http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2015; 22(2): 123–131 ! 2015 Informa UK Ltd. DOI: 10.3109/13506129.2015.1019610
ORIGINAL ARTICLE
Hereditary ATTR amyloidosis: a single-institution experience with 266 patients Paul L. Swiecicki1, David B. Zhen1, Michelle L. Mauermann2, Robert A. Kyle3, Steven R. Zeldenrust3, Martha Grogan4, Angela Dispenzieri3, and Morie A. Gertz3 Department of Internal Medicine, 2Department of Neurology, 3Division of Hematology, and 4Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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1
Abstract
Keywords
Background: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, clinically heterogeneous disease due to heritable mutations that lead to misfolding of a precursor protein and multisystem disease. This study sought to define the clinical characteristics, distribution of mutations and phenotypic presentation of patients presenting to our center with hereditary ATTR amyloidosis. Methods: With institutional review board approval, the study retrospectively identified patients who had hereditary ATTR amyloidosis and presented to Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. Results: Of the 266 patients with the diagnosis of hereditary ATTR amyloidosis, a pathogenic mutation was identified in 206; the most common mutation was Thr60Ala (68 patients [25%]). Median age at diagnosis was 63.3 years; median survival after diagnosis was 56.8 months (10th– 90th percentile, 16.0–297.9). On multivariate analysis, age at diagnosis (risk ratio, 15.65; p50.0001), Thr60Ala mutation (risk ratio, 1.52; p ¼ 0.04), Val122Ile mutation (risk ratio, 2.83; p ¼ 0.003), peripheral neuropathy (risk ratio, 1.69; p ¼ 0.013) and weight loss (risk ratio, 1.81; p ¼ 0.002) were risk factors for death. Conclusion: Our data characterize the features of hereditary ATTR amyloidosis in a large cohort, demonstrate the heterogeneity among mutations and support the need to better characterize the clinical progression of individual mutations.
Cardiomyopathy, mutation, peripheral neuropathy, phenotype, transthyretin History Received 6 May 2014 Revised 26 January 2015 Accepted 11 February 2015 Published online 27 May 2015
Abbreviations: ATTR amyloidosis: transthyretin amyloidosis; ECG: electrocardiogram; E/A: ratio of early to late diastolic mitral inflow velocity; IVS: interventricular septum; LVMI: left ventricular mass index; NYHA: New York Heart Association; RFLP: restriction fragment length polymorphism; TTR: transthyretin
Introduction Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare autosomal dominant inherited disorder that involves systemic deposition of a mutated insoluble protein. First described in 1952, this disease involves a familial sensorimotor and autonomic neuropathy affecting many families in Northern Portugal [1]. This neuropathy was typically found to affect the longest nerves first, leading to the term lengthdependent neuropathy. Since its description in the Portuguese population, the disease has been identified as being endemic in other areas, including Japan and Sweden [2,3]. Although originally identified as being associated with a mutation of the transthyretin (TTR) gene, multiple other precursor
Address for correspondence: Morie A. Gertz, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected]
proteins have since been identified, including apolipoproteins A-I and A-II, fibrinogen, lysozyme and gelsolin. Currently, TTR mutations are the most common cause of hereditary amyloidosis, with over 100 TTR mutations identified worldwide and reports of clinically different phenotypes varying from predominantly cardiac to predominantly neurologic disease [4]. Descriptions of ATTR amyloidosis mutations in case reports and case series have provided much of our knowledge about the phenotypes, but there have been few comparative studies. Although numerous mutations have been identified in the USA, our understanding of their relevance in ATTR amyloidosis is limited by a lack of large identifiable pedigrees. Owing to the rarity and genetic heterogeneity of ATTR amyloidosis, a large study examining the natural history of ATTR amyloidosis and comparing mutation phenotypes has not been conducted in the USA. We sought to analyze all patients seen with hereditary ATTR amyloidosis at our
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institution to better elucidate the disease course, including incidence of family history, distribution of pathogenic mutations, predictors of mortality and the relation between genotype and phenotype.
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Methods The study was approved by the Mayo Clinic Institutional Review Board. All patients gave written, informed consent that allowed the use of their medical records for research purposes. Patients did not receive a stipend for involvement in this study. Analyses were conducted by an author (P.L.S.), and all authors had access to the primary data. We performed a retrospective cross-sectional study of all patients with a diagnosis of hereditary ATTR amyloidosis seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. During our analysis, we verified the diagnosis of hereditary ATTR amyloidosis from clinical symptoms, family history and genetic testing. Documentation of race was based on patient self-identification at the initial evaluation. This was assessed to analyze the differences in genotype distribution. All patients had tissue proof of amyloidosis, defined as green birefringence under polarized light with Congo red staining. No patients with wild-type ATTR amyloidosis were included in the analysis. Patients with non-ATTR amyloidosis were excluded because of the clinical variability in the disease course. This resulted in the exclusion of 19 patients: 6 were identified as having apo A–I; 3, gelsolin; 7, fibrinogen; 1, ALECT; 1, apo A-II; and 1, lysozyme. Three patients with TTR mutation were excluded because genetic testing results were not available and the patients had a clinical syndrome consistent with wild-type ATTR amyloidosis. Each of these patients presented at an age older than 70 years with isolated cardiomyopathy, thickened myocardium and no evidence of other organ or end organ involvement (i.e. peripheral neuropathy, autonomic neuropathy). Based on the judgment of the physician at the time of consultation and the study investigators, it was decided that the syndrome at the time of presentation was due to wildtype ATTR amyloidosis rather than hereditary ATTR amyloidosis. The method of mutation identification was known for 169 patients (Table 1). Methods used for TTR mutation identification included DNA sequencing (93 patients), restriction fragment length polymorphism (RFLP) analysis (64), mass spectrometry (5) and a family history of known pathogenic mutation (7). Family history was considered a method of
mutation identification when a patient with multiple family members affected by ATTR amyloidosis presented with similar symptoms and tissue proof of amyloidosis. In this situation, there was documentation that relatives had the same clinical phenotypes and underwent testing identifying the same mutation. For 37 patients, the method of mutation identification was unknown because it had been performed at another center before the patient was assessed at our facility. For 60 patients, the pathogenic mutation was unknown since testing had either not been performed or was performed before the current techniques of mass spectrometry and DNA sequencing without identification of the pathogenic mutation. We reviewed the clinical notes, laboratory evaluations and correspondence from other centers to elucidate the natural history of the disease. The chief complaint and symptoms were based on clinical documentation. The chief complaint was defined as the primary concern reported to the physician at the initial presentation. The diagnosis of autonomic neuropathy was based on documentation of symptoms and autonomic function testing when available. Symptoms included all clinical phenomena present at the initial consultation, such as abnormalities of sweating, orthostatic hypotension, gastrointestinal tract motility disorders and genitourinary tract disorders (impotence, urinary retention, etc.). The diagnosis of peripheral neuropathy was based on both clinical symptomatology and electromyographic data. Cardiomyopathy was assessed from symptoms (further characterized by New York Heart Association [NYHA] functional heart failure classification), non-invasive evaluations such as echocardiography and tissue diagnosis. If endomyocardial tissue diagnosis was not available, other causes of heart failure were excluded before attributing the cardiomyopathy to hereditary ATTR amyloidosis. Weight loss was defined as loss of more than 10% of body weight over the course of 1 year. Date of symptom onset was reported by the patient as the date when the ATTR amyloidosis-associated symptoms first occurred. Date of diagnosis was the date when the diagnosis of amyloidosis was confirmed histologically. Kaplan–Meier survival was calculated from the date of the original diagnosis to the date of death or the most recent contact. The Social Security Death Index was queried to ensure accurate mortality information for follow-up analyses. Because this study was retrospective in nature, clinical documentation and Social Security Death Index were used to ensure comprehensive follow-up information. Statistical analysis was performed with JMP Software (SAS Institute Inc., Cary, NC). Frequency
Table 1. Method of transthyretin mutation identification (n ¼ 206).
Mutation Thr60Ala Val30Met Val122Ile Ser77Tyr Other TTR
Mass spectrometry
Restriction fragment length polymorphism analysis
2 1 0 0 2
29 18 1 7 9
Unknown (performed elsewhere)
Known pathogenic mutation in first-degree family member
DNA sequencing
6 8 7 3 13
3 0 1 2 1
28 15 19 3 28
Hereditary ATTR amyloidosis
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(percentage) and summary statistics (median and range) were calculated to describe the patient population. Comparisons of discrete variables were examined with 2 testing and Wilcoxon tests for continuous variables. Log-rank testing was performed in analysis of Kaplan–Meier survival curves. The Cox proportional hazards model was used to identify factors associated with survival. p Values less than 0.05 were considered significant.
