| Domain | Evidence-backed finding | Suggested ontology terms/identifiers | Evidence type/strength |
|---|---|---|---|
| Disease entity | Fatal familial insomnia (FFI) is an ultra-rare inherited human prion disease with insomnia, dysautonomia, progressive neurologic decline, and death typically within months after onset (pqac-00000000, pqac-00000001, pqac-00000004) | Disease label: Fatal familial insomnia; MONDO: curator verification needed; OMIM: curator verification needed; Orphanet: curator verification needed; MeSH/ICD: curator verification needed | Human clinical/review; moderate-strong |
| Causal gene/variant | Core causal genotype is germline PRNP p.Asp178Asn (D178N) in cis with methionine at codon 129 on the mutant allele; autosomal dominant inheritance (pqac-00000001, pqac-00000003, pqac-00000004) | PRNP (HGNC: curator verification needed); sequence variant: p.Asp178Asn / D178N; codon 129 Met on mutant allele; inheritance: autosomal dominant | Human genetic; strong |
| Penetrance/risk | Penetrance is described as very high; one large Italian kindred report summarized ~95% penetrance with 46 cases and 2 apparent non-penetrant individuals (pqac-00000000) | Inheritance annotation: age-dependent/high penetrance; family history present in many kindreds | Human family data; moderate |
| Onset/natural history | Age at onset is highly variable, reported from 19-76 years; average around 51 years; typical disease duration ~6-36 months after symptom onset (pqac-00000001, pqac-00000003) | HPO: Adult onset; Progressive neurologic deterioration; Reduced lifespan; Fatal outcome | Human cohort/review; strong |
| Genetic modifiers | Codon 129 on the non-mutated allele modifies phenotype but does not fully predict onset; WES study identified candidate modifier loci NR1H5P, GNA13P1, EXOC1L, SRSF11, MSANTD3 associated with later onset (pqac-00000001, pqac-00000005, pqac-00000006) | Modifier genes: NR1H5P, GNA13P1, EXOC1L, SRSF11, MSANTD3; note: provisional disease modifiers | Human exploratory genomics; preliminary-moderate |
| Core phenotypes | Hallmark manifestations include progressive insomnia/sleep loss, altered sleep-wake rhythm, autonomic dysfunction, dementia/cognitive decline, and motor signs (pqac-00000000, pqac-00000001, pqac-00000004) | HPO labels: Insomnia; Sleep disturbance; Abnormality of circadian rhythm; Autonomic nervous system dysfunction; Dementia; Cognitive impairment; Gait disturbance; Ataxia/parkinsonism/motor signs (IDs for curator verification) | Human clinical/review; strong |
| Phenotype severity/course | Disease course is progressive, severe, and usually fatal without remission; symptom heterogeneity is substantial even among patients sharing the same PRNP core genotype (pqac-00000001, pqac-00000006) | HPO labels: Progressive neurologic deterioration; Variable expressivity; Lethal phenotype | Human cohort/review; strong |
| Primary anatomy | Selective vulnerability centers on thalamus, especially anterior and dorsomedial/mediodorsal thalamic nuclei; additional involvement includes inferior olive and entorhinal cortex (pqac-00000000, pqac-00000001) | UBERON labels: thalamus; mediodorsal thalamic nucleus; anterior thalamic nuclei; inferior olivary nucleus; entorhinal cortex (IDs for curator verification) | Human neuropathology; strong |
| Tissue pathology | Neuropathology features severe neuronal loss/depletion, astrocytic gliosis/astrogliosis, and pathologic prion protein deposition in vulnerable regions (pqac-00000000, pqac-00000001) | GO/pathology labels: neuron death; astrocyte activation; protein aggregation; prion protein amyloid formation; CL: neuron, astrocyte | Human neuropathology; strong |
| Cell types implicated | Disease mechanisms and omics literature implicate neurons and astrocytes; experimental translatome work also highlights GABAergic and glutamatergic neuronal populations (pqac-00000005, pqac-00000006) | CL labels: neuron; astrocyte; GABAergic neuron; glutamatergic neuron (IDs for curator verification) | Human omics + animal model/review; moderate |
| Molecular mechanism | Pathogenesis is consistent with prion protein misfolding/conformational conversion leading to selective neurodegeneration, sleep/autonomic network failure, and downstream apoptotic/cellular stress pathways (pqac-00000000, pqac-00000001, pqac-00000005) | GO labels: protein misfolding; amyloid fibril formation; programmed cell death; caspase-mediated cleavage; regulation of circadian rhythm | Human genetics/neuropathology + experimental support; moderate-strong |
| Cellular processes | Candidate pathways include programmed cell death, apoptotic cleavage/caspase-mediated processes, proteostasis disruption, cytoskeletal injury, circadian dysregulation, and mitochondrial/ribosomal decline (pqac-00000005, pqac-00000006) | GO labels: apoptotic process; caspase-mediated cleavage; cytoskeleton organization; circadian rhythm; mitochondrial organization; ribosome biogenesis/translation | Human WES pathway analysis + animal translatome; moderate |
| Subcellular compartments | Omics/translatome evidence points to mitochondrial and ribosomal/translation machinery abnormalities early in disease-related responses (pqac-00000005, pqac-00000006) | GO cellular component labels: mitochondrion; ribosome; cytoskeleton (IDs for curator verification) | Human pathway inference + animal translatome; moderate |
