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@ARTICLE{DaSilvaCorreia:281793,
      author       = {Da Silva Correia, Angela and Laginha, Ines and Guimaraes,
                      Susana and Dittmar, Kathrin and Schmitz, Matthias and
                      Castilla, Joaquin and Zerr, Inga and Silva-Correia, Susana},
      title        = {{P}edigree analysis and genetic inheritance of fatal
                      familial insomnia ({FFI}) in a {P}ortuguese
                      multigenerational family.},
      journal      = {Journal of neurology},
      volume       = {272},
      number       = {10},
      issn         = {0367-004X},
      address      = {[Darmstadt]},
      publisher    = {Steinkopff},
      reportid     = {DZNE-2025-01183},
      pages        = {706},
      year         = {2025},
      abstract     = {Fatal 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.},
      keywords     = {Humans / Insomnia, Fatal Familial: genetics / Insomnia,
                      Fatal Familial: physiopathology / Male / Middle Aged /
                      Portugal / Female / Pedigree / Adult / Prion Proteins:
                      genetics / Aged / Age of Onset / Disease Progression /
                      Extended Family / FFI (Other) / Fatal familial insomnia
                      (Other) / Portugal (Other) / PrPC (Other) / PrPSc (Other) /
                      Prion diseases (Other) / Prion Proteins (NLM Chemicals) /
                      PRNP protein, human (NLM Chemicals)},
      cin          = {AG Zerr},
      ddc          = {610},
      cid          = {I:(DE-2719)1440011-1},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41107634},
      pmc          = {pmc:PMC12534306},
      doi          = {10.1007/s00415-025-13432-2},
      url          = {https://pub.dzne.de/record/281793},
}