographic findings.

SUBMITTER: Yang TW

PROVIDER: S-EPMC6392909 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review.

Yang Tae-Won TW Park Byeongsu B Kim Keun Tae KT Jun Jin-Sun JS Kim Young-Soo YS Lee Soon-Tae ST Jung Keun-Hwa KH Chu Kon K Lee Sang Kun SK Jung Ki-Young KY

Medicine 20180501 18

<h4>Rationale</h4>Fatal familial insomnia (FFI) is a human prion disease that is characterized by sleep-wake cycle deterioration, loss of slow-wave sleep, and motor overactivation over the daily 24-hour period.<h4>Patient concerns</h4>Here, we report the case of a 57-year-old man who had an irregular sleep-wake cycle and exhibited frequent movements and vocalizations during sleep.<h4>Diagnoses</h4>Video-polysomnography showed disrupted sleep structure, rapid alternation between sleep stages, and ...[more]

PMID: 29718878

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Project description:Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human-mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt-Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.

Project description:Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding. Author summary Fatal familial insomnia is a devastating disease characterized by progressively worsening sleep until the brain and body deterioration result in death. Degeneration of brain cells is associated with accumulation of mis-folded proteins called prions. The mis-folding of the prions is caused by a single point mutation, D178N, in the gene encoding the normal precursor protein of the prions, the prion protein. Herein, we have used a human brain model to investigate the how this mutation causes brain cell damage. Our findings show that the mutation causes brain cells to dysfunction without the need for mis-folding into prions. Brain cell dysfunction was associated with stress and abnormal metabolism in such a way as to change critical compounds needed for the brain cells to function correctly. The changes correlate with enhanced wakefulness, which could cause the sleep disturbance. Our data support that many of the disease associated changes are caused by the fatal familial insomnia D178N mutation corrupting prion protein function.

Dataset Information

Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review.

Publications

Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review.

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