P.088 Dysautonomia and Diabetes: A Prodrome to Fatal Familial Insomnia (FFI)

Background: Fatal Familial Insomnia (FFI) is an autosomal dominant multisystem prion disease, with sleep disorders often being the first presentation. Although autonomic dysfunctions are key features, the frequency and timing vary between reports, and may accompany early insomnia. Moreover, endocrine changes are reported, but diabetes rarely is - with unclear timing of onset in relation to the insomnia. Methods: N/A Results: Here we present a 46-year-old previously healthy male, who within 22 months prior to the onset of sleep disturbances, developed hypertension and diabetes. Then within 3-4 months after onset of sleep disturbances development tachycardia and diaphoresis. His sleep continued to deteriorate, and later developed bulbar impairment, ataxia, diplopia, sleep apnea and cognitive decline. He passed away 20 months from onset of insomnia. Polysomnography showed status dissociates and central apnea. He had positive genetic testing, PRNP c.532G>A (p.Asp178Asn) and PRNP c.385A>G (pMet129Val), a pathological confirmation, and a positive family history Conclusions: Here diabetes and hypertension significantly preceded sleep disturbances, and tachycardia and diaphoresis developed shortly after. This illustrates that dysautonomia and endocrine dysfunction may be unrecognized prodromes in some cases of FFI, and could be an early marker of clinical disease onset and therapeutic interventions, especially in genetically confirmed asymptotic patients.

Clinical profile of fatal familial insomnia: phenotypic variation in 129 polymorphisms and geographical regions

ObjectiveElucidate the core clinical and genetic characteristics and identify the phenotypic variation between different regions and genotypes of fatal familial insomnia (FFI).MethodsA worldwide large sample of FFI patients from our case series and literature review diagnosed by genetic testing were collected. The prevalence of clinical symptoms and genetic profile were obtained, and then the phenotypic comparison between Asians versus non-Asians and 129Met/Met versus 129Met/Val were conducted.ResultsIn total, 131 cases were identified. The age of onset was 47.51±12.53 (range 17–76) years, 106 patients died and disease duration was 13.20±9.04 (range 2–48) months. Insomnia (87.0%) and rapidly progressive dementia (RPD; 83.2%) occurred with the highest frequency. Hypertension (33.6%) was considered to be an objective indicator of autonomic dysfunction. Genotype frequency at codon 129 was Met/Met (84.7%) and Met/Val (15.3%), and allele frequency was Met (92.4%) and Val (7.6%).129 Met was a risk factor (OR: 3.728, 95% CI: 2.194 to 6.333, p=0.000) for FFI in the non-Asian population. Comparison of Asians and non-Asians revealed clinical symptoms and genetic background to show some differences (p<0.05). In the comparison of 129 polymorphisms, a longer disease duration was found in the 129 MV group, with alleviation of some clinical symptoms (p<0.05). After considering survival probability, significant differences in survival time between genotypes remained (p<0.0001).ConclusionsInsomnia, RPD and hypertension are representative key clinical presentations of FFI. Phenotypic variations in genotypes and geographic regions were documented. Prion protein gene 129 Met was considered to be a risk factor for FFI in the non-Asian population, and 129 polymorphisms could modify survival duration.

Defining the Prion Type of Fatal Familial Insomnia

Fatal familial insomnia (FFI) belongs to the genetic human transmissible spongiform encephalopathies (TSE), such as genetic Creutzfeldt-Jakob disease (CJD) or Gerstmann-Straeussler-Scheinker syndrome (GSS). Here, we analyzed the properties of the pathological prion protein in six FFI cases by Western blot analysis, a protein aggregate stability assay, and aggregate deposition characteristics visualized with the paraffin-embedded tissue blot. While in all cases the unglycosylated fragment in Western blot analysis shared the same size with sporadic CJD prion type 2, the reticular/synaptic deposition pattern of the prion aggregates resembled the ones found in sporadic CJD type 1 (CJD types according to the Parchi classification from 1999). Regarding the conformational stability against denaturation with GdnHCl, FFI prion aggregates resembled CJD type 1 more than type 2. Our results suggest that the size of the proteinase-K-resistant fragments is not a valid criterion on its own. Additional criteria supplying information about conformational differences or similarities need to be taken into account. FFI may resemble a prion type with its own conformation sharing properties partly with type 1 and type 2 prions.

