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000281793 041__ $$aEnglish
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000281793 1001_ $$00000-0003-1903-7172$$aDa Silva Correia, Angela$$b0
000281793 245__ $$aPedigree analysis and genetic inheritance of fatal familial insomnia (FFI) in a Portuguese multigenerational family.
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000281793 520__ $$aFatal familial insomnia (FFI) is a rare, autosomal dominant prion disease caused by a mutation in the PRNP gene, leading to the misfolding of the cellular prion protein (PrPC) into its pathogenic form (PrPSc). This results in neurodegeneration, particularly in the thalamus, a key region regulating sleep-wake cycles, which underlies the hallmark symptoms of FFI, including insomnia, autonomic dysfunctions, motor disturbances and cognitive decline. This study focuses on a Portuguese family with FFI, providing a detailed pedigree analysis spanning five generations and comprising 134 individuals, to elucidate inheritance patterns, disease onset, and clinical progression. The findings confirm the autosomal-dominant inheritance pattern and a strong familial clustering of the disease with age of onset in the late 50s (mean 57 years). Although 67% of affected individuals succumbing to the disease within months to 1.5 years, a notably 33% exhibited prolonged survival beyond the typical disease duration, exceeding proportions reported in the literature. Family members retrospectively reported prodromal symptoms, including generalized pain, headaches, tinnitus, pruritus, and behavioral changes, occurring up to five years before diagnosis. In several cases, reportedly, disease onset was associated with major phycological stressors (e.g., emotional stress or mourning). While the significance of these observations remains uncertain, they may provide insights into potential early features in this kindred. Further research integrating genomic sequencing, biomarkers, and longitudinal clinical assessments are needed to better understand the mechanisms underlying the heterogeneity of FFI and to explore potential therapeutic interventions.
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000281793 650_7 $$2Other$$aFFI
000281793 650_7 $$2Other$$aFatal familial insomnia
000281793 650_7 $$2Other$$aPortugal
000281793 650_7 $$2Other$$aPrPC
000281793 650_7 $$2Other$$aPrPSc
000281793 650_7 $$2Other$$aPrion diseases
000281793 650_7 $$2NLM Chemicals$$aPrion Proteins
000281793 650_7 $$2NLM Chemicals$$aPRNP protein, human
000281793 650_2 $$2MeSH$$aHumans
000281793 650_2 $$2MeSH$$aInsomnia, Fatal Familial: genetics
000281793 650_2 $$2MeSH$$aInsomnia, Fatal Familial: physiopathology
000281793 650_2 $$2MeSH$$aMale
000281793 650_2 $$2MeSH$$aMiddle Aged
000281793 650_2 $$2MeSH$$aPortugal
000281793 650_2 $$2MeSH$$aFemale
000281793 650_2 $$2MeSH$$aPedigree
000281793 650_2 $$2MeSH$$aAdult
000281793 650_2 $$2MeSH$$aPrion Proteins: genetics
000281793 650_2 $$2MeSH$$aAged
000281793 650_2 $$2MeSH$$aAge of Onset
000281793 650_2 $$2MeSH$$aDisease Progression
000281793 650_2 $$2MeSH$$aExtended Family
000281793 7001_ $$0P:(DE-HGF)0$$aLaginha, Ines$$b1$$eFirst author
000281793 7001_ $$aGuimaraes, Susana$$b2
000281793 7001_ $$0P:(DE-2719)2811355$$aDittmar, Kathrin$$b3
000281793 7001_ $$0P:(DE-2719)9000287$$aSchmitz, Matthias$$b4$$udzne
000281793 7001_ $$aCastilla, Joaquin$$b5
000281793 7001_ $$0P:(DE-2719)2000058$$aZerr, Inga$$b6$$eLast author$$udzne
000281793 7001_ $$0P:(DE-2719)9000766$$aSilva-Correia, Susana$$b7$$eLast author$$udzne
000281793 773__ $$0PERI:(DE-600)1421299-7$$a10.1007/s00415-025-13432-2$$gVol. 272, no. 10, p. 706$$n10$$p706$$tJournal of neurology$$v272$$x0367-004X$$y2025
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