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Does the clinical phenotype of fatal familial insomnia depend on PRNP codon 129 methionine-valine polymorphism?
Sven Rupprecht1, Alexander Grimm, Torsten Schultze
1Hans-Berger-Department of Neurology, Jena University Hospital, Germany ; Center for Sepsis Control and Care, Jena University Hospital, Germany.
Abstract:
Fatal familial insomnia (FFI) is a rare, hereditary prion-protein disease. Methionine-valine polymorphism at codon 129 of the prion-protein gene (PRNP) determines the phenotype in other hereditary prion-protein diseases, but association with the clinical phenotype in FFI remains uncertain. Early clinical findings in FFI comprise disturbances of the sleep-wake cycle and mild neuropsychiatric changes which typically emerge during middle to late adulthood. Here we describe an unusually early onset and rapid progression of FFI associated with dorsal midbrain involvement in a female patient with PRNP mutation at codon 178 and homozygote methionine polymorphism at codon 129. Early dorsal midbrain involvement became apparent by total loss of REM sleep and isolated bilateral trochlear nerve palsy. Early onset and rapid progression disease type associated with dorsal midbrain involvement may indicate a different spatiotemporal distribution of the neurodegenerative process in FFI patients with PRNP mutation and codon 129 methionine homozygosity compared to methioninevaline heterozygosity.
Insights
Fatal familial insomnia (FFI) is a rare prion disease. Early-onset FFI with methionine homozygosity may present with distinct neurological symptoms and faster progression, suggesting altered disease pathways.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Fatal familial insomnia (FFI) is a rare, autosomal dominant prion disease.
- The methionine-valine polymorphism at codon 129 of the prion-protein gene (PRNP) influences phenotypes in other prion diseases, but its role in FFI is unclear.
- Typical FFI onset occurs in middle to late adulthood with sleep disturbances and neuropsychiatric changes.
Observation:
- A case of unusually early-onset FFI with rapid progression is presented.
- The patient had a PRNP mutation at codon 178 and was homozygous for methionine at codon 129.
- Early signs included total loss of REM sleep and bilateral trochlear nerve palsy, indicating dorsal midbrain involvement.
Findings:
- Early-onset FFI associated with dorsal midbrain involvement was observed.
- This presentation occurred in a patient with PRNP codon 178 mutation and methionine homozygosity at codon 129.
- The findings suggest a different spatiotemporal progression of neurodegeneration in this specific genetic profile.
Implications:
- Early-onset FFI with dorsal midbrain involvement may represent a distinct subtype of the disease.
- Methionine homozygosity at PRNP codon 129 might be associated with a more aggressive and atypical FFI phenotype.
- Understanding these variations is crucial for diagnosing and potentially managing FFI, especially in early-onset cases.
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