Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as “red flags,” have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy.
Material and methodsWe analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients.
ResultsThe frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags.
ConclusionRed flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset.
La polineuropatía relacionada con el depósito de amiloide por transtirretina (hATTR, por sus siglas en inglés) es una enfermedad poco común, multisistémica, de inicio en la edad adulta con un pronóstico ominoso sin tratamiento. Para reconocer la enfermedad en la etapa más temprana posible, se ha propuesto un grupo de signos y síntomas, comúnmente conocidos como "red flags", y su presencia puede sugerir la presencia de un hATTR subyacente en pacientes con polineuropatía sensitivo-motora progresiva.
Materiales y métodosSe analizó la frecuencia de "red flags" en el momento del diagnóstico en 30 pacientes hATTR de un área no endémica de España, con una mayoría de pacientes de inicio tardío.
ResultadosLas frecuencias de "red flags" fueron las siguientes: síndrome del túnel carpiano bilateral (STC) 15/30 (50%); disautonomía temprana en 17/30 (56%); síntomas gastrointestinales en 14/30 (46,6%); pérdida inexplicable de peso en 8/30 (26,6%); enfermedad cardiaca en 12/30 (40%); hallazgos cardiacos asintomáticos en 13/30 (43,3%); enfermedad renal en 1/30 (3,3%); opacidades vítreas en 0/30 (0%); neuropatía familiar en 21/30 (70%); cardiopatía familiar en 15/30 (50%) y antecedentes familiares gastrointestinales en 3/30 (10%). Todos los pacientes presentaron al menos una bandera roja en el momento del diagnóstico, con una mediana de cuatro banderas rojas.
ConclusiónLas "red flags", incluso en los pacientes de inicio tardío, fueron hallazgos comunes en el momento del diagnóstico, y su presencia en un paciente con polineuropatía sensitivo-motora simétrica debería alertarnos y conducir el diagnóstico a lo largo del hATTR hasta excluirlo, independientemente de la edad de inicio o de la región endémica.
Hereditary transthyretin amyloidosis (hATTR), first described by Andrade1 in 1952, is a rare, adult-onset, multisystem disease that dramatically reduces the life expectancy of affected patients. In hATTR, amyloid deposition preferentially involves the peripheral nervous system and heart, causing progressive autonomic and sensorimotor peripheral neuropathy and restrictive cardiomyopathy.2 Other common sites of amyloid deposition are the kidneys, eyes, and central nervous system.3 If left untreated, prognosis is poor, with death within 9–10 years after diagnosis.2 To date, over 120 TTR mutations have been described,4 with Val30Met (also known as p.Val50Met) being the most common in both endemic and non-endemic areas worldwide.5
Early diagnosis requires a high level of suspicion, and the disease is often associated with a diagnostic delay of 2–5 years. The availability today of disease-modifying therapies has improved the prognosis of these patients, especially when treatment is started early.6–9 Early diagnosis is therefore essential.
With a view to facilitating the early detection of the disease, a series of red flag signs and symptoms have been proposed to alert clinicians to the possibility of underlying hATTR in patients with progressive sensorimotor polyneuropathy.10 However, these red flags were originally described in endemic areas, in patients with early-onset disease (EOD) associated with the Val30Met (V30M) mutation. Therefore, their diagnostic value in patients from non-endemic areas, with non-V30M mutations, or with late-onset disease (LOD) has been questioned, mainly due to variations in the clinical expression of the disease in these populations.11–13
This study aims to establish the incidence of hATTR red flags at diagnosis in patients from a non-endemic area of Spain, the majority of whom presented LOD.
Material and methodsPatientsAll patients were recruited at the neuromuscular diseases unit of Hospital Clínico San Carlos in Madrid. This university hospital receives patients with suspected or confirmed hATTR from central Spain, considered a non-endemic region. The study was conducted in accordance with the good clinical practice guidelines and with the legislation in force on the protection of patient data.
Study designWe conducted a retrospective, observational, single-centre study based on the review of clinical records collected prospectively over a 10-year period (2008–2018). With a view to minimising selection bias, the sample included all patients with a definitive diagnosis of hATTR and assessed at our centre during the study period. Definitive diagnosis of hATTR was defined as the presence of clinical and neurophysiological signs of sensorimotor polyneuropathy plus genetic confirmation of heterozygous presence of a pathogenic or probably pathogenic variant in the TTR gene, according to the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology.14
Data collectionFor all patients with hATTR, the following data were systematically recorded at the baseline clinical assessment and during follow-up: sex, date of birth, age of onset, type of mutation, and presence and number of red flags at the time of definitive diagnosis.