| Proteomics/omics | Human prion-disease brain proteomics found broad terminal-stage protein changes with shared pathways across FFI and other prion diseases, including oxidative phosphorylation, lysosome, protein export, and drug metabolism pathways (context from retrieved literature summarized alongside FFI-specific evidence) (pqac-00000001) | GO/Pathway labels: oxidative phosphorylation; lysosome; protein export | Human tissue proteomics; limited-direct FFI specificity |
| Diagnostic approach | Diagnosis is centered on clinical syndrome plus confirmatory PRNP testing; in at-risk or symptomatic subjects, longitudinal neurologic exam, neuropsychology, laboratory studies, and polysomnography are used in research/monitoring settings (pqac-00000008, pqac-00000004) | MAXO labels: genetic testing; neurologic examination; neuropsychological assessment; polysomnography; laboratory monitoring | Human clinical trial protocol/review; moderate |
| Biomarkers | Plasma neurofilament light chain is cited as a biomarker in FFI-related literature, but quantitative performance was not available in the retrieved evidence here (pqac-00000007) | Biomarker label: neurofilament light chain; specimen: plasma | Human biomarker citation in recent literature; limited in current evidence set |
| Imaging/electrophysiology | Sleep studies/polysomnography are important in FFI evaluation; thalamic functional abnormalities are central, but specific sensitivity/specificity values for PSG, EEG, MRI, or FDG-PET were not available in the retrieved evidence here (pqac-00000008) | MAXO labels: polysomnography; electroencephalography; brain MRI; FDG-PET (IDs for curator verification) | Human clinical context; limited-direct quantitative evidence |
| Supportive treatment | No curative therapy is established; care is mainly palliative/supportive, targeting neurologic, sleep, and autonomic complications (pqac-00000004) | MAXO labels: palliative care; supportive care; symptom management; autonomic monitoring | Human clinical/review; strong for absence of cure |
| Investigational drug therapy | Doxycycline has been tested as preventive/repurposed therapy in at-risk carriers due to anti-prion and neuroprotective rationale; 10 D178N carriers received 100 mg/day in the DOXIFF protocol (pqac-00000000, pqac-00000002, pqac-00000008) | CHEBI/drug label: doxycycline; MAXO labels: preventive pharmacotherapy; oral antibiotic repurposing; clinical trial participation | Human trial protocol + preclinical rationale; moderate |
| Doxycycline trial design | DOXIFF enrolled 10 carriers (ages 44-53) on doxycycline and 15 non-carriers on placebo, with 10-year follow-up and blinded assessments; trial lacked validated surrogate biomarkers and relied on historical comparison (pqac-00000002, pqac-00000008) | Trial ID: EudraCT 2010-022233-28; MAXO labels: longitudinal surveillance; preventive treatment trial | Human interventional protocol; moderate |
| Current clinical trials | Broader genetic-prion/PRNP-lowering trials now recruiting may be relevant to FFI families, including ION717 (NCT06153966, phase 1/2), PrP-targeting siRNA safety/mechanism study (NCT07444580, phase 1), and observational biomarker/natural-history studies (NCT05124392, NCT05746715, NCT07732608) | ClinicalTrials.gov IDs: NCT06153966; NCT07444580; NCT05124392; NCT05746715; NCT07732608 | Trial registry evidence; strong for existence/status, limited for efficacy |
| Prevention/genetic counseling | For this Mendelian disease, prevention is mainly family-based risk assessment, predictive PRNP testing in appropriate counseling settings, and potential enrollment in surveillance/prevention studies (pqac-00000002, pqac-00000004) | MAXO labels: genetic counseling; predictive genetic testing; cascade testing; clinical surveillance | Human clinical/research practice; moderate |
| Model organisms | Mouse models carrying FFI-associated PRNP mutations and prion-disease translatome systems are used to study selective vulnerability, early cell-type responses, and therapeutic hypotheses, but they may incompletely capture the full human sleep/autonomic syndrome (pqac-00000006) | Model labels: PRNP D178N/129M knock-in mouse (curator verification needed); CL labels: astrocyte, GABAergic neuron, glutamatergic neuron | Animal model; moderate with translational limitations |
| Evidence gaps | Important gaps in the currently retrieved evidence set: verified ontology numeric IDs; robust prevalence/incidence estimates specific to FFI; test sensitivity/specificity for PSG/EEG/MRI/PET/RT-QuIC in FFI; validated prognostic biomarkers; controlled efficacy data for any disease-modifying therapy; nonhuman natural disease analogs (pqac-00000004, pqac-00000006, pqac-00000008) | Curator action items: verify MONDO/OMIM/Orphanet/MeSH/ICD IDs; add PMID-linked diagnostic accuracy and epidemiology sources | Evidence synthesis; strong for gap identification |


*Table: This compact table summarizes evidence-backed findings for fatal familial insomnia in a knowledge-base-ready format, including genetics, phenotypes, anatomy, mechanisms, diagnostics, treatment, and evidence gaps. It also flags ontology identifiers that should be curator-verified rather than inferred.*