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

Abstract

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.

A case of rapidly progressive insomnia and dysautonomia

“…5 In Asians diagnosed with FFI, neuropsychiatric symptoms, dysautonomia and sleep apnoea are more common than in non-Asians. 6 This patient's abrupt disease course is consistent with that described in an FFI cohort, where death occurred on average 13 months from disease onset. 6 Certain differential diagnoses of rapidly progressive, early-onset dementia should be considered, including sporadic Creutzfeldt-Jakob disease (CJD).…”

“…6 This patient's abrupt disease course is consistent with that described in an FFI cohort, where death occurred on average 13 months from disease onset. 6 Certain differential diagnoses of rapidly progressive, early-onset dementia should be considered, including sporadic Creutzfeldt-Jakob disease (CJD). As with FFI, sporadic CJD can also be associated with the PRNP variant D178N, but in the latter, valine instead of methionine is found at codon 129.…”

Amino Acid Substitution within Seven-Octapeptide Repeat Insertions in the Prion Protein Gene Associated with Short-Term Course

“…However, the effect of codon 129 polymorphism on the age of onset and duration of disease varies among PrDs. For example, V carriers with sCJD are typically younger patients with a longer disease course [ 26 ], V carriers with FFI have a longer disease course, and gCJD patients with the V genotype have an earlier onset [ 27 , 28 , 29 ]. Among OPRIs patients, however, V carriers tend to experience a later onset and shorter disease duration [ 5 , 30 ].…”

Proposal of new diagnostic criteria for fatal familial insomnia

“…Human prion diseases are a group of fatal progressive neurodegenerative disorders with various manifestations caused by the presence of scrapie-like prion protein, and encompass Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann–Sträussler–Scheinker syndrome (GSS) [ 1 – 3 ]. FFI is an autosomal dominant inherited disease, characterized by sleep-related, neuropsychiatric, and progressive sympathetic symptoms, with genetic analysis as a gold standard [ 4 – 6 ]. However, clinically early recognition and diagnosis of FFI remains difficult because of the incomplete penetrance, high clinical heterogeneity, no specificity of auxiliary examinations, and overlapping clinical profile with other prion diseases such as CJD and GSS [ 7 , 8 ].…”