Skip to main content

Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression

Abstract

Background

Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback.

Monitoring disease and progression

A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment.

Conclusions

We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis.

Background

Disease definition

Hereditary transthyretin-mediated amyloidosis, also known as ATTRv (v for variant) amyloidosis, is a rare, progressively debilitating, and fatal systemic disease caused by pathogenic variants in the transthyretin (TTR) gene [1,2,3,4]. Primarily synthesized by the liver [5,6,7], TTR circulates as a tetramer involved in the transport of the vitamin A–retinol binding protein complex and plays a minor role in thyroxine transport [8, 9]. However, in the case of ATTRv amyloidosis, pathogenic TTR variants result in synthesis of unstable TTR tetramers, which then dissociate into monomers, misfold, and aggregate into amyloid fibrils [10, 11]. These fibrils subsequently accumulate in the extracellular spaces of multiple (mostly non-mitotic) organs and tissues, such as the nerves, heart, eyes, and gastrointestinal (GI) tract [1, 3]. The result is a multisystem disease, which can manifest with intractable somatic and autonomic neuropathy, and/or cardiomyopathy, in addition to other disease signs and symptoms [2, 3, 12,13,14] (Table 1).

Table 1 Symptomatology of ATTRv amyloidosis

Transmission of ATTRv amyloidosis is autosomal dominant and multiple factors may affect time of onset and disease natural history [4]. Over 120 pathogenic TTR variants have been identified [28], with prevalence of different mutations varying by geography. The most common TTR mutation in Europe is V30M (V50M) [29], with prevalence reaching up to 1 in 1000 in endemic areas in Portugal, Sweden, and Japan [3, 29]. In comparison, the most common TTR mutation in the US is V122I (V142I), which has a reported prevalence of approximately 4% in African Americans [17]. There is a notable genotype–phenotype variability, and some specific TTR mutations have historically been associated with particular disease manifestations, with V30M most often associated with predominant polyneuropathy and V122I most often associated with predominant cardiomyopathy [30]. However, progress in understanding the disease, and careful clinical and imaging observation, has led to recognition that there is frequent multisystem involvement across all TTR variants [31], and a mixed phenotype including polyneuropathy and cardiomyopathy can be found in the majority of patients with ATTRv amyloidosis [30,31,32,33]. Furthermore, there is considerable variability in the penetrance, symptoms, and course of the disease across TTR variants [34, 35], even within families [36]. This variability and lack of specificity of symptoms, allied to low disease awareness and incomplete penetrance of ATTRv amyloidosis, presents a challenge for diagnosis of symptomatic patients [37,38,39].

Natural history and mortality

The age of disease onset and rate of progression of ATTRv amyloidosis can differ among various target organs, yet, overall, once symptoms appear the disease advances rapidly without treatment. This disease progression is associated with increasingly severe symptomatology, disability, and mortality [1]. Among patients with ATTRv amyloidosis with predominant polyneuropathy, disease progression manifests with the extension of sensory loss from the feet to proximal lower limbs, onset of weakness in lower limbs extending later to hands, and autonomic dysfunction of increasing severity. The rapidity of worsening is increased in late-onset (LO, onset > 50 years) disease compared with early-onset (EO) disease. The impact on locomotion is progressive and major, with patients requiring assistance with walking within 3–5 years from onset, and being wheelchair-bound within 5–10 years, depending on the age of onset and TTR variant. The multifaceted impairment related to ATTRv amyloidosis is associated with poor prognosis, with the median overall survival following diagnosis reported to be 4.7 years [40]. Survival in patients presenting with predominant cardiomyopathy is further reduced to 3.4 years [40, 41], with death usually due to progressive heart failure (HF) or to life-threatening cardiac arrhythmia [42, 43]. Survival from disease onset in patients with ATTRv amyloidosis with polyneuropathy ranges from approximately 12 years in the EO V30M variant to approximately 7 years in other variants such as LO V30M and I107V [44, 45]. The variation in survival shown in Additional file 1: Table S1 (see Additional file 1) highlights the shorter survival seen in patients with variants associated with predominant cardiomyopathy.

