Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain

Amyloid. 2023 Jun;30(2):199-207. doi: 10.1080/13506129.2022.2142110. Epub 2022 Nov 7.


Background: The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain.

Methods: Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals.

Results: Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain.

Conclusions: Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.

Keywords: Amyloidosis; Glu89Lys; founder effect; hereditary ATTR; transthyretin.

MeSH terms

  • Amyloid Neuropathies, Familial* / epidemiology
  • Amyloid Neuropathies, Familial* / genetics
  • Heart
  • Humans
  • Phenotype
  • Prealbumin / genetics
  • Spain / epidemiology


  • Prealbumin

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related