Red flagsThe following clinical characteristics were considered red flags for hATTR in patients with progressive sensorimotor polyneuropathy10: family history (first-degree relatives) of peripheral neuropathy; autonomic dysfunction (including orthostatic hypotension, sexual dysfunction, urinary retention, sweating abnormalities, or abnormal findings from autonomic tests [sympathetic skin response, variability of RR interval]); cardiac symptoms; gastrointestinal symptoms (including diarrhoea, constipation, and alternating episodes of diarrhoea and constipation); unintentional weight loss; bilateral carpal tunnel syndrome (CTS); renal involvement (laboratory findings suggesting kidney failure); and vitreous opacification. In addition to these signs, the following were also considered red flags: family history (first-degree relatives) of heart, gastrointestinal, or kidney disease; abnormal electrocardiography (ECG), DPD-scintigraphy, or echocardiography findings without cardiac symptoms; and unilateral CTS.
Data analysisWe initially conducted a descriptive analysis of the clinical, neurophysiological, and genetic characteristics of all patients included in the study (n=30). Secondly, we analysed the frequency of red flags among patients with hATTR in our cohort. Finally, we compared the frequency of red flags between patients with EOD (age of onset ≤ 50 years) and those with LOD (> 50 years) and between carriers of the V30M mutation and non-V30M mutations.
Categorical variables are expressed as numbers and percentages. Contingency tables were analysed using the Pearson chi-square test or the Fisher exact test; where appropriate, we also calculated odds ratios with 95% confidence intervals. Non-parametric data are expressed as medians and quartiles 1 and 3 (Q1–Q3) and were compared using the Mann-Whitney U test or the Kruskal-Wallis test. All tests were 2-tailed; statistical significance was set at P<.05. Statistical analysis was conducted using the SPSS software, version 25 (IBM Corp.; Armonk, NY, USA).
ResultsThe study included a total of 30 patients with confirmed hATTR. Of these, 6 (20%) had EOD and 24 (80%) had LOD. Median age of onset was 65 years (Q1–Q3, 54.8–72.3). Median age in the EOD group was 42 years (Q1–Q3, 37.8–47), compared to 67.5 years (Q1–Q3, 61.5–73.0) in the LOD group. Median diagnostic delay (symptom onset to genetic confirmation) was 1.25 years (Q1–Q3, 0.87–3). Eighteen patients (60%) were carriers of the V30M mutation. Table 1 lists patients’ clinical and molecular genetics characteristics.
Clinical and demographic characteristics of patients with hereditary transthyretin amyloidosis.
| Total (n=30) | |
|---|---|
| Sex, n (%) | |
| Men | 17 (56.7) |
| Women | 13 (43.3) |
| Age at symptom onset (mean [SD]) | 62.47 (12.6) |
| Red flags at diagnosis, n (%) | |
| Bilateral CTS | 15 (50) |
| Unilateral CTS | 2 (6.7) |
| Autonomic dysfunction | 17 (56.7) |
| Gastrointestinal symptoms | 14 (46.7) |
| Unintended weight loss | 8 (26.7) |
| Cardiac symptoms | 12 (40) |
| Asymptomatic cardiological alterations | 13 (43.3) |
| Kidney disease | 1 (3.3) |
| Vitreous opacification | 0 (0) |
| Family history of neuropathy | 21 (70) |
| Family history of heart disease | 15 (50) |
| Family history of gastrointestinal symptoms | 3 (10) |
| Red flags at diagnosis, n (%) | |
| 1 | 2 (6.7) |
| 2 | 1 (3.3) |
| 3 | 8 (26.7) |
| 4 | 10 (33.3) |
| 5 | 5 (16.7) |
| 6 | 2 (6.7) |
| 7 | 1 (3.3) |
| 8 | 1 (3.3) |
| Age of onset, n (%) | |
| Early onset (≤ 50 years) | 6 (20) |
| Late onset (> 50 years) | 24 (80) |
| Mutation, n (%) | |
| p.Val30Met | 18 (60) |
| Other | 12 (40) |
CTS: carpal tunnel syndrome.
The initial symptom was determined in 27 cases. By order of frequency, symptoms were distributed as follows: positive sensory symptoms (paraesthesia) (9/27; 33.3%), symptoms of heart failure or arrhythmia (7/27; 25.9%), neuropathic pain (5/27; 18.5%), dysautonomic symptoms (4/27; 14.8%), unintended weight loss (2/27; 7.4%), uni- or bilateral CTS (1/27; 3.7%), and limb weakness (1/27; 3.7%). The initial symptom could not be precisely determined in 3 patients. Table 2 compares the initial symptoms in patients with EOD and LOD. Dysautonomic symptoms were the most common form of presentation in EOD, occurring in 50% of patients.
Comparison of initial manifestations between patients with early and late onset and between patients with the V30M mutation and with other TTR mutations.
| Early onset (≤ 50 years) (n=5) | Late onset (> 50 years) (n=22) | P | V30M (n=16) | Other TTR mutations (n=11) | P | |
|---|---|---|---|---|---|---|
| Weakness | 0 | 1 | > .1 | 1 | 0 | > .1 |
| Dyspnoea | 0 | 3 | > .1 | 2 | 1 | > .1 |
| Atrial fibrillation | 0 | 1 | > .1 | 0 | 1 | > .1 |
| Dysautonomia | 3 | 1 | .018 | 2 | 2 | > .1 |
| Pain | 2 | 3 | > .1 | 3 | 2 | > .1 |
| Paraesthesia | 0 | 9 | 0.09 | 7 | 2 | > .1 |
| Weight loss | 0 | 2 | > .1 | 0 | 2 | > .1 |
| CTS | 0 | 1 | > .1 | 1 | 0 | > .1 |
CTS: carpal tunnel syndrome.