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Results We identified 266 patients with hereditary ATTR amyloidosis. Specific mutations were identified in 206 (77.4%) of these patients, all of whom were symptomatic. The majority of patients were male (212 patients [80%]). Of the identified mutations among patients with mutant TTR, the four most common were Thr60Ala (68 patients [26%]), Val30Met (42 patients [16%]), Val122Ile (28 patients [11%]) and Ser77Tyr (15 patients [6%]). Median follow-up of survivors (n ¼ 95) was 46 months (10th–90th percentile, 9.2–164.4 months). Table 2 summarizes the baseline demographics of the study population. The median time from symptom onset to diagnosis was 39.0 months (10th–90th percentile, 7.0–101.3 months). Further analysis showed that the median time from symptom onset to diagnosis varied by organ involvement at diagnosis: median time for patients with peripheral neuropathy was 41.5 months (10th–90th percentile, 12.7–112.2 months); for patients with autonomic neuropathy, 40.5 months (10th–90th percentile, 10.3–93.6 months) and for patients with cardiomyopathy, 38.7 months (10th–90th percentile, 5.4–103.4 months). Syndromes did not distribute evenly over time from symptoms to diagnosis. We divided patients into those with symptoms for more than 3 years and those with symptoms for less than 3 years. There was no difference in the frequency of cardiomyopathy or weight loss in early versus late diagnosis, but peripheral neuropathy (p ¼ 0.0008) and autonomic neuropathy (p ¼ 0.04) were weighted into the latediagnosis group. The frequency of a specific TTR mutation was borderline significant between the early and late diagnosis groups as well (p ¼ 0.04). Syndromes present at diagnosis among the entire cohort (N ¼ 266) were as follows: peripheral neuropathy, 186 patients (70%); autonomic neuropathy, 142 patients (53%); weight loss, 91 patients (34%) and cardiomyopathy, 161 patients (61%). We compared survival of patients who received a diagnosis before (n ¼ 49) or after (n ¼ 210) 1 January 1990; the median survivals were 68.2 and 55.5 months, respectively (p ¼ 0.84) (for 7 patients, the exact date of diagnosis was unknown). Figure 1 shows the symptoms present at diagnosis among patients grouped by TTR mutation. The most common chief complaint overall was peripheral neuropathy, although this varied significantly by mutation. Differences in the rates of peripheral neuropathy, autonomic neuropathy and cardiomyopathy were statistically significant between the mutations. Cardiomyopathy was present in 161 patients (61%) at diagnosis; prevalence was highest among patients with Val122Ile mutations (28 patients [100.0%]) and Thr60Ala mutations (56 patients [82.4%]). Among the patients with cardiomyopathy, the most common functional class at presentation was NYHA class I (42.7%), although distribution was
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statistically different between mutation groups. Among patients with cardiac amyloidosis, the NYHA class was I for 42.9%, II for 28.6%, III for 24.2% and IV for 4.3%. The respective median survivals were 48.0, 51.6, 45.7 and 28.8 months (p ¼ 0.38). Age at symptom onset is shown in Figure 2; of note, the oldest patients carried the Val122Ile mutation. For 23 of the 266 patients (8.6%), the onset of symptoms was after age 70. In this aged population, the mutation frequencies were as follows: Thr60Ala, 5 of 68 patients (7.4%); Val122Ile, 7 of 28 patients (25.0%); Ser77Tyr, 0 of 15 patients; and Val30Met, 9 of 42 patients (21.4%). Baseline results from cardiac studies are shown in Table 2. Patients with the Val122Ile mutation, compared with patients with other mutations, had the worst systolic function (median ejection fraction, 34%) and the worst diastolic function (median ratio of early to late diastolic mitral inflow velocity [E/A], 2.5). The two most common electrocardiogram (ECG) abnormalities were conduction block (defined as first-degree, seconddegree or complete heart block), which was present in 58 patients (27.5%), and a pseudoinfarction pattern, which was present in 51 patients (24.2%). Fifty-four patients received a liver transplant: 8 patients with Val30Met mutations, 13 with Thr60Ala, 2 with Val122Ile, 7 with Ser77Tyr, 18 with other mutations and 6 with unknown TTR mutations. Their median survival was 167 months. The median survival of the TTR patients who did not receive a transplant was 50.6 months (p50.0001). Figure 3(A) demonstrates the median age at death by mutation. Patients with Ser77Tyr died at the youngest age (65.4 years), while Val30Met patients died at a median age of 74.6 years. Figure 3(B) shows the Kaplan–Meier survival curve from the time of histologic diagnosis, by mutation; the shortest survival was for Val122Ile patients since all had cardiac involvement at diagnosis. Of the 266 patients, 172 (64.7%) have died. Eighteen patients have been lost to follow-up. On univariate analysis, age at diagnosis, Thr60Ala mutation, Val122Ile mutation, autonomic neuropathy, peripheral neuropathy, weight loss and cardiomyopathy at diagnosis were risk factors for early death. Table 3 summarizes the multivariate analysis results for correlations between survival time after diagnosis and various baseline patient characteristics. On multivariate analysis, age at diagnosis, Thr60Ala mutation, Val122Ile mutation, peripheral neuropathy and weight loss at diagnosis retained significance. In Supplemental Figure 1(A)– (D), Kaplan–Meier survival curves demonstrate the significant impact on overall survival associated with peripheral neuropathy (Supplemental Figure 1A), autonomic neuropathy (Supplemental Figure 1B), cardiomyopathy (Supplemental Figure 1C) and weight loss (Supplemental Figure 1D).
Discussion There are currently more than 100 described TTR mutations associated with ATTR amyloidosis, and patients vary in clinical presentation and disease progression by not only genotype but also geography. This study describes a large single-center experience with hereditary ATTR amyloidosis over 43 years and identifies the largest American cohort to date. In a previous article on a subset of this cohort, we described echocardiographic and survival characteristics of
Patients Male Race White Black Asian Unknown International Age at symptom onset, years Age at diagnosis, years Age at death, years Symptom onset to diagnosis, mo Survival, mo Family history of ATTR amyloidosis Chief complaint Peripheral neuropathy Autonomic neuropathy Cardiomyopathy Nephropathy Other Present at diagnosis Peripheral neuropathy Autonomic neuropathy Weight loss Cardiomyopathy NYHA classy I II III IV ECG findings Patients with ECG available Conduction blockz Low voltage Left atrial enlargement Pseudoinfarction pattern LV hypertrophy Right bundle branch block Left bundle branch block Normal ECG Echocardiogram findings Patients with echocardiogram available Ejection fraction 55% LV mass index (reference range, 43–115 g/m2), g/m2
Variable
Entire cohort
(51.4) (13.4) (26.4) (5.6) (3.2) (69.9) (53.4) (34.2) (60.6) (42.9) (28.6) (24.2) (4.3) (79.0) (27.5) (24.2) (4.7) (24.2) (3.3) (9.0) (6.2) (13.7)
146 38 75 16 9 186 142 91 161 69 46 39 7 211 58 51 10 51 7 19 13 29
(79.4) (33.3) (27.8) (0.0) (31.5) (7.4) (9.2) (5.6) (7.4)
(39.3) (35.7) (25.0) (0.0)
(64.7) (64.7) (39.7) (82.4)
(39.7) (22.1) (36.8) (0.0) (1.5)
(100) (0.0) (0.0) (0.0) (13.2) (50.1–67.9) (54.5–72.0) (57.9–75.4) (8.3–110.4) (14.3–66.7) (57.4)
62 (91.2) 52 (32–65) 167 (110–253)