Unmet need in disease monitoring and progression

Disease-modifying therapies (DMTs) for ATTRv amyloidosis have evolved considerably over the past 30 years [4]. From the 1990s to the early 2010s, orthotopic liver transplantation was the only treatment strategy available that targeted the pathogenic variant TTR protein [15, 46], yet a range of disease-modifying pharmacotherapies are now available including small-molecule TTR stabilizers such as tafamidis and diflunisal, and gene-silencing drugs such as patisiran and inotersen [32, 33, 47,48,49].

To address the challenges around choice and initiation of these DMTs, careful monitoring of the multiple potential signs of disease progression is required. While some guidance exists for monitoring presymptomatic individuals [50, 51], there is limited consensus on monitoring symptomatic individuals [52], and progression remains poorly defined. Here, it is likely important to utilize multiple measures at baseline and during follow-up assessments, as often these can detect progression before clear clinical worsening.

The authors, a panel with expertise in ATTR amyloidosis comprising a neurologist and 2 cardiologists from France and a neurologist and 2 cardiologists from the US, answered a questionnaire on monitoring disease state and detecting disease progression based on a literature review of expert opinion articles and management guidelines on ATTRv amyloidosis. At a virtual roundtable meeting in July 2019, the author team met to discuss the pooled questionnaire results. A set of recommendations on monitoring and disease progression were formulated using the team’s experience of treating patients with ATTRv amyloidosis, their knowledge of the literature, and an analysis of clinical trials. These were further developed over 4 rounds of feedback.

The recommendations have 3 aims. First, to identify the signs, symptoms, and tests with which to monitor patients with ATTRv amyloidosis. Second, to define changes in the identified measures that signify meaningful disease progression and thereby identify non-responders. Finally, to specify the frequency of disease-monitoring assessments required for timely identification of progression.

Disease monitoring

Baseline assessment

Patient monitoring should start immediately after diagnosis to provide a baseline assessment from which to judge the disease course. Ideally, assessments should take place at a specialist center with experience of ATTRv amyloidosis and utilize a multidisciplinary team that reflects the multisystemic nature of this disease. At minimum, this team should comprise a neurologist and a cardiologist, a genetic counselor, and an ophthalmologist. Other specialties such as gastroenterologists, nutritionists, physical therapists, nephrologists, and urologists, should be consulted as needed.

Members of the multidisciplinary team should strive to capture the full range of disease manifestations by assessing somatic and autonomic neuropathy, cardiac dysfunction, and other disease manifestations. Particular attention should be paid to using a quantified approach when possible, as clinical signs and symptoms can vary from patient to patient. Proposed signs and symptoms to be assessed are shown in Table 2.

Table 2 Monitoring signs and symptoms in patients with ATTRv amyloidosis

Somatic neuropathy

Most patients presenting with neuropathy have both sensory and motor symptoms. Early motor involvement can often distinguish ATTRv amyloidosis from sensory-predominant neuropathies such as those associated with diabetes. Additionally, ATTRv amyloidosis can often be associated with early hand involvement due to focal neuropathies such as carpal tunnel syndrome. Common somatic neuropathy symptoms include pain, paresthesia, walking difficulties, balance disorders, and difficulties with fine dexterity. On examination, signs include extent of sensory loss for pain in the lower limbs, areflexia, apallesthesia in the feet, and weakness (Table 2).

A clinical assessment should cover familial amyloid polyneuropathy (FAP) stage [53] and/or polyneuropathy disability (PND) score [54] by interview, and the neuropathy impairment score (NIS) [55] by examination. FAP stage and PND score assess disability with a focus on impairment of ambulation [53, 54, 56]. A simple NIS should be captured at baseline, to reflect the severity of the somatic neuropathy [1], although a range of different composite NIS tools are available [57, 58]. These composite measures have been used in clinical trials as they have evolved for use in ATTRv amyloidosis, although in their full iteration they are often considered too complex and time-consuming for routine clinical purposes. It should also be noted that the NIS, like many other scales used in the assessment of ATTRv amyloidosis, is not a linear scale so the impact of a specific score change may differ according to the patient’s starting level of neuropathy impairment. A simpler clinical examination can include the 10-m walk test [59] or the Timed Get Up and Go test [60], which can be used to assess gait and balance, even in patients with disabling neuropathy. Other relevant neurologic tests include the Jamar Hydraulic Hand Dynamometer (Sammons Preston Rolyan, Bolingbrook, IL, US) [1] both hands grip strength test, which can be performed in consultations, nerve conduction studies, skin punch biopsies, and quantitative sensory testing using CASE IV (WR Medical Electronics Co, Maplewood, MN, US).

