# Pedigree analysis and genetic inheritance of fatal familial insomnia (FFI) in a Portuguese multigenerational family

## TL;DR

This study examines the genetic inheritance and clinical features of fatal familial insomnia in a Portuguese family across five generations.

## Contribution

The study provides a detailed pedigree analysis of FFI in a multigenerational family, revealing prolonged survival in some cases and potential early symptoms.

## Key findings

- The disease follows an autosomal-dominant inheritance pattern with a mean age of onset at 57 years.
- Approximately 33% of affected individuals survived longer than the typical disease duration.
- Prodromal symptoms such as pain, headaches, and behavioral changes were reported years before diagnosis.

## 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.

The online version contains supplementary material available at 10.1007/s00415-025-13432-2.