54 18 15 0 17 4 5 3 4
22 20 14 0
44 44 27 56
27 15 25 0 1
68 0 0 0 9 60.2 64.5 67.6 41.5 38.6 39
68 52 (76.5)
Thr60Ala
(71.4) (30.0) (26.7) (3.3) (20.0) (3.3) (16.7) (10.0) (13.3)
(94.4) (5.6) (0.0) (0.0)
(95.2) (59.5) (26.2) (42.9)
(85.7) (7.1) (2.4) (2.4) (2.4)
(90.5) (2.4) (7.1) (0.0) (19.0) (44.2–73.1) (48.2–76.4) (52.8–83.0) (12.7–87.0) (11.6–95.0) (31.0)
37 (88.1) 64 (50–75) 160 (83–239)
30 9 8 1 6 1 5 3 4
17 1 0 0
40 25 11 18
36 3 1 1 1
38 1 3 0 8 64.3 67.8 74.7 60.3 42.0 13
42 36 (85.7)
Val30Met
(96.4) (37.0) (22.2) (22.2) (14.8) (3.7) (3.7) (7.4) (3.7)
(3.6) (35.7) (46.4) (14.3)
(29.6) (17.9) (29.6) (100)
(7.1) (3.6) (89.3) (0.0) (0.0)
(17.9) (75.0) (3.6) (3.6) (7.1) (49.5–74.7) (52.3–77.9) (62.8–80.9) (3.5–87.2) (2.2–90.7) (25.0)
27 (96.4) 34 (13–54) 178 (121–288)
27 10 6 6 4 1 1 2 1
1 10 13 4
8 5 8 28
2 1 25 0 0
5 21 1 1 2 63.7 69.0 72.9 28.2 25.6 7
28 27 (96.4)
Val122Ile
Ser77Tyr
(86.7) (23.1) (46.1) (7.7) (23.1) (0.0) (0.0) (15.4) (23.1)
(50.0) (20.0) (30.0) (0.0)
(100) (53.3) (66.7) (66.7)
(73.3) (6.7) (13.3) (0.0) (6.7)
(100) (0.0) (0.0) (0.0) (0.0) (40.1–63.2) (47.6–66.8) (55.7–71.2) (10.8–151.2) (27.4–157.7) (66.7)
13 (86.7) 49 (20–73) 176 (74–212)
13 3 6 1 3 0 0 2 3
5 2 3 0
15 8 10 10
11 1 2 0 1
15 0 0 0 0 55.8 60.1 65.8 38.6 47.9 10
15 12 (80.0)
Mutation
(90.6) (18.8) (20.8) (4.2) (18.8) (0.0) (4.2) (0.0) (18.8)
(45.2) (32.2) (16.1) (6.4)
(75.5) (56.6) (43.4) (58.5)
(56.6) (15.1) (20.7) (3.8) (3.8)
(75.5) (9.4) (11.3) (3.8) (13.2) (37.3–65.9) (39.7–68.7) (43.5–75.9) (4.9–109.2) (12.3–105.1) (62.3)
48 (90.6) 60 (22–73) 153 (83.8–256)
48 9 10 2 9 0 2 0 9
14 10 5 2
40 30 23 31
30 8 11 2 2
40 5 6 2 7 53.1 56.7 62.1 30.8 36.9 33
53 36 (67.9)
Other TTR mutations
(65) (23.1) (15.4) (0.0) (30.8) (2.6) (15.4) (7.7) (20.5)
(52.0) (20.0) (24.0) (4.0)
(78.3) (65.0) (30.0) (41.7)
(66.7) (15.0) (13.3) (5.0) (0.0)
(95.0) (1.7) (0.0) (3.3) (8.3) (34.3–70.4) (41.6–77.3) (52.8–83.8) (6.9–113.9) (13.8–168.4) (41.7)
35 (58.3) 59 (31–74) 166 (86–236)
39 9 6 0 12 1 6 3 8
13 5 6 1
47 39 18 25
40 9 8 3 0
57 1 0 2 5 59.1 62.3 70.9 42.2 53.7 25
60 48 (80.0)
Unknown
(continued )
0.001 0.5
0.54 0.36 0.002 0.47 0.29 0.13 0.14 0.13
0.0001 0.0007 0.07 0.0001 0.0001
0.20 0.0001 0.0001 0.0001 0.18 0.04 0.001 0.0001
0.04 50.0001
p Value
P. L. Swiecicki et al.
221 (82.8) 55 (30–72) 166 (97–245)
(83.8) (10.5) (3.8) (1.9) (11.7) (42.0–70.2) (46.0–73.8) (52.2–78.7) (7.0–101.3) (16.0–297.9) (47.7)
223 28 10 5 31 59.6 63.3 67.8 39.0 56.8 127
266 211 (79.3)
Table 2. Baseline characteristics and studies.*
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Hereditary ATTR amyloidosis Abbreviations: ATTR amyloidosis, transthyretin amyloidosis; e0 , early diastolic mitral annular velocity; E/A, ratio of early to late diastolic mitral inflow velocity; ECG, electrocardiogram; IVS, interventricular septum; LV, left ventricular; NYHA, New York Heart Association; TTR, transthyretin. *Data are presented as number of patients, number of patients (percentage), or median (10th–90th percentile). yNYHA class data are presented for patients who had cardiomyopathy at diagnosis. zConduction block includes first-degree, second-degree and complete heart block.
0.0001 1.4 (0.7–2.7) 1.23 (0.68–3.0) 2.5 (0.7–6.0) 2.5 (1.5–6.6) 1 (0.6–2.6) 1.4 (0.8–4.0) 1.5 (0.7–3.7)
0.41 0.006 0.05 (0.02–0.12) 197 (140–284) 0.05 (0.003–0.088) 176 (129.2–261) 0.06 (0.02–0.12) 151 (138.4–257.2) 0.03 (0.02–0.06) 152 (105–204.5) 0.05 (0.03–0.07) 217 (168.5–305.6) 0.05 (0.03–0.07) 182.5 (140.2–243.3) 0.05 (0.03–0.07) 180 (136–261)
0.03 15 (10–20) 15 (10–21.1) 15.5 (8.6–21.2) 18 (12.6–29) 14 (12–21) 16 (13–21) 15 (11–21)
IVS thickness (reference range, 10–13 mm), mm e0 , m/s Deceleration time (reference range, 157–245 ms), ms E/A (reference range, 0.6–1.4)
Ser77Tyr Variable
Entire cohort
Thr60Ala
Val30Met
Val122Ile
Mutation Table 2. Continued
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Other TTR mutations
Unknown
p Value
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three of the most common mutations (Val30Met, Thr60Ala and Val122Ile) [5]. We noted a male predominance of nearly 3:1, with a normal distribution of age at symptom onset. This distribution varies from the previously described bimodal distribution [6] owing to geographic differences in genotype expression. Past studies have elucidated that ATTR amyloidosis cases in areas where ATTR amyloidosis is endemic tend to occur in younger patients and in patients who have a clearer family history than in areas where ATTR amyloidosis is not endemic [7–11]. In the present study, Thr60Ala was the most common mutation identified, accounting for 25.6% of cases of hereditary ATTR amyloidosis. This is in contrast to past findings demonstrating Val122Ile as the most prevalent mutation in the USA, identified with an allele prevalence of 4% among the US black population [12]. This difference is due to the low prevalence of black patients in our study population as well as to the ethnic heterogeneity in the USA leading to a diverse number and distribution of mutations. In addition, a lack of suspicion for hereditary ATTR amyloidosis in elderly US blacks with cardiomyopathy likely contributes to underrecognition of this mutation. Interestingly, our study is the first to note a large population (17.9%) of self-reported white patients with ATTR amyloidosis associated with the Val122Ile mutation. This finding could be associated with the racial referral base of our institution accompanied by comprehensive evaluations for patients presenting with cardiomyopathy. Our study also points to a delay in reaching the diagnosis of hereditary ATTR amyloidosis – the median time from symptom onset to diagnosis overall was 39.1 months, and the longest delay was 389 months. In addition, a lack of full penetrance may contribute to the delay in diagnosis even among those with a family history of ATTR amyloidosis. Since older age at diagnosis is associated with shorter overall survival, early detection by clinicians is important. The paradox of shortest survival after diagnosis but old age at death among patients with the Val122Ile mutation was striking. Early diagnosis may allow clinicians not only to identify patients with hereditary ATTR amyloidosis before the onset of multiorgan damage but also to identify more patients who would benefit from liver transplant or emerging therapies such as tafamidis or therapies that interfere with TTR mRNA expression. A defined family history of ATTR amyloidosis was found for only 47.7% of patients overall; depending on the mutation, the percentage ranged from 25.0% to 66.7%. Past studies have documented a family history of ATTR amyloidosis ranging from 31% to 83% of patients, depending on whether ATTR amyloidosis was endemic in the population [6,10,11,13,14]. The lack of identifiable family history and the difference in rates of presentation between sexes may be from a lack of disease recognition, variable penetrance of the mutant allele [15,16] and previously described genetic anticipation in areas where the disease is endemic [17]. Our study identified a high incidence of cardiomyopathy on presentation, but many of the patients were asymptomatic for cardiac involvement. This finding emphasizes the role of a comprehensive multidisciplinary evaluation at the time of diagnosis of hereditary ATTR amyloidosis. Early detection of
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Figure 1. Symptoms present at diagnosis among patients grouped by mutation. TTR indicates transthyretin.
