Spanish centers following up patients with ATTRv amyloidosis were invited to participate in this longitudinal cohort study. The inclusion criteria included patients diagnosed with ATTRv amyloidosis who were confirmed carriers of the p.Val142Ile TTR variant. Relatives carrying the same variant were identified through cascade screening and were also included, regardless of their phenotype. Genetic analysis was conducted either at the participating centers or at accredited genetic laboratories, using next-generation sequencing or Sanger sequencing techniques. The study complies with the ethical principles outlined in the Declaration of Helsinki and was approved by the ethics committee of Hospital Universitari de Bellvitge (PR115/23). Written informed consent was waived by the committee.

The authors from each participating center ensured the integrity and accuracy of the data collected.

Data were retrieved from medical records and anonymized by each participating center. The dataset included demographics and family history, with a particular focus on participants’ birthplaces and the geographical origins of their ancestors. Signs and symptoms related to ATTRv amyloidosis were recorded at both the initial and final evaluations, with an emphasis on cardiac, neurological, and ophthalmologic features.

The onset of cardiac involvement was defined as the first documentation of left ventricular hypertrophy (maximal wall thickness ≥ 12mm) or grade 2 or 3 cardiac uptake on bone scintigraphy. Neurological involvement was defined as the appearance of signs or symptoms related to ATTRv amyloidosis, along with abnormal neurological test results (nerve conduction study or sympathetic skin response) and associated signs. Ophthalmologic involvement was defined as vitreous opacities, as previously described.13 Data from complementary tests, such as electrocardiograms (ECGs), laboratory tests, bone scintigraphy, echocardiography, and nerve conduction studies, were also included when available. Information on the initiation of disease-modifying therapies for ATTRv amyloidosis was also collected. Clinical events recorded during follow-up included stroke or transient ischemic attacks, pacemaker or implantable cardioverter-defibrillator implantation, atrial fibrillation (AF), heart failure (HF) hospitalizations, heart transplantation, liver transplantation, or death.

Penetrance from birth was estimated based on the phenotypic expression of cardiac or neurological involvement and was compared according to sex. Overall mortality was analyzed from the time of ATTRv diagnosis. Disease progression at 1 year was defined as a significant increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (absolute increase >700 ng/L and relative percentage increase >30.0%) or outpatient diuretic intensification, as outlined in a recently validated progression assessment tool published by Ioannou et al.14 A combined endpoint of cardiovascular-related death or disease progression was analyzed among patients who initiated treatment with Tafamidis. A post hoc analysis was conducted to compare new cases diagnosed with p.Val50Met and p.Val142Ile during the periods 2010 to 2014 and 2015 to 2019 in Spain. This analysis was based on data previously published from a multicenter Spanish registry to identify temporal trends.11

The population allele frequency in Spain was analyzed by accessing 2 population databases. First, the Spanish National DNA Bank-Carlos III, which contains 3400 samples from healthy individuals representative of the Spanish population, analyzed using 2 different chips: the Infinium Global Screening Array (Illumina Platform) (n=1000) and the Axiom Spanish BioBank array (Affymetrix Platform, Thermo Fisher Scientific) (n=3400). Second, the Catalan Biobank GCAT, which includes samples from 19 267 volunteers aged between 40 and 65 years old, recruited between 2014 and 2017 in Catalonia. Of these, 790 samples have undergone whole-genome sequencing at an overall coverage of 30 X, using paired-end sequencing by synthesis on a HiSeq 4000 sequencer (Illumina, USA).15 In addition, the birth province of probands was described and adjusted based on the current population born in Spain for each province, as extracted from the 2022 Spanish National Statistics Institute (Instituto Nacional de Estadística, INE).

Data for quantitative variables are presented as mean±standard deviation or as median [P25-P75] for variables with a nonnormal distribution, as assessed by the Shapiro-Wilk test. Qualitative variables are presented as No. (%). The Student t-test was used to compare continuous variables with a normal distribution, while the nonparametric Wilcoxon (Mann-Whitney) rank-sum test was applied to variables that did not follow a normal distribution. For categorical variables, comparisons between groups were made using either the parametric chi-square test or the nonparametric Fisher exact test, depending on the data characteristics. Kaplan-Meier survival analysis was used to describe penetrance and survival.

All analyses were performed using STATA software version 15.1 (StataCorp, College Station, USA). A 2-tailed P value <.05 was considered statistically significant.

Information was collected from 177 participants with the p.Val142Ile TTR variant at 16 Spanish centers. Two referral centers for ATTRv located in Northwest Spain (Complexo Hospitalario Universitario de A Coruña and Hospital Universitario Central Asturias) were contacted but reported no cases. Patients included by each participating center and additional investigators are listed in supplementary data 1 and 2.

Among the 177 participants, 4 cases were excluded due to insufficient data to establish phenotypic involvement, and 9 cases were excluded due to duplicate inclusion by 2 centers. The final cohort comprised 164 participants, including 75 probands (45.7%) and 89 relatives (54.3%) (supplementary data 3). All patients were heterozygous, except for one case who was homozygous for the p.Val142Ile variant. Notably, the parents of this homozygous individual were nonconsanguineous and originated from different provinces.

The most frequent reason leading to ATTRv diagnosis was cardiac symptoms (n=64; 85.3%), followed by incidental findings (n=8; 10.7%) and neurological symptoms (n=3; 4.0%). Figure 1 shows the number of new cases diagnosed over time, with a significant increase (P<.001) in recent years, in most cases as probands. This finding was further supported by data extracted from a previous Spanish registry, showing a 5.88% increase in the diagnosis of p.Val50Met between 2015 and 2019 compared with the 2010 to 2014 period, in contrast with a 466.67% increase in p.Val142Ile in the same period (supplementary data 4).

