Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain
Fernando de Frutos, Juan Pablo Ochoa, Cristina Gómez‐González, David Reyes‐Leiva, Juan I. Aróstegui, Carlos Casasnovas, Roberto Barriales‐Villa, Teresa Sevilla, Esther González-López, Elvira Ramil, Lucía Galán, José González‐Costello, Ana García‐Álvarez, Ricard Rojas‐García, María Ángeles Espinosa, Pablo García‐Pavía
Abstract
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.