Patient disability assessment by the Rasch-built Overall Disability Scale (R-ODS) [61] questionnaire is also of notable value, since this is tailored to patients with peripheral neuropathy and measures the effect on activities of daily living [61]. Scores on this scale can capture functional impairment by assessing the ability of an individual to function independently in daily life. R-ODS score should be assessed before each consultation.

Autonomic neuropathy

Autonomic neuropathy affects several organs and its signs and symptoms can be some of the earliest manifestations of ATTRv amyloidosis. Despite this, the extent of autonomic neuropathy can be difficult to assess due to the large variety of possible symptoms that may be related to this condition and the relatively few empirical signs that can be used to measure progression (Table 2).

Autonomic dysfunction can manifest with a range of symptoms, including GI (e.g. early satiety, chronic diarrhea, constipation, and gastroparesis) and genitourinary (e.g. sexual dysfunction, urinary retention, and urinary incontinence) problems which should all be monitored (Table 2). Sexual dysfunction and constipation are typically early symptoms, with sexual dysfunction often apparent within the first 2 years of onset of symptomatic disease. Conversely, urinary retention and urinary incontinence typically manifest in the later stages of the disease. Overall, the Compound Autonomic Dysfunction Test [62], integrating evaluation of postural hypotension, nausea/vomiting, diarrhea/constipation, and sphincter disturbances, is a simple and reproducible scale which is adapted to evaluate the main symptoms of autonomic dysfunction observed in ATTRv amyloidosis with polyneuropathy [62]. Specific signs of autonomic neuropathy include skin conductance, which can be assessed for sudomotor function by Sudoscan® [63, 64], and autonomic and sensory symptoms, which can be captured by the small-fiber neuropathy and symptom inventory questionnaire.

Cardiac dysautonomia involves both sympathetic and parasympathetic systems, and/or the balance between them (Table 2). Signs of cardiac dysautonomia can be detected by: assessment of orthostatic hypotension (asymptomatic or resulting in faintness or syncope) using lying/standing measurement or tilt table test; heart rate variability with deep breathing test; heart rate variability (standard deviation [SD] of normal-to-normal R–R interval variability on a 24-h electrocardiogram [ECG] Holter recording); or the Valsalva maneuver [65, 66]. The parasympathetic system can be tested with the heart rate response to atropine intravenous infusion [67], and the sympathetic system by metaiodobenzylguanidine cardiac scintigraphy [68]. As with other signs and symptoms of autonomic neuropathy in ATTRv amyloidosis, tests for cardiac dysautonomia have a powerful early diagnostic and prognostic value, but are still rarely used [21, 22].

The Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire [60] is recommended for broad assessment of the severity and extent of a range of autonomic symptoms, including vasomotor, secretomotor, GI, and bladder dysfunction [69]. Although COMPASS-31 is not commonly used in a clinical setting, it has been used successfully in clinical trials to measure longitudinal changes in dysautonomia [23, 32] and could be collected before consultations.

Amyloid cardiomyopathy

There are no specific signs of ATTR amyloid cardiomyopathy. Typical age of onset is > 50 years old, but variations can appear within a given family, so patients should be warned to seek medical advice in the event of any potential cardiac sign. Patients should be more closely monitored within 10 years of the typical age of onset in their family.

When monitoring cardiomyopathy, symptoms to be aware of include exertional dyspnea, volume overload, jugular distension, lower limb edema, cachexia, fatigue, weight increase, abdominal swelling, excessive exertional tachycardia, syncope, bradycardia, and palpitations (Table 2). History of recent unplanned cardiac hospitalization should also be recorded and taken into account.

All patients should undergo ECG, assessment of cardiac biomarkers [70] (N-terminal prohormone of brain-type natriuretic peptide [NT-proBNP], troponin I or troponin T, or high-sensitivity troponin), and functional exercise-based tests, such as the 6-min walk test (6MWT) [71]. However, interpretation of exercise-based tests, such as 6MWT can be complicated by concurrent peripheral neuropathy. Similarly, New York Heart Association (NYHA) classification, which is routinely used to assess the patient condition, has limited reproducibility and meaning in patients with peripheral neuropathy [72]. Cardiopulmonary exercise testing could be used as a second-line tool to quantify exercise tolerance in terms of blood pressure and heart rate response, and measure gas exchange to quantify the severity of HF; currently it is not routinely used for monitoring. However, it provides prognostic information in patients who have cardiac deterioration and are being considered for heart transplantation.