P023 Quantitative EEG analysis of polysomnography in a case of Fatal Familial Insomnia

Purpose To report on quantitative electroencephalograph (EEG) activity during polysomnography (PSG) in a rare case of confirmed Fatal Familial Insomnia (FFI). Methods Sleep/wake characteristics of a 32-year-old male patient were quantitatively analysed using central EEG recordings during two PSGs (FFI-1 and FFI-2) first, for investigation of insomnia and PLMS but with no suspicion of FFI and second, 120 days later with suspected but unconfirmed FFI at the time; 89 days prior to death. PSG metrics; absolute EEG power in specified frequency bands; EEG slowing ratio of slow-to-fast frequencies ((delta + theta)/ (alpha + sigma + beta)); and sleep spindle density were calculated. Results were compared with gender and age-matched insomnia and healthy controls (two of each). Results FFI-1 and FFI-2 PSGs revealed total time in bed of 413.5 and 392 minutes, total sleep times of 208.5 and 7.5 minute, including NREM 153.0 and 2.5 minutes, and REM 55.5 and 5.0 minutes, respectively. FFI-1 had approximately 1.5 times lower slow wave activity (SWA, 0.5–4.5Hz) during N3 than insomnia and controls.​ FFI-1 had 2 times and 1.8 times higher slowing ratio during REM than insomnia and controls, respectively. Spindle density (per minute of NREM sleep) for FFI-1 was 0.9, compared to pair-averages of 1.2 for insomnia disorder and 4.7 for healthy controls. Conclusions PSG in FFI revealed poor sleep efficiency that severely deteriorated with disease progression. Quantitative analysis of EEG revealed lower spindle density, lower SWA in N3, and higher slowing ratio in REM, when compared to insomnia patients and healthy sleepers.

Prion diseases: fatal familial insomnia

Introduction. Fatal familial insomnia (FFI) is one of the transmissible spongiform encephathalopathies characterized by neuronal loss, sleep impairment, subsequent non-specific disturbances of autonomic nervous system (e.g. tachycardia) and endocrine dysfunctions. It is fatal autosomal dominant prion disease, which is extremaly rare- FFI affects only about one person per milion annually. The aim of this study is to review the literature and systematize knowledge about fatal familial insomnia.Brief description of the state of knowledge. The causative agent of this disease is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. Major vulnerable regions in FFI are mediodorsal and anterior ventral nuclei of the thalamus. Average survival time after the onset of symptoms is 18 months. Hence molecular mechanisms involved in pathogenesis are poorly understood, the disease is incureable yet. However, there are a number of therapeutic options currently under investigation, e.g. immunotherapy or doxycycline usage.Conclusions. Subsequent researches are essential to improve understending of fatal familial insomnia. The prime issue is to develop functioning therapeutic or preventive treatment. While some of presented terapeutic approches appers promising, all of them require profoud research.

Insomnia as a benign presentation of fatal familial insomnia (FFI). A case report from Malaysia

Fatal familial insomnia (FFI) is an extremely rare autosomal dominant prion disease. The chief clinical features include an organic sleep disorder associated with sympathetic overdrive, motor and bulbar compromise as well as progressive cognitive decline. Death ensures in 100% of cases with a mean survival duration of 18 months from time of symptom onset. Treatment strategies in the management of FFI remains largely symptomatic with greater emphasis placed on palliative care services. We report a case of a 31-year old gentleman (Mr G) who presented with insomnia, sleep behavior disturbances, diplopia, myoclonus and transient global amnesia. A family history of a paternal aunt with similar presentation who passed away raised the suspicion of probable FFI, which was subsequently confirmed by genetic testing. Mr G is the first reported definitive FFI case of Malaysian Chinese descent. Standard MRI imaging and CSF analyses are insufficient in the workup of an individual with probable FFI. PET scan, polysomnogram and genetic studies are required for cases with high index of suspicion. In view of the rapid progression of the disease with significant cognitive impairment within months of symptom onset, we advocate for early diagnosis and a biopsychosocial patient-centered treatment approach.

PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

Background:Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).Methods:In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.Results:All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.Conclusions:Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.Funding:This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).