Figure 2. Age at symptom onset among patients grouped by transthyretin (TTR) mutation.
cardiomyopathy with, for example, echocardiography or magnetic resonance imaging, may facilitate earlier medical intervention, including involvement in clinical trials. Cardiac involvement was especially prevalent in patients with Thr60Ala or Val122Ile mutation. Patients with Val122Ile mutation also presented with later-onset cardiomyopathy; the majority were in NYHA class III or IV at diagnosis (17 of 28 patients; 61%). Patients with Val122Ile mutation had the shortest median survival (25.6 months). Although the reason for diagnosis among patients with advanced heart failure cannot be clearly defined from this study, Dungu et al. [18] previously identified that Val122Ile patients frequently present with NYHA class III heart failure. This finding may be due to a lack of early recognition and racial disparities in access to health care [19]. Lack of access to healthcare could delay the diagnosis until later in the disease course and hence increase the mortality. However, because similar patterns of disease presentation have been noted in the UK, where there are fewer issues with access to healthcare, a more malignant cardiac pathophysiology may be responsible [18]. Also, as
demonstrated by the present study, older age at diagnosis is independently associated with worse overall survival. Patients with Val122Ile mutation received a diagnosis when they were approximately 5 years older than other hereditary ATTR amyloidosis patients (median age at diagnosis, 69.0 years versus 63.3 years for entire cohort). This could be a factor in why these patients had the shortest median survival. The lag in diagnosis could have led to progressive protein deposition and cardiomyopathy contributing to the observed severe cardiac dysfunction and mortality. Overall, for the entire cohort, left ventricular mass index (LVMI) and interventricular septum (IVS) thicknesses were increased. These findings are consistent with a restrictive cardiomyopathy due to an infiltrative process, as with amyloidosis. Val122Ile mutation was associated with a significantly decreased ejection fraction as well as the largest median LVMI and median IVS thickness; these findings are consistent with the majority of patients presenting with latestage heart failure. Our study reports a significantly lower frequency of ECG abnormalities than previously reported,
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Figure 3. Kaplan–Meier survival curves for patients grouped by mutation. (A) Frequency surviving at a given age. (B) Survival after diagnosis. p values were calculated with the log-rank test.
with only 24.2% of patients having low-voltage findings and 24.2% having pseudoinfarction on ECG. Past studies have documented ECG variability [6,14,18,20]. ECG changes are likely the result of deposition within the ventricular conduction system as well as cardiac muscle infiltration. The finding of a lower incidence of ECG abnormalities likely represents the fact that our study was not limited to patients with cardiac amyloidosis. These findings support the concept that classic ECG findings associated with AL amyloidosis are less common in hereditary amyloidosis. The absence of ECG
abnormalities does not exclude cardiac involvement, and further studies including echocardiography or magnetic resonance imaging should be pursued for a clearer evaluation of organ involvement. The presence of peripheral neuropathy was associated with shorter survival both on Kaplan-Meier analysis and on multivariate analysis (Supplemental Figure 1A). We suspect that the finding of shorter survival among patients with peripheral neuropathy is multifactorial. The lag time for diagnosis was greater among patients with peripheral
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Table 3. Multivariate survival analysis. Univariate proportional hazards Variable Male Age at diagnosisy Thr60Ala versus non-Thr60Ala Val30Met versus non-Val30Met Val122Ile versus non-Val122Ile Ser77Tyr versus non-Ser77Tyr Family history Autonomic neuropathy at diagnosis Peripheral neuropathy at diagnosis Weight loss at diagnosis Cardiomyopathy at diagnosis
Multivariate analysis
Risk Ratio*
95% CI
p Value
Risk Ratio*
95% CI
p Value
1.05 11.95 1.46 0.86 1.76 0.81 0.89 1.38 1.45 1.73 1.51
0.71–1.52 4.63–30.3 1.02–2.05 0.55–1.29 1.01–2.88 0.40–1.45 0.65–1.21 1.01–1.90 1.01–2.52 1.25–2.38 1.09–2.11
0.79 0.0001 0.038 0.48 0.048 0.49 0.44 0.04 0.05 0.004 0.013
– 15.65 1.52 – 2.83 – – 1.32 1.69 1.81 1.05
– 5.3–47.1 1.01–2.25 – 1.45–5.29 – – 0.92–1.89 1.12–2.63 1.25–2.61 0.72–1.55
– 50.0001 0.04 – 0.003 – – 0.113 0.013 0.002 0.78
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Abbreviation: TTR, transthyretin. *Calculated by likelihood ratio. yDefined as a continuous variable.
neuropathy than among patients with autonomic neuropathy or cardiomyopathy. Although objective measures of neuropathy are not available, it could be hypothesized that the diagnosis of hereditary ATTR amyloidosis in patients with peripheral neuropathy was of low clinical suspicion until later in the disease course. In addition, although neuropathy by itself is not fatal, it leads to severe debility and functional decline, predisposing the patient to early death. Multivariate analysis showed that several variables present at clinical diagnosis are associated with shorter survival, including age at diagnosis, TTR mutation (Thr60Ala and Val122Ile) (Figure 3B), autonomic neuropathy (Supplemental Figure 1B), peripheral neuropathy and weight loss (Supplemental Figure 1C and D). Survival varied significantly with mutation type (i.e. Thr60Ala, Val30Met, Val122Ile, or Ser77Tyr) as shown in Figure 3(A) and (B). Similar findings on survival have been noted in the past analysis of a subset of this population, where patients with Thr60Ala, Val30Met, or Val122Ile mutation had decreased survival compared with similar patients of the same age and sex [5]. Mutation type had significantly different clinical manifestations among the populations, as shown in Table 2, including a predominant cardiac phenotype with Val122Ile and a peripheral neuropathy phenotype with Val30Met and Ser77Tyr. Interestingly, weight loss was independent of both cardiomyopathy and neuropathy in predicting overall survival, which has not previously been reported. It may be hypothesized that weight loss represents a physiologic marker of inflammation or neuropathic muscle atrophy. Although we could not assess it in this study, weight loss may correlate with the underlying functional status of patients at diagnosis; hence, it may correlate with prognosis. That is, patients with poorer functional status may have increased mortality compared with other patients. Similar findings have been reported in studies of patients with solid and hematologic malignancies [21]. Although significant on univariate analysis, the presence of cardiomyopathy at the time of diagnosis was not independently associated with mortality on multivariate analysis. This finding likely reflects the strong correlation between mutation type and cardiac phenotype. The Thr60Ala and Val122Ile mutations were independently
associated with increased mortality, but patients with these mutations also had the highest prevalence of cardiac involvement at diagnosis (Thr60Ala, 82.4%; Val122Ile, 100%). This finding emphasizes the variability between mutation phenotypes and the adverse prognosis associated with ATTR amyloidosis syndromes involving cardiomyopathy. Although this study is comprehensive, it has several weaknesses. The definition of presence of symptoms at diagnosis depended on documentation at the time of patient encounter. Similarly, it may be theorized that some symptoms attributed to ATTR amyloidosis (most notably, those with a long lead time) may not have been due to the underlying disease; however, because this study is based on documentation, we have based our analysis as such. It is possible that not all symptoms were fully documented or that the disease duration was not fully explored, but we think that by reviewing the entire clinical course of involved patients, we minimized this error. A large group of patients had unknown mutations. Determining the responsible pathogenic mutation may have allocated these patients to one of the other mutation groups and potentially affected intergroup comparisons. Because the goal of this study was to comprehensively describe patients presenting with hereditary ATTR amyloidosis, excluding the patients without known mutations would have been inappropriate. This is an inherent limitation of a retrospective study, and RFLP assays (used until the introduction of sequencing) included analysis for only the most common mutations noted in this study. Finally, complete information regarding treatment modalities, including transplantation, was not available because patients sought transplant evaluations at multiple centers throughout the USA. In conclusion, this study describes a large single-institution experience with hereditary ATTR amyloidosis and delineates patient presentation, clinical characteristics and survival over 43 years. We identified factors associated with decreased survival, including mutation type (Val122Ile or Thr60Ala), peripheral neuropathy and weight loss before diagnosis and age at diagnosis. Further research is necessary to better characterize the clinical pattern of disease so as to best tailor medical interventions.
Hereditary ATTR amyloidosis
DOI: 10.3109/13506129.2015.1019610
Declaration of interest The authors declare no conflicts of interest. The study did not receive financial support from a funding organization or sponsor.
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References 1. Andrade C. A peculiar form of peripheral neuropathy: familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952;75:408–27. 2. Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y. Polyneuritic amyloidosis in a Japanese family. Arch Neurol 1968; 18:593–602. 3. Andersson R. Familial amyloidosis with polyneuropathy: a clinical study based on patients living in northern Sweden. Acta Med Scand Suppl 1976;590:1–64. 4. Zeldenrust SR. Genotype: phenotype correlation in FAP. Amyloid 2012;19:22–4. 5. Arruda-Olson AM, Zeldenrust SR, Dispenzieri A, Gertz MA, Miller FA, Bielinski SJ, Klarich KW, et al. Genotype, echocardiography, and survival in familial transthyretin amyloidosis. Amyloid 2013;20:263–8. 6. Coelho T, Maurer MS, Suhr OB. THAOS: The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin 2013;29:63–76. 7. Benson MD, Cohen AS. Generalized amyloid in a family of Swedish origin: a study of 426 family members in seven generations of a new kinship with neuropathy, nephropathy, and central nervous system involvement. Ann Intern Med 1977;86:419–24. 8. Sousa A, Andersson R, Drugge U, Holmgren G, Sandgren O. Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. Hum Hered 1993;43:288–94. 9. Plante-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011;10:1086–97. 10. Ki M, Hattori N, Nagamatsu M, Si I, Ando Y, Nakazato M, Takei YI, et al. Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan: clinicopathological and genetic features. Brain 1999;122:1951–62.