Multimodal cardiac imaging [73] (including echocardiography, “bone” scintigraphy [74, 75], and cardiac magnetic resonance imaging [cMRI] [76, 77]) is useful in monitoring the disease, particularly at crucial junctures. For example, this multimodal approach can be valuable at the patient's first evaluation or after significant progression has been detected using other assessments. For more regular patient monitoring, when there is no clear change in disease status, it is possible to just include a single imaging modality, such as echocardiography.

Typical echocardiography is that of preserved ejection fraction with a reduced left ventricular (LV) chamber and thickened myocardial walls. The thickened interatrial septum, thickened valves, and progressive dilatation of the left atrium are typically accompanied by elevation of LV filling pressure and pulmonary hypertension, while ejection fraction remains normal and end diastolic LV volume is normal or reduced. It is informative to obtain echocardiographic strain measurements, as this pathology is associated with reduced LV global longitudinal strain with apical sparing (typical apical-to-basal strain ratio > 2.1) with LV ejection fraction-to-strain ratio > 4. In the late stage of the disease systolic function is also impaired. cMRI typically shows thickened myocardium and morphologic features similar to those provided by echocardiogram, and may also show late gadolinium enhancement in ventricles and atria, increased values of longitudinal relaxation time (T1) mapping, and increased extracellular volume. Finally, cardiac scintigraphy shows uptake of the tracers used for bone scintigraphy (99mTc-3,3-diphosphono-1,2-propanodicarboxylicacid or pyrophosphate) (which is never observed in a normal heart) in the setting of ATTR amyloidosis or light-chain amyloidosis. As such, it may be preferable to perform scintigraphy after gammopathy has been excluded by serum and protein electrophoresis or immunofixation electrophoresis. Single photon emission computed tomography of “bone” tracers allows quantification and reclassification of cardiac uptake grading in patients with ambiguous results on conventional planar acquisitions.

For the cardiac imaging techniques of echocardiography, “bone” scintigraphy, and cMRI, we recommend that, as far as possible, each type of assessment is performed by the same operator with experience of amyloid cardiomyopathy, on the same machine, using the same software, in order to ensure consistency and enable the tracking of small changes in measurements. The use of “cut off values” can be misleading, as they do not take into account the existence of a “gray zone” corresponding to disease onset. The limited reproducibility of cardiac imaging should also be taken into account during monitoring. For this reason, it is important that multiple assessments are taken, and that disease progression is not over-diagnosed based on changes in a single imaging modality.

Vigilance should be maintained regarding symptomatic or asymptomatic conduction abnormalities such as new bundle branch block or sinus node dysfunction, atrioventricular block (which may require electrophysiologic testing and/or pacemaker implantation), and cardiac arrhythmias (usually atrial fibrillation). An implantable cardiac monitor may assess the arrhythmia burden and identify the need for pacemakers or other treatments. If the patient already has a pacemaker implanted, interrogating the pacemaker memory can allow detection of bouts of asymptomatic atrial fibrillation requiring anticoagulation. Electrophysiologic study could also be considered in cases of asymptomatic conduction abnormalities, such as left or right bundle branch block and/or prolonged PR interval, or in cases of infiltrative cardiomyopathy, even if the ECG is normal [22].

In conjunction with these tests, it may also be useful to monitor patients using a cardiac amyloidosis-specific prognostic staging system. Grogan et al. described a system that classified patient risk based on threshold levels of 2 cardiac biomarkers (troponin T and NT-proBNP) in patients with amyloidogenic transthyretin (wild-type) (ATTRwt) amyloidosis [70]. Gillmore et al. described a similar system based on thresholds of NT-proBNP and estimated glomerular filtration rate (eGFR) in patients with either ATTRwt or ATTRv amyloidosis [78]. The staging systems predict increased risk of mortality in patients with levels of cardiac biomarkers above threshold and/or eGFR below threshold compared with patients not meeting those criteria [70, 78]. Recently, a retrospective study of 945 patients with ATTR amyloidosis with cardiomyopathy showed that baseline evaluation and progression of ATTR stage could predict mortality at follow-up [79]. However, their routine use in patient monitoring is not yet established worldwide.

