title: The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy.
abstract: BACKGROUND
  Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant.
  
  
  RESULTS
  This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and (99m)Tc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by (99m)Tc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%.
  
  
  CONCLUSIONS
  This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates.
authors.affiliation: Department of Cardiology, Angiology, and Respiratory Medicine, University Hospital Heidelberg , Heidelberg , Germany .
authors.forename: Ralf
authors.initials: R
authors.lastname: Bauer
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.forename: Andreas
authors.initials: A
authors.lastname: Brauer
authors.forename: Michael
authors.initials: M
authors.lastname: Kreuter
authors.forename: Sebastian
authors.initials: S
authors.lastname: Buss
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Schnabel
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.forename: Philipp
authors.initials: P
authors.lastname: Ehlermann
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Arnt V
authors.initials: AV
authors.lastname: Kristen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011228:Prealbumin / Q000235:genetics*
chemical_list: D011228:Prealbumin
keywords: Amyloidosis; cardiomyopathy; heart transplantation; pulmonary amyloidosis; transthyretin