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11. Ikeda S, Nakazato M, Ando Y, Sobue G. Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. Neurology 2002;58:1001–7. 12. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466–73. 13. Plante-Bordeneuve V, Lalu T, Misrahi M, Reilly MM, Adams D, Lacroix C, Said G. Genotypic–phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology 1998; 51:708–14. 14. Gertz MA, Kyle RA, Thibodeau SN. Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period. Mayo Clin Proc 1992;67:428–40. 15. Hellman U, Alarcon F, Lundgren HE, Suhr OB, Bonaiti-Pellie C, Plante-Bordeneuve V. Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population. Amyloid 2008;15:181–6. 16. Plante-Bordeneuve V, Carayol J, Ferreira A, Adams D, ClergetDarpoux F, Misrahi M, Said G, et al. Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. J Med Genet 2003;40:e120. 17. Yamamoto K, Ikeda S, Hanyu N, Takeda S, Yanagisawa N. A pedigree analysis with minimised ascertainment bias shows anticipation in Met30-transthyretin related familial amyloid polyneuropathy. J Med Genet 1998;35:23–30. 18. Dungu J, Sattianayagam PT, Whelan CJ, Gibbs SD, Pinney JH, Banypersad SM, Rowczenio D, et al. The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin isoleucine 122 type in Afro-Caribbean patients. Am Heart J 2012; 164:72–9. 19. Ford ES, Cooper RS. Racial/ethnic differences in health care utilization of cardiovascular procedures: a review of the evidence. Health Serv Res 1995;30:237–52. 20. Kristen AV, Perz JB, Schonland SO, Hegenbart U, Schnabel PA, Kristen JH, Goldschmidt H, et al. Non-invasive predictors of survival in cardiac amyloidosis. Eur J Heart Fail 2007;9:617–24. 21. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, et al., Eastern Cooperative Oncology Group. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 1980;69:491–7.
Supplementary material available online Supplemental Figure 1(A–D)
ORIGINAL ARTICLE
Hereditary ATTR amyloidosis: a single-institution experience with 266 patients Paul L. Swiecicki1, David B. Zhen1, Michelle L. Mauermann2, Robert A. Kyle3, Steven R. Zeldenrust3, Martha Grogan4, Angela Dispenzieri3, and Morie A. Gertz3 Department of Internal Medicine, 2Department of Neurology, 3Division of Hematology, and 4Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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1
Abstract
Keywords
Background: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, clinically heterogeneous disease due to heritable mutations that lead to misfolding of a precursor protein and multisystem disease. This study sought to define the clinical characteristics, distribution of mutations and phenotypic presentation of patients presenting to our center with hereditary ATTR amyloidosis. Methods: With institutional review board approval, the study retrospectively identified patients who had hereditary ATTR amyloidosis and presented to Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. Results: Of the 266 patients with the diagnosis of hereditary ATTR amyloidosis, a pathogenic mutation was identified in 206; the most common mutation was Thr60Ala (68 patients [25%]). Median age at diagnosis was 63.3 years; median survival after diagnosis was 56.8 months (10th– 90th percentile, 16.0–297.9). On multivariate analysis, age at diagnosis (risk ratio, 15.65; p50.0001), Thr60Ala mutation (risk ratio, 1.52; p ¼ 0.04), Val122Ile mutation (risk ratio, 2.83; p ¼ 0.003), peripheral neuropathy (risk ratio, 1.69; p ¼ 0.013) and weight loss (risk ratio, 1.81; p ¼ 0.002) were risk factors for death. Conclusion: Our data characterize the features of hereditary ATTR amyloidosis in a large cohort, demonstrate the heterogeneity among mutations and support the need to better characterize the clinical progression of individual mutations.
Cardiomyopathy, mutation, peripheral neuropathy, phenotype, transthyretin History Received 6 May 2014 Revised 26 January 2015 Accepted 11 February 2015 Published online 27 May 2015
Abbreviations: ATTR amyloidosis: transthyretin amyloidosis; ECG: electrocardiogram; E/A: ratio of early to late diastolic mitral inflow velocity; IVS: interventricular septum; LVMI: left ventricular mass index; NYHA: New York Heart Association; RFLP: restriction fragment length polymorphism; TTR: transthyretin
Introduction Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare autosomal dominant inherited disorder that involves systemic deposition of a mutated insoluble protein. First described in 1952, this disease involves a familial sensorimotor and autonomic neuropathy affecting many families in Northern Portugal [1]. This neuropathy was typically found to affect the longest nerves first, leading to the term lengthdependent neuropathy. Since its description in the Portuguese population, the disease has been identified as being endemic in other areas, including Japan and Sweden [2,3]. Although originally identified as being associated with a mutation of the transthyretin (TTR) gene, multiple other precursor
Address for correspondence: Morie A. Gertz, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected]
proteins have since been identified, including apolipoproteins A-I and A-II, fibrinogen, lysozyme and gelsolin. Currently, TTR mutations are the most common cause of hereditary amyloidosis, with over 100 TTR mutations identified worldwide and reports of clinically different phenotypes varying from predominantly cardiac to predominantly neurologic disease [4]. Descriptions of ATTR amyloidosis mutations in case reports and case series have provided much of our knowledge about the phenotypes, but there have been few comparative studies. Although numerous mutations have been identified in the USA, our understanding of their relevance in ATTR amyloidosis is limited by a lack of large identifiable pedigrees. Owing to the rarity and genetic heterogeneity of ATTR amyloidosis, a large study examining the natural history of ATTR amyloidosis and comparing mutation phenotypes has not been conducted in the USA. We sought to analyze all patients seen with hereditary ATTR amyloidosis at our
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Amyloid, 2015; 22(2): 123–131
institution to better elucidate the disease course, including incidence of family history, distribution of pathogenic mutations, predictors of mortality and the relation between genotype and phenotype.
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Methods The study was approved by the Mayo Clinic Institutional Review Board. All patients gave written, informed consent that allowed the use of their medical records for research purposes. Patients did not receive a stipend for involvement in this study. Analyses were conducted by an author (P.L.S.), and all authors had access to the primary data. We performed a retrospective cross-sectional study of all patients with a diagnosis of hereditary ATTR amyloidosis seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. During our analysis, we verified the diagnosis of hereditary ATTR amyloidosis from clinical symptoms, family history and genetic testing. Documentation of race was based on patient self-identification at the initial evaluation. This was assessed to analyze the differences in genotype distribution. All patients had tissue proof of amyloidosis, defined as green birefringence under polarized light with Congo red staining. No patients with wild-type ATTR amyloidosis were included in the analysis. Patients with non-ATTR amyloidosis were excluded because of the clinical variability in the disease course. This resulted in the exclusion of 19 patients: 6 were identified as having apo A–I; 3, gelsolin; 7, fibrinogen; 1, ALECT; 1, apo A-II; and 1, lysozyme. Three patients with TTR mutation were excluded because genetic testing results were not available and the patients had a clinical syndrome consistent with wild-type ATTR amyloidosis. Each of these patients presented at an age older than 70 years with isolated cardiomyopathy, thickened myocardium and no evidence of other organ or end organ involvement (i.e. peripheral neuropathy, autonomic neuropathy). Based on the judgment of the physician at the time of consultation and the study investigators, it was decided that the syndrome at the time of presentation was due to wildtype ATTR amyloidosis rather than hereditary ATTR amyloidosis. The method of mutation identification was known for 169 patients (Table 1). Methods used for TTR mutation identification included DNA sequencing (93 patients), restriction fragment length polymorphism (RFLP) analysis (64), mass spectrometry (5) and a family history of known pathogenic mutation (7). Family history was considered a method of
mutation identification when a patient with multiple family members affected by ATTR amyloidosis presented with similar symptoms and tissue proof of amyloidosis. In this situation, there was documentation that relatives had the same clinical phenotypes and underwent testing identifying the same mutation. For 37 patients, the method of mutation identification was unknown because it had been performed at another center before the patient was assessed at our facility. For 60 patients, the pathogenic mutation was unknown since testing had either not been performed or was performed before the current techniques of mass spectrometry and DNA sequencing without identification of the pathogenic mutation. We reviewed the clinical notes, laboratory evaluations and correspondence from other centers to elucidate the natural history of the disease. The chief complaint and symptoms were based on clinical documentation. The chief complaint was defined as the primary concern reported to the physician at the initial presentation. The diagnosis of autonomic neuropathy was based on documentation of symptoms and autonomic function testing when available. Symptoms included all clinical phenomena present at the initial consultation, such as abnormalities of sweating, orthostatic hypotension, gastrointestinal tract motility disorders and genitourinary tract disorders (impotence, urinary retention, etc.). The diagnosis of peripheral neuropathy was based on both clinical symptomatology and electromyographic data. Cardiomyopathy was assessed from symptoms (further characterized by New York Heart Association [NYHA] functional heart failure classification), non-invasive evaluations such as echocardiography and tissue diagnosis. If endomyocardial tissue diagnosis was not available, other causes of heart failure were excluded before attributing the cardiomyopathy to hereditary ATTR amyloidosis. Weight loss was defined as loss of more than 10% of body weight over the course of 1 year. Date of symptom onset was reported by the patient as the date when the ATTR amyloidosis-associated symptoms first occurred. Date of diagnosis was the date when the diagnosis of amyloidosis was confirmed histologically. Kaplan–Meier survival was calculated from the date of the original diagnosis to the date of death or the most recent contact. The Social Security Death Index was queried to ensure accurate mortality information for follow-up analyses. Because this study was retrospective in nature, clinical documentation and Social Security Death Index were used to ensure comprehensive follow-up information. Statistical analysis was performed with JMP Software (SAS Institute Inc., Cary, NC). Frequency
Table 1. Method of transthyretin mutation identification (n ¼ 206).