Right-heart catheterization is clinically useful in patients undergoing evaluation for heart transplantation but is invasive in nature and thus considered unsuitable for routine monitoring. It is commonly replaced by refined echocardiographic assessment and use of NT-proBNP for a more physiologic hemodynamic assessment.

Ophthalmologic manifestations

Ophthalmologic dysfunction caused by amyloid deposits in the vitreous body can be captured by testing for vitreous opacities and glaucoma whereas ocular autonomic dysfunction can be identified by testing for abnormal conjunctival vessels (ACVs), keratoconjunctivitis sicca (KCS), and pupillary abnormalities [80,81,82,83].

Other disease manifestations and quality of life

Symptoms and signs caused by dysfunction in the renal systems are also shown in Table 2. Relevant renal tests include eGFR, creatinine clearance, albuminuria, and proteinuria.

Multiple organs and systems affected by ATTRv amyloidosis can cause a range of symptoms including unexplained weight loss, nausea, and fatigue. Reduction in quality of life (QOL) due to this multisystem impairment has been measured in clinical trials using the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Questionnaire, 36-item Short-Form Health Survey (SF-36), and Kansas City Cardiac Questionnaire (KCCQ) [32, 33, 48, 84]. Although these questionnaires are not typically used in clinical practice, with suitable training they are easy to administer and can even be completed outside the clinic. Patient health more generally should be assessed by measuring body mass index (BMI), modified BMI (mBMI; BMI [kg/m2] × serum albumin [g/L]), and weight. mBMI is preferred to measure nutritional status in patients with ATTRv amyloidosis as low serum albumin levels and fluid retention may result in normal BMI measurements despite worsening nutritional status [85]. In patients receiving TTR gene-silencing therapies, it is also useful to monitor serum prealbumin at baseline and every 6 months.

Disease progression

As ATTRv amyloidosis progresses, affected organs become increasingly impaired, and most of the associated symptoms become worse over the course of the disease [1]. Patient-based assessments must be considered, and the patient should be followed by the same physician to minimize subjective bias. Consequently, disease progression can be defined as:

  • The worsening of several existing quantifiable symptoms, signs, or objective test results (Tables 2, 3, 4). For example, increased weight and dyspnea requiring increase of diuretics dose.

  • The appearance of a new symptom.

  • The worsening of a single symptom that results in a meaningful increase in functional impairment. For example, sensory loss in the fingertips which precludes a patient from dressing, or cooking for themselves, or interferes with their job.

  • Several specific combinations of signs and symptoms that can indicate progression (Table 5).

Table 3 Assessments for monitoring progression in somatic and autonomic neuropathy in recommended order of importance
Table 4 Assessments for monitoring progression in cardiac dysfunction
Table 5 Scenarios of clinically significant worsening in ATTRv amyloidosis that may prompt a change of therapy

Progression should also be viewed in light of the aggressive nature of ATTRv amyloidosis, such that rate of worsening remains an important measure for physicians.

Somatic neuropathy

Somatic neuropathy in ATTRv amyloidosis frequently affects the distal lower limbs first, followed by the distal upper limbs, with the neuropathy spreading proximally as the disease advances. However, the upper limbs are also affected earlier in the course of ATTRv amyloidosis than other neuropathies.

The appearance of new somatic neuropathy symptoms or the worsening of existing signs or symptoms may indicate progression (Tables 2, 3).

Gait disturbances

In general, FAP stage is too insensitive to be useful in tracking gradual disease progression, especially in patients with EO V30M, as it may take 5 years to transition between stages [56]. However, changes in PND score can occur approximately every 18 months in patients with LO V30M disease [44, 45, 56], signposting increased functional impairment and thus progression.

Disability

Alternative measures of neuropathy impairment include the R-ODS score; here changes of −4.0 points and −8.9 points over 9 and 18 months, respectively, were observed in the placebo arm of the APOLLO trial in patients with ATTRv amyloidosis with polyneuropathy (from a baseline mean [SD] of 29.8 [10.8]) [32]. As such, this can be used as a guide as to whether the patient’s disease is progressing [86], although this subjective score should be assessed in association with objective tests.