At the time of diagnosis, the distribution of red flags was as follows (Table 1): unilateral CTS (2/30; 6%); bilateral CTS (15/30; 50%); early autonomic dysfunction (17/30; 56.7%); gastrointestinal symptoms (14/30; 46.7%); unintended weight loss (8/30; 26.7%); cardiac symptoms (12/30; 40%); asymptomatic ECG, echocardiography, or DPD-scintigraphy alterations (13/30; 43.3%); kidney failure (1/30; 3.3%); vitreous opacification (0/30; 0%); family history of peripheral neuropathy (21/30; 70%); family history of heart disease (15/30; 50%); and family history of gastrointestinal disease (3/30; 10%). No patient had family history of kidney disease. Overall, every patient presented at least one red flag at diagnosis (median of 4; Q1–Q3, 3–5). All 6 patients with EOD and 22 patients with LOD (22/24; 92%) presented 3 or more red flags at diagnosis.
Table 3 shows the distribution of red flags at diagnosis for the total patient cohort (n=30), comparing data between patients with EOD and LOD and between those with the V30M mutation and with non-V30M mutations.
Comparison of red flags at diagnosis between patients with early and late onset and between patients with the V30M mutation and with other TTR mutations.
| Red flags at diagnosis | Early onset (≤ 50 years) (n=6) | Late onset (> 50 years) (n=24) | P | V30M (n=18) | Other TTR mutations (n=12) | P |
|---|---|---|---|---|---|---|
| Bilateral CTS | 3 | 12 | .67 | 7 | 8 | .132 |
| Dysautonomia | 5 | 12 | .156 | 9 | 8 | .301 |
| Gastrointestinal symptoms | 3 | 11 | .605 | 9 | 5 | .471 |
| Cardiac symptoms | 2 | 10 | .545 | 6 | 6 | .296 |
| Asymptomatic cardiological alterations | 1 | 12 | .133 | 8 | 5 | .664 |
| Unintended weight loss | 0 | 8 | .126 | 4 | 4 | .396 |
| Kidney disease | 0 | 1 | .800 | 1 | 0 | .600 |
| Vitreous opacification | 0 | 0 | – | 0 | 0 | – |
| Family history of neuropathy | 6 | 15 | .091 | 12 | 9 | .472 |
| Family history of heart disease | 4 | 11 | .326 | 7 | 8 | .132 |
CTS: carpal tunnel syndrome.
The main findings of this study show that red flags were relatively common among all patients, with the majority presenting more than 3 red flags, independently of age of onset or time from onset to diagnosis. Comparisons between groups revealed no statistically significant differences between patients with LOD and those with EOD in terms of the number of red flags at diagnosis. We also found no significant differences in the number of red flags between patients with the V30M mutation and with non-V30M mutations.
Therefore, our results seem to contradict the findings of previous authors, who suggest that these red flags are not reliable diagnostic markers in patients with LOD or in non-endemic areas.13
Regarding the initial manifestation, dysautonomia was the only symptom showing a statistically significant difference between groups, appearing as the initial symptom in 50% of patients with EOD and only 0.21% of those with LOD. While only 3 patients with EOD (50%) presented the V30M mutation in our series, previous studies report that dysautonomia tends to be the initial symptom in patients with EOD presenting this mutation, in approximately 50% to 60% of cases.11,15 This is probably due to greater loss of unmyelinated fibres in V30M patients with EOD than in those with LOD, which would explain the earlier onset of dysautonomia in this group.16
Therefore, due to the phenotypic variability and heterogeneous presentation of hATTR, the presence of red flags may differ between endemic and non-endemic regions.
Our series presents limited statistical power due to the small sample size; nonetheless, hATTR is a rare disease, and this small sample was expected. Therefore, our results should be interpreted with caution, in the context of a small series, and should not be the basis for definitive assumptions.
ConclusionRed flags were common at the time of diagnosis, even in patients with LOD. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR, independently of age of onset or geographical region. This is particularly important considering that early treatment appears to be associated with a better response.17
Conflicts of interestDr Silva-Hernández has consulted for Pfizer. Dr Lucía Galán has received lecture honoraria and consulting fees from Pfizer, Alnylam, Akcea, and Grunenthal, and financial assistance to attend scientific meetings from Pfizer, Alnylam, and Akcea. Dr Alejandro Horga has received consulting fees from Pharnext.
We are very grateful to our patients and their families; to all the neurology residents and Dr García-Pavía and his cardiology team at Hospital Puerta de Hierro; and to Dr Pérez-Castejón of our hospital’s nuclear medicine department.