Mutation Thr60Ala Val30Met Val122Ile Ser77Tyr Other TTR
Mass spectrometry
Restriction fragment length polymorphism analysis
2 1 0 0 2
29 18 1 7 9
Unknown (performed elsewhere)
Known pathogenic mutation in first-degree family member
DNA sequencing
6 8 7 3 13
3 0 1 2 1
28 15 19 3 28
Hereditary ATTR amyloidosis
DOI: 10.3109/13506129.2015.1019610
(percentage) and summary statistics (median and range) were calculated to describe the patient population. Comparisons of discrete variables were examined with 2 testing and Wilcoxon tests for continuous variables. Log-rank testing was performed in analysis of Kaplan–Meier survival curves. The Cox proportional hazards model was used to identify factors associated with survival. p Values less than 0.05 were considered significant.
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Results We identified 266 patients with hereditary ATTR amyloidosis. Specific mutations were identified in 206 (77.4%) of these patients, all of whom were symptomatic. The majority of patients were male (212 patients [80%]). Of the identified mutations among patients with mutant TTR, the four most common were Thr60Ala (68 patients [26%]), Val30Met (42 patients [16%]), Val122Ile (28 patients [11%]) and Ser77Tyr (15 patients [6%]). Median follow-up of survivors (n ¼ 95) was 46 months (10th–90th percentile, 9.2–164.4 months). Table 2 summarizes the baseline demographics of the study population. The median time from symptom onset to diagnosis was 39.0 months (10th–90th percentile, 7.0–101.3 months). Further analysis showed that the median time from symptom onset to diagnosis varied by organ involvement at diagnosis: median time for patients with peripheral neuropathy was 41.5 months (10th–90th percentile, 12.7–112.2 months); for patients with autonomic neuropathy, 40.5 months (10th–90th percentile, 10.3–93.6 months) and for patients with cardiomyopathy, 38.7 months (10th–90th percentile, 5.4–103.4 months). Syndromes did not distribute evenly over time from symptoms to diagnosis. We divided patients into those with symptoms for more than 3 years and those with symptoms for less than 3 years. There was no difference in the frequency of cardiomyopathy or weight loss in early versus late diagnosis, but peripheral neuropathy (p ¼ 0.0008) and autonomic neuropathy (p ¼ 0.04) were weighted into the latediagnosis group. The frequency of a specific TTR mutation was borderline significant between the early and late diagnosis groups as well (p ¼ 0.04). Syndromes present at diagnosis among the entire cohort (N ¼ 266) were as follows: peripheral neuropathy, 186 patients (70%); autonomic neuropathy, 142 patients (53%); weight loss, 91 patients (34%) and cardiomyopathy, 161 patients (61%). We compared survival of patients who received a diagnosis before (n ¼ 49) or after (n ¼ 210) 1 January 1990; the median survivals were 68.2 and 55.5 months, respectively (p ¼ 0.84) (for 7 patients, the exact date of diagnosis was unknown). Figure 1 shows the symptoms present at diagnosis among patients grouped by TTR mutation. The most common chief complaint overall was peripheral neuropathy, although this varied significantly by mutation. Differences in the rates of peripheral neuropathy, autonomic neuropathy and cardiomyopathy were statistically significant between the mutations. Cardiomyopathy was present in 161 patients (61%) at diagnosis; prevalence was highest among patients with Val122Ile mutations (28 patients [100.0%]) and Thr60Ala mutations (56 patients [82.4%]). Among the patients with cardiomyopathy, the most common functional class at presentation was NYHA class I (42.7%), although distribution was
125
statistically different between mutation groups. Among patients with cardiac amyloidosis, the NYHA class was I for 42.9%, II for 28.6%, III for 24.2% and IV for 4.3%. The respective median survivals were 48.0, 51.6, 45.7 and 28.8 months (p ¼ 0.38). Age at symptom onset is shown in Figure 2; of note, the oldest patients carried the Val122Ile mutation. For 23 of the 266 patients (8.6%), the onset of symptoms was after age 70. In this aged population, the mutation frequencies were as follows: Thr60Ala, 5 of 68 patients (7.4%); Val122Ile, 7 of 28 patients (25.0%); Ser77Tyr, 0 of 15 patients; and Val30Met, 9 of 42 patients (21.4%). Baseline results from cardiac studies are shown in Table 2. Patients with the Val122Ile mutation, compared with patients with other mutations, had the worst systolic function (median ejection fraction, 34%) and the worst diastolic function (median ratio of early to late diastolic mitral inflow velocity [E/A], 2.5). The two most common electrocardiogram (ECG) abnormalities were conduction block (defined as first-degree, seconddegree or complete heart block), which was present in 58 patients (27.5%), and a pseudoinfarction pattern, which was present in 51 patients (24.2%). Fifty-four patients received a liver transplant: 8 patients with Val30Met mutations, 13 with Thr60Ala, 2 with Val122Ile, 7 with Ser77Tyr, 18 with other mutations and 6 with unknown TTR mutations. Their median survival was 167 months. The median survival of the TTR patients who did not receive a transplant was 50.6 months (p50.0001). Figure 3(A) demonstrates the median age at death by mutation. Patients with Ser77Tyr died at the youngest age (65.4 years), while Val30Met patients died at a median age of 74.6 years. Figure 3(B) shows the Kaplan–Meier survival curve from the time of histologic diagnosis, by mutation; the shortest survival was for Val122Ile patients since all had cardiac involvement at diagnosis. Of the 266 patients, 172 (64.7%) have died. Eighteen patients have been lost to follow-up. On univariate analysis, age at diagnosis, Thr60Ala mutation, Val122Ile mutation, autonomic neuropathy, peripheral neuropathy, weight loss and cardiomyopathy at diagnosis were risk factors for early death. Table 3 summarizes the multivariate analysis results for correlations between survival time after diagnosis and various baseline patient characteristics. On multivariate analysis, age at diagnosis, Thr60Ala mutation, Val122Ile mutation, peripheral neuropathy and weight loss at diagnosis retained significance. In Supplemental Figure 1(A)– (D), Kaplan–Meier survival curves demonstrate the significant impact on overall survival associated with peripheral neuropathy (Supplemental Figure 1A), autonomic neuropathy (Supplemental Figure 1B), cardiomyopathy (Supplemental Figure 1C) and weight loss (Supplemental Figure 1D).