Autonomic neuropathy

A case for disease progression can be made if a current autonomic symptom worsens or new symptoms develop. For example, the combination of de novo persistent diarrhea with weight loss could indicate progression. Alternatively, the onset of orthostatic hypotension may herald disease progression. Table 3 includes a list of tests that have been used to detect autonomic symptoms and their sensitivity to progression.

Amyloid cardiomyopathy

In contrast to the symptoms of neuropathy, some cardiac symptoms do not worsen in a linear fashion but rather follow a threshold pattern or may be reversible over the short to medium term with suitable symptomatic treatment, such as diuretics, despite underlying progression of cardiac impairment. This situation complicates the use of worsening cardiac symptoms or NYHA classification (Table 2) alone to evaluate the progression of cardiac dysfunction, yet a range of potential avenues of investigation are available (Table 4).

The progression of amyloid cardiomyopathy should be suspected if the clinical events described in Table 5 are observed. However, care must be taken during the interpretation of these assessments and certain caveats should be considered. While the combination or worsening of echocardiogram parameters and cMRI parameters can indicate progression, both modalities have less than perfect reproducibility and problems detecting meaningful short-term variations. For example, in the 30-month ATTR-ACT study, the treatment difference in the interventricular wall thickness determined by echocardiogram was less than 0.5 mm and not reported as being significant, despite significant improvements in other disease measures (e.g. 6MWT and KCCQ-Overall Summary score) [84]. However, instead of absolute size measurements, recent data suggest that changes in echocardiographic strain measurements may serve as a more specific measure of progression in cardiac amyloidosis [87].

Among the other imaging methodologies, cMRI T1 and extracellular volume measurements have high sensitivity which allow changes to be observed between consecutive scans. However, caution should be used as these measurements have a wide standard deviation. With respect to scintigraphy, this technique represents a major advancement for diagnosis, but it lacks spatial resolution and its ability to provide absolute quantification of amyloid load remains to be demonstrated, and thus cannot be used widely to accurately assess modest variations during longitudinal follow-up. Furthermore, and considering radiation exposure, scintigraphy should only be repeated if the initial scan was negative, and then in the case of suspicion of disease progression based on clinical judgment, modifications of ECG, NT-proBNP, and/or echocardiography or cMRI, with a minimal interval of 3 years.

Both cardiac amyloidosis staging systems use levels of biomarkers (high-sensitivity troponin and NT-proBNP) that reflect myocyte injury and stress rather than factors directly driving disease progression [70, 78]. As such, they fail to capture progression in cardiac dysautonomia and conduction abnormalities. Furthermore, NT-proBNP levels can fluctuate in response to atrial fibrillation, diuretic treatment, or renal insufficiency [88] and for this reason some clinicians prefer to use the staging systems as prognostic instruments rather than tools to track progression. Staging assessment can only provide insight into the status of cardiac dysfunction when used in conjunction with other appropriate tests, although a persistent change in the patient’s stage could also be recognized as disease progression.

In summary, clinical judgment should remain the cornerstone of patient assessment when monitoring cardiac disease progression. Clinical examination, ECG, echocardiography (by the same operator), and biomarker analysis should be performed at each appointment. Care must be taken when looking for specific combinations of symptoms, weight, and the need for diuretics dose adjustment. All other modalities should be used as clinically needed.

General health and other organs

Signs and symptoms to consider for disease progression in other organs and systems are listed in Table 2. Onset of new ophthalmologic dysfunction can be captured by testing for ACVs, KCS, vitreous opacities, pupillary abnormalities, and glaucoma at monitoring visits. eGFR should be monitored carefully as a reduction can indicate progression in renal dysfunction and low values are a predictor of mortality [78]. Onset of albuminuria and urine proteinuria can also indicate disease progression.

Weight change

Among the symptoms of general health, weight loss is very important. In combination with worsening or onset of other symptoms, reduction in mBMI of 12% over 18 months (the decline in mBMI observed in patients treated with placebo in the APOLLO trial from a baseline mean [SD] of 989.9 [214.2]) [32] could be an indicator of disease progression.

