Clinical features, pathophysiology and management of fatal familial insomnia

ABSTRACT

Introduction: Fatal Familial Insomnia (FFI) is an inherited prion disorder caused by a point mutation at codon 178 of the PRNP gene, resulting in aspartic acid to asparagine substitution (D178N) in coupling phase with methionine at position 129. The disease is associated with sleep alterations, autonomic dysfunctions, loss of weight and motor signs. After symptoms onset, the disease usually leads to death within 2 years and no treatments are available at present.

Areas covered: This review focuses on classical and innovative aspects of FFI, with special emphasis on recent indications that infectious prion are not only confined to the central nervous system but can be detected in peripheral tissues of diseased patients.

Expert opinion: Although FFI can be genetically diagnosed, the ability of innovative techniques to specifically detect minute amount of infectious prion in peripheral tissues (such as the olfactory mucosa) is of fundamental importance for disease monitoring and to evaluate the efficacy of specific treatments to interfere with disease progression. Overall, the ability of these techniques to mimic the process of prion propagation in vitro can be exploited to perform preliminary high throughput screenings of compounds in order to select the most effective for FFI treatment.

KEYWORDS:

• FFI
• doxycycline
• prion
• PMCA
• neurodegeneration

Article highlights

• Fatal Familial Insomnia is a genetic prion disease caused by a mutation at codon 178 of PRNP gene (D178N). Polymorphisms at codon 129 (methionine/valine) significantly influence the clinical phenotype of the disease.

• There are no instrumental (MRI, CT) or laboratory tests able to show alterations specifically associated with FFI. Only PET scans might highlight early hypomethabolism (13-21 months before disease onset) in the thalamus of D178N carriers.

• Ultrastructural studies revealed the presence of alterations (TVS) in bioptic samples of frontal cortex of FFI patients, although the majority of neuropathological changes are mainly confined to the thalamus.

• Innovative techniques (RT-QuIC and PMCA) revealed that infectious PrP^Sc can be detected in the olfactory mucosa of FFI patients, thus confirming that a disease-specific biomarker circulates in peripheral tissues and can be used to monitor disease progression, especially for patients under pharmacological treatment.

• High throughput screening of specific compounds able to interfere with the process of FFI-PrP^Sc propagation in vitro can be performed by means of RT-QuIC and PMCA.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.