Discussion There are currently more than 100 described TTR mutations associated with ATTR amyloidosis, and patients vary in clinical presentation and disease progression by not only genotype but also geography. This study describes a large single-center experience with hereditary ATTR amyloidosis over 43 years and identifies the largest American cohort to date. In a previous article on a subset of this cohort, we described echocardiographic and survival characteristics of
Patients Male Race White Black Asian Unknown International Age at symptom onset, years Age at diagnosis, years Age at death, years Symptom onset to diagnosis, mo Survival, mo Family history of ATTR amyloidosis Chief complaint Peripheral neuropathy Autonomic neuropathy Cardiomyopathy Nephropathy Other Present at diagnosis Peripheral neuropathy Autonomic neuropathy Weight loss Cardiomyopathy NYHA classy I II III IV ECG findings Patients with ECG available Conduction blockz Low voltage Left atrial enlargement Pseudoinfarction pattern LV hypertrophy Right bundle branch block Left bundle branch block Normal ECG Echocardiogram findings Patients with echocardiogram available Ejection fraction 55% LV mass index (reference range, 43–115 g/m2), g/m2
Variable
Entire cohort
(51.4) (13.4) (26.4) (5.6) (3.2) (69.9) (53.4) (34.2) (60.6) (42.9) (28.6) (24.2) (4.3) (79.0) (27.5) (24.2) (4.7) (24.2) (3.3) (9.0) (6.2) (13.7)
146 38 75 16 9 186 142 91 161 69 46 39 7 211 58 51 10 51 7 19 13 29
(79.4) (33.3) (27.8) (0.0) (31.5) (7.4) (9.2) (5.6) (7.4)
(39.3) (35.7) (25.0) (0.0)
(64.7) (64.7) (39.7) (82.4)
(39.7) (22.1) (36.8) (0.0) (1.5)
(100) (0.0) (0.0) (0.0) (13.2) (50.1–67.9) (54.5–72.0) (57.9–75.4) (8.3–110.4) (14.3–66.7) (57.4)
62 (91.2) 52 (32–65) 167 (110–253)
54 18 15 0 17 4 5 3 4
22 20 14 0
44 44 27 56
27 15 25 0 1
68 0 0 0 9 60.2 64.5 67.6 41.5 38.6 39
68 52 (76.5)
Thr60Ala
(71.4) (30.0) (26.7) (3.3) (20.0) (3.3) (16.7) (10.0) (13.3)
(94.4) (5.6) (0.0) (0.0)
(95.2) (59.5) (26.2) (42.9)
(85.7) (7.1) (2.4) (2.4) (2.4)
(90.5) (2.4) (7.1) (0.0) (19.0) (44.2–73.1) (48.2–76.4) (52.8–83.0) (12.7–87.0) (11.6–95.0) (31.0)
37 (88.1) 64 (50–75) 160 (83–239)
30 9 8 1 6 1 5 3 4
17 1 0 0
40 25 11 18
36 3 1 1 1
38 1 3 0 8 64.3 67.8 74.7 60.3 42.0 13
42 36 (85.7)
Val30Met
(96.4) (37.0) (22.2) (22.2) (14.8) (3.7) (3.7) (7.4) (3.7)
(3.6) (35.7) (46.4) (14.3)
(29.6) (17.9) (29.6) (100)
(7.1) (3.6) (89.3) (0.0) (0.0)
(17.9) (75.0) (3.6) (3.6) (7.1) (49.5–74.7) (52.3–77.9) (62.8–80.9) (3.5–87.2) (2.2–90.7) (25.0)
27 (96.4) 34 (13–54) 178 (121–288)
27 10 6 6 4 1 1 2 1
1 10 13 4
8 5 8 28
2 1 25 0 0
5 21 1 1 2 63.7 69.0 72.9 28.2 25.6 7
28 27 (96.4)
Val122Ile
Ser77Tyr
(86.7) (23.1) (46.1) (7.7) (23.1) (0.0) (0.0) (15.4) (23.1)
(50.0) (20.0) (30.0) (0.0)
(100) (53.3) (66.7) (66.7)
(73.3) (6.7) (13.3) (0.0) (6.7)
(100) (0.0) (0.0) (0.0) (0.0) (40.1–63.2) (47.6–66.8) (55.7–71.2) (10.8–151.2) (27.4–157.7) (66.7)
13 (86.7) 49 (20–73) 176 (74–212)
13 3 6 1 3 0 0 2 3
5 2 3 0
15 8 10 10
11 1 2 0 1
15 0 0 0 0 55.8 60.1 65.8 38.6 47.9 10
15 12 (80.0)
Mutation
(90.6) (18.8) (20.8) (4.2) (18.8) (0.0) (4.2) (0.0) (18.8)
(45.2) (32.2) (16.1) (6.4)
(75.5) (56.6) (43.4) (58.5)
(56.6) (15.1) (20.7) (3.8) (3.8)
(75.5) (9.4) (11.3) (3.8) (13.2) (37.3–65.9) (39.7–68.7) (43.5–75.9) (4.9–109.2) (12.3–105.1) (62.3)
48 (90.6) 60 (22–73) 153 (83.8–256)
48 9 10 2 9 0 2 0 9
14 10 5 2
40 30 23 31
30 8 11 2 2
40 5 6 2 7 53.1 56.7 62.1 30.8 36.9 33
53 36 (67.9)
Other TTR mutations
(65) (23.1) (15.4) (0.0) (30.8) (2.6) (15.4) (7.7) (20.5)
(52.0) (20.0) (24.0) (4.0)
(78.3) (65.0) (30.0) (41.7)
(66.7) (15.0) (13.3) (5.0) (0.0)
(95.0) (1.7) (0.0) (3.3) (8.3) (34.3–70.4) (41.6–77.3) (52.8–83.8) (6.9–113.9) (13.8–168.4) (41.7)
35 (58.3) 59 (31–74) 166 (86–236)
39 9 6 0 12 1 6 3 8
13 5 6 1
47 39 18 25
40 9 8 3 0
57 1 0 2 5 59.1 62.3 70.9 42.2 53.7 25
60 48 (80.0)
Unknown
(continued )
0.001 0.5
0.54 0.36 0.002 0.47 0.29 0.13 0.14 0.13
0.0001 0.0007 0.07 0.0001 0.0001
0.20 0.0001 0.0001 0.0001 0.18 0.04 0.001 0.0001
0.04 50.0001
p Value
P. L. Swiecicki et al.
221 (82.8) 55 (30–72) 166 (97–245)
(83.8) (10.5) (3.8) (1.9) (11.7) (42.0–70.2) (46.0–73.8) (52.2–78.7) (7.0–101.3) (16.0–297.9) (47.7)
223 28 10 5 31 59.6 63.3 67.8 39.0 56.8 127
266 211 (79.3)
Table 2. Baseline characteristics and studies.*
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Hereditary ATTR amyloidosis Abbreviations: ATTR amyloidosis, transthyretin amyloidosis; e0 , early diastolic mitral annular velocity; E/A, ratio of early to late diastolic mitral inflow velocity; ECG, electrocardiogram; IVS, interventricular septum; LV, left ventricular; NYHA, New York Heart Association; TTR, transthyretin. *Data are presented as number of patients, number of patients (percentage), or median (10th–90th percentile). yNYHA class data are presented for patients who had cardiomyopathy at diagnosis. zConduction block includes first-degree, second-degree and complete heart block.
0.0001 1.4 (0.7–2.7) 1.23 (0.68–3.0) 2.5 (0.7–6.0) 2.5 (1.5–6.6) 1 (0.6–2.6) 1.4 (0.8–4.0) 1.5 (0.7–3.7)
0.41 0.006 0.05 (0.02–0.12) 197 (140–284) 0.05 (0.003–0.088) 176 (129.2–261) 0.06 (0.02–0.12) 151 (138.4–257.2) 0.03 (0.02–0.06) 152 (105–204.5) 0.05 (0.03–0.07) 217 (168.5–305.6) 0.05 (0.03–0.07) 182.5 (140.2–243.3) 0.05 (0.03–0.07) 180 (136–261)
0.03 15 (10–20) 15 (10–21.1) 15.5 (8.6–21.2) 18 (12.6–29) 14 (12–21) 16 (13–21) 15 (11–21)
IVS thickness (reference range, 10–13 mm), mm e0 , m/s Deceleration time (reference range, 157–245 ms), ms E/A (reference range, 0.6–1.4)
Ser77Tyr Variable
Entire cohort
Thr60Ala
Val30Met
Val122Ile
Mutation Table 2. Continued
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Other TTR mutations
Unknown
p Value
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three of the most common mutations (Val30Met, Thr60Ala and Val122Ile) [5]. We noted a male predominance of nearly 3:1, with a normal distribution of age at symptom onset. This distribution varies from the previously described bimodal distribution [6] owing to geographic differences in genotype expression. Past studies have elucidated that ATTR amyloidosis cases in areas where ATTR amyloidosis is endemic tend to occur in younger patients and in patients who have a clearer family history than in areas where ATTR amyloidosis is not endemic [7–11]. In the present study, Thr60Ala was the most common mutation identified, accounting for 25.6% of cases of hereditary ATTR amyloidosis. This is in contrast to past findings demonstrating Val122Ile as the most prevalent mutation in the USA, identified with an allele prevalence of 4% among the US black population [12]. This difference is due to the low prevalence of black patients in our study population as well as to the ethnic heterogeneity in the USA leading to a diverse number and distribution of mutations. In addition, a lack of suspicion for hereditary ATTR amyloidosis in elderly US blacks with cardiomyopathy likely contributes to underrecognition of this mutation. Interestingly, our study is the first to note a large population (17.9%) of self-reported white patients with ATTR amyloidosis associated with the Val122Ile mutation. This finding could be associated with the racial referral base of our institution accompanied by comprehensive evaluations for patients presenting with cardiomyopathy. Our study also points to a delay in reaching the diagnosis of hereditary ATTR amyloidosis – the median time from symptom onset to diagnosis overall was 39.1 months, and the longest delay was 389 months. In addition, a lack of full penetrance may contribute to the delay in diagnosis even among those with a family history of ATTR amyloidosis. Since older age at diagnosis is associated with shorter overall survival, early detection by clinicians is important. The paradox of shortest survival after diagnosis but old age at death among patients with the Val122Ile mutation was striking. Early diagnosis may allow clinicians not only to identify patients with hereditary ATTR amyloidosis before the onset of multiorgan damage but also to identify more patients who would benefit from liver transplant or emerging therapies such as tafamidis or therapies that interfere with TTR mRNA expression. A defined family history of ATTR amyloidosis was found for only 47.7% of patients overall; depending on the mutation, the percentage ranged from 25.0% to 66.7%. Past studies have documented a family history of ATTR amyloidosis ranging from 31% to 83% of patients, depending on whether ATTR amyloidosis was endemic in the population [6,10,11,13,14]. The lack of identifiable family history and the difference in rates of presentation between sexes may be from a lack of disease recognition, variable penetrance of the mutant allele [15,16] and previously described genetic anticipation in areas where the disease is endemic [17]. Our study identified a high incidence of cardiomyopathy on presentation, but many of the patients were asymptomatic for cardiac involvement. This finding emphasizes the role of a comprehensive multidisciplinary evaluation at the time of diagnosis of hereditary ATTR amyloidosis. Early detection of
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Figure 1. Symptoms present at diagnosis among patients grouped by mutation. TTR indicates transthyretin.