Well-being

There is good evidence from a number of clinical trials that decline in QOL can be used as a parallel, holistic measure of disease progression [32, 33, 48, 84]. As a guide to aid clinical judgment, a change in Norfolk QOL-DN of + 14.4 points has been observed over 18 months from a baseline mean (SD) of 55.5 (24.3) in a placebo-treated population of patients with either FAP stage 1 (48%), or FAP stage 2 or 3 (51%) disease [32]. Additionally, a change in Norfolk QOL-DN of approximately + 4 points over 12 months from a baseline mean (SD) of 30.8 (26.7) has been observed in patients treated with placebo with V30M FAP stage 1 disease [47]. Similarly, using data from the placebo arm of clinical studies, a change in the SF-36 physical component of − 1.9 points was observed over 12 months from a baseline mean (SD) of 34.8 (11) in patients with ATTRv amyloidosis with polyneuropathy (FAP stage 1 [66.6%], or FAP 2 or 3 [33.4%]) [48], while the KCCQ score decreased by approximately − 5.6 points over 6 months from a baseline mean (SD) of 65.9 (21.7) in patients with ATTRv amyloidosis with cardiomyopathy at NYHA ≤ III [84]. However, QOL questionnaires are subjective measurements and should always be assessed in association with objective tests.

Frequency of monitoring and time required to confirm worsening

Predicting the symptoms and rapidity of progression from the patient’s TTR genotype is difficult due to the variability of ATTRv amyloidosis. Therefore, even patients presenting with only 1 class of symptoms (e.g. neuropathy or cardiac) should have at least a yearly follow-up with appropriate specialists to check the different classes of ATTRv amyloidosis symptoms (somatic and autonomic neuropathy, amyloid cardiomyopathy, and other disease manifestations). Figure 1 summarizes monitoring of ATTRv amyloidosis in a simple algorithm covering baseline assessment, treatment initiation, and follow-up.

Fig. 1
figure1

Disease-monitoring algorithm. aQuestionnaire to be performed prior to consultation. bAdditional test. 6MWT 6-min walk test, ACV abnormal conjunctival vessel, cMRI cardiac magnetic resonance imaging, COMPASS-31 Composite Autonomic Symptom Score-31, DPD 99mTc-3,3-diphosphono-1,2-propanodicarboxylicacid, ECG electrocardiogram, eGFR estimated glomerular filtration rate, HRDB heart rate deep breathing, KCCQ Kansas City Cardiac Questionnaire, KCS keratoconjunctivitis sicca, mBMI modified body mass index, NCS nerve conduction study, Norfolk QOL-DN Norfolk Quality of Life-Diabetic Neuropathy, NT-proBNP N-terminal prohormone of brain-type natriuretic peptide, OH orthostatic hypotension, OLT orthotopic liver transplantation, PND polyneuropathy disability, PYP 99mTc-pyrophosphate, QOL quality of life, R-ODS Rasch-built Overall Disability Scale, SF-36 36-item Short-Form Healthy Survey, SFN-SIQ small-fiber neuropathy and symptom inventory questionnaire

Assessments can be adjusted based on the patient’s evolving symptoms. For example, stable patients (e.g. post-orthotopic liver transplantation patients with EO V30M disease) may only need to be seen once a year whereas the frequency of monitoring should be increased to once every 6 months in patients with worsening neurologic scores and symptoms. For patients with predominant peripheral neuropathy, monitoring over at least 1 year, including 2 consecutive measures, is needed to confirm worsening.

In patients with cardiac involvement, the typical interval should be 6 months adjusted by clinical judgment of risk. For example, the period between assessments could be shortened if the patient shows an increased severity of HF and/or HF events, whereas it could be extended in patients who respond well to symptomatic treatments. For V122I, T60A, and other variants or familial history associated with severe amyloid cardiomyopathies, more aggressive monitoring with cardiac screening is recommended. Patients should also be screened with echocardiography every 12 months, and with cMRI if clinically indicated.

Treatment initiation

Each patient with symptomatic ATTRv amyloidosis should benefit from DMT, with early treatment imperative as ATTRv amyloidosis is rapidly progressive [1]. While symptomatic treatment is a key consideration for physicians, patients with a diagnosis of ATTRv amyloidosis should be prescribed a DMT immediately, providing that the symptoms can be proven to be related to the disease.