Figure 1.

New cases of transthyretin amyloidosis with an autosomal dominant inheritance pattern caused by the Val142Ile variant diagnosed over time in Spain.

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The main characteristics of all individuals at the initial evaluation are listed in table 1. Among probands, the mean age at diagnosis was 73.9±8.5 years (median, 76.0 [IQR 68.8-78.9]) and 47 (62.7%) were male. A total of 67 probands (89.3%) self-reported having European ancestry, while only 6 individuals (8%) reported African or Afro-American ancestry. Isolated cardiomyopathy was observed in 68.0% (n=51) of probands, followed by 24.0% (n=18) of participants with mixed neurological and cardiac involvement. Three probands (4.0%) had isolated neuropathy at disease onset.

Relatives identified through cascade screening had a mean age of 53.0±12.3 years, and 49 (55.1%) were female. After evaluation, 93.3% of relatives (n=83) were defined as healthy carriers, whereas 4.5% (N=4) had isolated cardiomyopathy and 2.3% (n=2) had mixed neurological and cardiac involvement. Overall, cardiomyopathy was characterized by advanced New York Heart Association (II or higher) in 67.1% (n=51) of cases. The mean NT-proBNP level was 3798±3627 pg/mL, and high cardiac uptake at scintigraphy (Perugini Grade 3) was observed in 93.2% of cases (n=69). Among patients with neurological involvement, 70.8% (n=17) had a polyneuropathy disability score of I, and the mean nerve impairment score was 10.7±9.0.

The median follow-up was 2.6 years [IQR 1.5-4.1] from the first evaluation in all individuals, while 2 patients (1.2%) were lost to follow-up or were evaluated only once at participating centers. figure 2A displays the overall penetrance from birth, estimated at 11.9%, 43.8%, and 94.1% at ages 65, 75, and 85 years, respectively. Women had a later age of onset compared with men (log-rank test P=.03), as shown in figure 2B. Penetrance at 75 years was estimated at 48.5% for males and 36.9% for females. At final assessment, 41 cases (25.0%) had evidence of neuropathy, with a mean nerve impairment score of 9.1±10.4. Ophthalmologic involvement was observed in 3 cases (1.8%) at the last follow-up, with vitreous deposits identified in 2 of these cases.

Figure 2.

A: Overall phenotypic expression. B: Phenotypic expression according to sex.

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At the last follow-up, 30 individuals (18.5%) had died. The most frequent causes were HF (n=14; 46.7%), noncardiovascular causes (n=10; 33.3%), and sudden death (n=5; 16.7%). The median survival from diagnosis was estimated at 5.37 years (figure 3), and the median age of deceased individuals was 78.7 [72.9-83.6] years. Relevant clinical events are summarized in table 2. Notably, 31 carriers (19.1%) had a HF admission during follow-up. One patient underwent sequential heart and liver transplantation in 2011 at the age of 67 years.

Figure 3.

Overall survival from diagnosis transthyretin amyloidosis with an autosomal dominant inheritance pattern diagnosis.

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Among patients with cardiac involvement and available data to assess disease progression at 1 year from diagnosis (n=52), 31 patients (59.6%) showed disease progression. The most frequent cause was isolated diuretic intensification (n=12, 23.1%), followed by a combination of diuretic intensification and NT-proBNP increase (n=11, 21.2%) and isolated NT-proBNP increase (n=8, 15.4%).

Tafamidis was initiated in 38 patients during follow-up, with 28 patients (73.7%) receiving 20mg and 10 patients (26.3%) receiving 61mg, due to neurologic or cardiac/mixed involvement. After 1 year of treatment, 14 patients (38.9%) met the combined endpoint, with 12 cases attributed to disease progression and 2 cases to cardiovascular death. One patient died due to extracardiac causes (meningitis), and another had insufficient information about disease progression; both were excluded from the analysis.

The birthplace of probands and participating centers is displayed in figure 4. Only 9 probands (12%) were born outside of Spain, while the remaining 66 probands (88%) were born in Spain. The province of birth of 1 participant born in Spain was unknown due to adoption. The overall prevalence of cases was 0.16 per 100 000 inhabitants in Spain, with significant differences between provinces (supplementary data 5 and 6). The prevalence reached 2.3 cases per 100 000 inhabitants in provinces like Cuenca and Salamanca. In contrast, no cases were reported in provinces of the Cantabrian basin (northwestern Spain), despite the participation of 3 centers from this region.

Figure 4.

Birthplace of probands, participating centers, and estimated population frequency.

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A query to the Spanish National DNA Bank returned no cases among the 3400 participants (prevalence 0.0%), whereas 1 case was identified among 790 participants in the Catalan Biobank GCAT (prevalence 0.12%). This case involved a 64-year-old woman with no previous history of ATTRv.

The findings of this study could translate into practical clinical recommendations. First, given that phenotypic expression was almost absent before the age of 50 years, reducing the screening frequency for heterozygous carriers of the Val142Ile variant until the age of 45 years might be advisable, particularly to minimize the use of costly or invasive tests. Furthermore, our findings suggest that the screening for ophthalmologic involvement in these cases has a very low diagnostic yield, supporting its omission unless symptoms appear.

This study has several limitations. As with all retrospective and observational studies, it is prone to selection bias. Additionally, diagnostic procedures and follow-up protocols may vary among participating centers. The ancestral origin of our cohort was inferred from birthplace and self-reported information provided by patients and treating physicians; however, no genetic testing was performed to confirm ancestry. Lastly, the assessment of response to disease-modifying therapies was constrained by the relatively short follow-up period.