Figure 2. Age at symptom onset among patients grouped by transthyretin (TTR) mutation.
cardiomyopathy with, for example, echocardiography or magnetic resonance imaging, may facilitate earlier medical intervention, including involvement in clinical trials. Cardiac involvement was especially prevalent in patients with Thr60Ala or Val122Ile mutation. Patients with Val122Ile mutation also presented with later-onset cardiomyopathy; the majority were in NYHA class III or IV at diagnosis (17 of 28 patients; 61%). Patients with Val122Ile mutation had the shortest median survival (25.6 months). Although the reason for diagnosis among patients with advanced heart failure cannot be clearly defined from this study, Dungu et al. [18] previously identified that Val122Ile patients frequently present with NYHA class III heart failure. This finding may be due to a lack of early recognition and racial disparities in access to health care [19]. Lack of access to healthcare could delay the diagnosis until later in the disease course and hence increase the mortality. However, because similar patterns of disease presentation have been noted in the UK, where there are fewer issues with access to healthcare, a more malignant cardiac pathophysiology may be responsible [18]. Also, as
demonstrated by the present study, older age at diagnosis is independently associated with worse overall survival. Patients with Val122Ile mutation received a diagnosis when they were approximately 5 years older than other hereditary ATTR amyloidosis patients (median age at diagnosis, 69.0 years versus 63.3 years for entire cohort). This could be a factor in why these patients had the shortest median survival. The lag in diagnosis could have led to progressive protein deposition and cardiomyopathy contributing to the observed severe cardiac dysfunction and mortality. Overall, for the entire cohort, left ventricular mass index (LVMI) and interventricular septum (IVS) thicknesses were increased. These findings are consistent with a restrictive cardiomyopathy due to an infiltrative process, as with amyloidosis. Val122Ile mutation was associated with a significantly decreased ejection fraction as well as the largest median LVMI and median IVS thickness; these findings are consistent with the majority of patients presenting with latestage heart failure. Our study reports a significantly lower frequency of ECG abnormalities than previously reported,
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Figure 3. Kaplan–Meier survival curves for patients grouped by mutation. (A) Frequency surviving at a given age. (B) Survival after diagnosis. p values were calculated with the log-rank test.
with only 24.2% of patients having low-voltage findings and 24.2% having pseudoinfarction on ECG. Past studies have documented ECG variability [6,14,18,20]. ECG changes are likely the result of deposition within the ventricular conduction system as well as cardiac muscle infiltration. The finding of a lower incidence of ECG abnormalities likely represents the fact that our study was not limited to patients with cardiac amyloidosis. These findings support the concept that classic ECG findings associated with AL amyloidosis are less common in hereditary amyloidosis. The absence of ECG
abnormalities does not exclude cardiac involvement, and further studies including echocardiography or magnetic resonance imaging should be pursued for a clearer evaluation of organ involvement. The presence of peripheral neuropathy was associated with shorter survival both on Kaplan-Meier analysis and on multivariate analysis (Supplemental Figure 1A). We suspect that the finding of shorter survival among patients with peripheral neuropathy is multifactorial. The lag time for diagnosis was greater among patients with peripheral
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Table 3. Multivariate survival analysis. Univariate proportional hazards Variable Male Age at diagnosisy Thr60Ala versus non-Thr60Ala Val30Met versus non-Val30Met Val122Ile versus non-Val122Ile Ser77Tyr versus non-Ser77Tyr Family history Autonomic neuropathy at diagnosis Peripheral neuropathy at diagnosis Weight loss at diagnosis Cardiomyopathy at diagnosis
Multivariate analysis
Risk Ratio*
95% CI
p Value
Risk Ratio*
95% CI
p Value
1.05 11.95 1.46 0.86 1.76 0.81 0.89 1.38 1.45 1.73 1.51
0.71–1.52 4.63–30.3 1.02–2.05 0.55–1.29 1.01–2.88 0.40–1.45 0.65–1.21 1.01–1.90 1.01–2.52 1.25–2.38 1.09–2.11
0.79 0.0001 0.038 0.48 0.048 0.49 0.44 0.04 0.05 0.004 0.013
– 15.65 1.52 – 2.83 – – 1.32 1.69 1.81 1.05
– 5.3–47.1 1.01–2.25 – 1.45–5.29 – – 0.92–1.89 1.12–2.63 1.25–2.61 0.72–1.55
– 50.0001 0.04 – 0.003 – – 0.113 0.013 0.002 0.78
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Abbreviation: TTR, transthyretin. *Calculated by likelihood ratio. yDefined as a continuous variable.
neuropathy than among patients with autonomic neuropathy or cardiomyopathy. Although objective measures of neuropathy are not available, it could be hypothesized that the diagnosis of hereditary ATTR amyloidosis in patients with peripheral neuropathy was of low clinical suspicion until later in the disease course. In addition, although neuropathy by itself is not fatal, it leads to severe debility and functional decline, predisposing the patient to early death. Multivariate analysis showed that several variables present at clinical diagnosis are associated with shorter survival, including age at diagnosis, TTR mutation (Thr60Ala and Val122Ile) (Figure 3B), autonomic neuropathy (Supplemental Figure 1B), peripheral neuropathy and weight loss (Supplemental Figure 1C and D). Survival varied significantly with mutation type (i.e. Thr60Ala, Val30Met, Val122Ile, or Ser77Tyr) as shown in Figure 3(A) and (B). Similar findings on survival have been noted in the past analysis of a subset of this population, where patients with Thr60Ala, Val30Met, or Val122Ile mutation had decreased survival compared with similar patients of the same age and sex [5]. Mutation type had significantly different clinical manifestations among the populations, as shown in Table 2, including a predominant cardiac phenotype with Val122Ile and a peripheral neuropathy phenotype with Val30Met and Ser77Tyr. Interestingly, weight loss was independent of both cardiomyopathy and neuropathy in predicting overall survival, which has not previously been reported. It may be hypothesized that weight loss represents a physiologic marker of inflammation or neuropathic muscle atrophy. Although we could not assess it in this study, weight loss may correlate with the underlying functional status of patients at diagnosis; hence, it may correlate with prognosis. That is, patients with poorer functional status may have increased mortality compared with other patients. Similar findings have been reported in studies of patients with solid and hematologic malignancies [21]. Although significant on univariate analysis, the presence of cardiomyopathy at the time of diagnosis was not independently associated with mortality on multivariate analysis. This finding likely reflects the strong correlation between mutation type and cardiac phenotype. The Thr60Ala and Val122Ile mutations were independently
associated with increased mortality, but patients with these mutations also had the highest prevalence of cardiac involvement at diagnosis (Thr60Ala, 82.4%; Val122Ile, 100%). This finding emphasizes the variability between mutation phenotypes and the adverse prognosis associated with ATTR amyloidosis syndromes involving cardiomyopathy. Although this study is comprehensive, it has several weaknesses. The definition of presence of symptoms at diagnosis depended on documentation at the time of patient encounter. Similarly, it may be theorized that some symptoms attributed to ATTR amyloidosis (most notably, those with a long lead time) may not have been due to the underlying disease; however, because this study is based on documentation, we have based our analysis as such. It is possible that not all symptoms were fully documented or that the disease duration was not fully explored, but we think that by reviewing the entire clinical course of involved patients, we minimized this error. A large group of patients had unknown mutations. Determining the responsible pathogenic mutation may have allocated these patients to one of the other mutation groups and potentially affected intergroup comparisons. Because the goal of this study was to comprehensively describe patients presenting with hereditary ATTR amyloidosis, excluding the patients without known mutations would have been inappropriate. This is an inherent limitation of a retrospective study, and RFLP assays (used until the introduction of sequencing) included analysis for only the most common mutations noted in this study. Finally, complete information regarding treatment modalities, including transplantation, was not available because patients sought transplant evaluations at multiple centers throughout the USA. In conclusion, this study describes a large single-institution experience with hereditary ATTR amyloidosis and delineates patient presentation, clinical characteristics and survival over 43 years. We identified factors associated with decreased survival, including mutation type (Val122Ile or Thr60Ala), peripheral neuropathy and weight loss before diagnosis and age at diagnosis. Further research is necessary to better characterize the clinical pattern of disease so as to best tailor medical interventions.
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DOI: 10.3109/13506129.2015.1019610
Declaration of interest The authors declare no conflicts of interest. The study did not receive financial support from a funding organization or sponsor.
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Supplementary material available online Supplemental Figure 1(A–D)
