Hereditary transthyretin amyloidosis caused by Val142Ile variant in Spain: phenotypic characteristics, geographic distribution and population frequency

Abstract Background During recent years, several cases of hereditary transthyretin amyloidosis (ATTRv) due to p.Val142Ile have been described in patients without African ancestry in countries like Japan, Spain or Italy (1,2,3,4). All this evidence suggests that p.Val142Ile might be more prevalent than expected worldwide. Objectives The aim of this study was to analyze the impact of ATTRv caused p.Val142Ile in Spain to define its phenotypic characteristics, to explore endemic geographical areas and define its population frequency. Methods Patients diagnosed with ATTRv caused by p.Val142Ile and carriers irrespective of their phenotype were recruited from 16 centers in Spain. Baseline characteristics and events during follow-up were retrieved. Population frequency was assessed through the Spanish National DNA bank (N=3,569) and the Catalan Health Databank (N=790). Results The cohort included information regarding 164 subjects (75 probands [45.7%] and 89 relatives [54.3%]). Among probands, mean age was 73.9 ± 8.5 years and 47 (62.7%) were males. 67 probands (89.3%) had self-declared European ancestry and only 6 cases (8%) referred African or Afro-American ancestry. Cardiac symptoms were the most frequent reason leading to ATTRv diagnosis (N=64, 85.3%) followed by incidental finding (N=8, 10.7%) and neurologic symptoms (N=3, 4%). (Figure 1). Median follow-up was 1.6 years (Interquartile range 0.6-3.2). Neurologic involvement was observed in 35 probands (46.7%) at first evaluation or during follow-up. Overall penetrance at 65, 75 and 85 years was 12.8%, 44.3% and 94.2% respectively. Male sex was associated with earlier penetrance than women (P = 0.02). 38 patients initiated treatment with tafamidis during follow-up (28 [73.7%] 20 mg and 10 [26.3%] 61 mg), despite treatment, disease progression at 1 year (cardiovascular death or 30% increase of NTProBNP) was observed in 10 patients (40%). Population frequency was estimated between 0.0% and 0.12% based on the Spanish and Catalan databases respectively. Birthplace of probands suggests a higher prevalence in the Mediterranean basin. (Figure 2) Conclusions Our data suggests that ATTRv caused by p.Val142Ile has a significant prevalence in Spain, mostly in some specific regions. Phenotypic features are defined by late onset, male predominance, and cardiac involvement although a significant proportion develop neuropathy. Disease progression was observed in 40% of patients despite disease-modifying therapies.