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fatal familial insomnia (FFI) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

fatal familial insomnia

MONDO:0010808

Also known as:FFIInsomnia familial fatalInsomnia, fatal familial

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Overview

Fatal familial insomnia (FFI) is a very rare form of prion disease characterized by subacute onset of insomnia showing as a reduced overall sleep time, autonomic dysfunction, and motor disturbances.

GeneticsAutosomal dominant · PRNP (chr 20)

Clinical Trials1 registered · 1 recruiting

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Sudden, brief involuntary muscle jerks (myoclonus); and very common findings: Ataxia and Insomnia. 16 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	9	Difficulty swallowing (dysphagia), Dysarthria, Ataxia

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

PRNP function has not been fully characterized.

Fatal familial insomnia is associated with mutations in the PRNP gene on chromosome 20.

GeneReviews

Clinical Guidance

Although some PRNP pathogenic variants are associated with specific neuropathologic phenotypes , evidence also suggests that heterozygotes for the same variant in the same family may develop distinct clinicopathologic phenotypes . Note that the phenotype may be modified by the presence of the polymorphic codon 129 (p.Asp178Asn) on the same allele as the PRNP variant. The phenotype in individuals with the p.Asp178Asn pathogenic variant typically depends on which variant – Met129 or Val129 – is on the same allele as the PRNP variant. In general, the onset of genetic prion disease is earlier and its course shorter (11 months) in individuals homozygous for Met129 compared to either heterozygotes or homozygotes for Val129, in whom the phenotype is usually typical genetic CJD. See .

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Suggestive Findings

Genetic prion disease should be suspected in individuals with the following clinical, laboratory, and imaging findings and family history.

Clinical

Genetic prion disease is a progressive neurodegenerative syndrome with rapid evolution of clinical signs (which reflect involvement of various neuroanatomic structures) – typically, dementia in combination with the following developing within a few months or (rarely) a few years:

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for fatal familial insomnia. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with genetic prion disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Because of very rapid disease progression and short survival time after the diagnosis, evaluations for supportive care must be performed early. They include the following:

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Because of very rapid disease progression, close periodic monitoring by the multidisciplinary team is needed, typically every 14 days to evaluate need for treatment of symptoms.

Source: GeneReviews — "Genetic Prion Disease"

Phenotype severity distribution: 1 always present feature, 2 very common features.

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

1 clinical trial registered, 1 recruiting. Interventions under study include other interventions. Research is primarily sponsored by academic and government institutions.

29 publications have been identified in PubMed for fatal familial insomnia. Research spans Basic Science / Preclinical (38%), Case Report / Case Series (24%), and Epidemiology / Natural History (17%).

Research Type	Count	% of Total
Laboratory research	11	38%

Data assembled from 8 of 12 sources · Last updated Sep 19, 2026, 11:53 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:600072

Orphanet

European rare disease database

Orphanet:466

GARD

Genetic and Rare Diseases Info Center

GARD:6429

Questions for Your Care Team

→Are any of the 1 active clinical trial a good fit for my situation?
→Should I pursue genetic testing for PRNP, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Clinical Guidance

Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Strussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from ages 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome. provides information on the frequency of neurologic features in the most frequent genetic prion disease phenotypes that emerge during the disease course. While some PRNP pathogenic variants are associated with specific neuropathologic phenotypes, individuals in the same family who are heterozygous for the same PRNP variant may develop distinct clinicopathologic phenotypes . Table 2. Select Features of Genetic Prion Disease by Phenotype and PRNP Pathogenic Variant Feature | % of Persons w/Feature by Phenotype PRNP Variant

gCJD	FFI	GSS
Dementia	95%	92%
Ataxia	100%	100%
Myoclonus	85%	92%
Extrapyramidal	65%	92%
Pyramidal	70%	71%
Visual/Cortical blindness	70%	85%
Dysarthria	Yes	Yes
Sleep disturbances	Yes	Yes
Weight loss	Yes	Yes

Source: GeneReviews — "Genetic Prion Disease"

Kisho

fatal familial insomnia

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Clinical

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Penetrance

Laboratory

Differential Diagnosis

Treatment of Manifestations

Therapies Under Investigation

Clinical Trials

Recent Publications

Latest News & Developments

Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.

Interleukin-17A as a Potential Mediator in Inflammatory Mechanisms of Insomnia.

fatal familial insomnia

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Clinical

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Penetrance

Laboratory

Differential Diagnosis

Treatment of Manifestations

Therapies Under Investigation

Clinical Trials

Recent Publications

Latest News & Developments

Therapeutic potential of targeting the orexin (hypocretin) system in sleep disorders.

Interleukin-17A as a Potential Mediator in Inflammatory Mechanisms of Insomnia.