Based on current country-specific indications, clinicians should consider which therapies are suitable for the patient’s symptoms (polyneuropathy, cardiac amyloidosis, or both) and the patient’s disease stage. At present, there are no DMTs for the ocular or central nervous system symptoms of ATTRv amyloidosis, although RNA interference agents targeting these systems are under development [89, 90]. Furthermore, strategies to reduce TTR levels are also in planned/ongoing studies in patients with ATTR amyloidosis with cardiomyopathy [91, 92]. It should also be noted that there is currently a lack of head-to-head evidence for the approved therapies, so no universal guidelines can be proposed, and thus clinical judgment should be exercised over the choice of treatment.

Conclusions

ATTRv amyloidosis is a rare, progressive, and fatal disease in which early therapeutic intervention is key to achieving better patient outcomes. While recently approved DMTs have greatly enhanced treatment options, they have also highlighted the need for guidance on managing ATTRv amyloidosis. In order to monitor the disease course, clinicians should undertake detailed assessment of the multiple symptoms and signs of somatic and autonomic neuropathy, cardiac dysfunction, and other disease manifestations at baseline and during follow-up. Regular monitoring of signs and symptoms (both patient-based assessments and follow-up by the same physician) across these categories is required to detect disease progression and identify non-responders, supported by clinical scales, additional tests, and biomarkers. This multisystem approach to management reflects the mixed phenotype observed in the majority of symptomatic patients and highlights the need to develop therapies that target disease pathophysiology that can thus impact multiple manifestations.

There have been great advances in treatments for ATTRv amyloidosis. However, the management of patients whose disease has progressed despite first-line therapy is currently uncertain. Clearly, there is a need for agreement on how to identify non-responders to new treatments and how/when to change their treatment. We hope that our recommendations can contribute toward this goal by providing definitions and examples of clinically meaningful disease progression. These proposals should be validated by a wider group of physicians using the Delphi method to reach a consensus on monitoring disease progression in ATTRv amyloidosis. Treatment of asymptomatic patients with proven target organ involvement will be the subject of future guidance.

Availability of data and materials

Not applicable.

Abbreviations

6MWT:

6-min walk test

10MWT:

10-m walk test

ACV:

Abnormal conjunctival vessel

ATTRv:

Hereditary transthyretin (v for variant)

AV:

Atrioventricular

BMI:

Body mass index

BP:

Blood pressure

CADT:

Compound Autonomic Dysfunction Test

CHF:

Chronic heart failure

cMRI:

Cardiac magnetic resonance imaging

COMPASS-31:

Composite Autonomic Symptom Score-31

DMT:

Disease-modifying therapy

DPD:

99mTc-3,3-diphosphono-1,2-propanodicarboxylicacid

ECG:

Electrocardiogram

ECV:

Extracellular volume

EF:

Ejection fraction

eGFR:

Estimated glomerular filtration rate

EO:

Early-onset

EPS:

Electrophysiologic study

FAP:

Familial amyloid polyneuropathy

GI:

Gastrointestinal

GU:

Genitourinary

HF:

Heart failure

HRDB:

Heart rate deep breathing

H/L:

Heart-to-lung

HRV:

Heart rate variability

IV:

Intravenous

KCCQ:

Kansas City Cardiac Questionnaire

KCS:

Keratoconjunctivitis sicca

LL:

Lower limb

LO:

Late-onset

LV:

Left ventricular

mBMI:

Modified body mass index

MIBG:

Metaiodobenzylguanidine

NCS:

Nerve conduction study

NIS:

Neuropathy impairment score

Norfolk QOL-DN:

Norfolk Quality of Life-Diabetic Neuropathy

NT-proBNP:

N-Terminal prohormone of brain-type natriuretic peptide

NYHA:

New York Heart Association

OH:

Orthostatic hypotension

OLT:

Orthotopic liver transplantation

PND:

Polyneuropathy disability

PYP:

99mTc-pyrophosphate

QOL:

Quality of life

R-ODS:

Rasch-built Overall Disability Scale

SF-36:

36-Item Short-Form Health Survey

SFN-SIQ:

Small-fiber neuropathy and symptom inventory questionnaire

SNAP:

Sensory nerve action potential

T1:

Longitudinal relaxation time

UL:

Upper limb

VAS:

Visual analog scale

VF:

Ventricular fibrillation

VT:

Ventricular tachycardia

References

  1. 1.

    Adams D, Coelho T, Obici L, Merlini G, Mincheva Z, Suanprasert N, et al. Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology. 2015;85(8):675–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep. 2014;11(1):50–7.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625–38.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387–404.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Soprano DR, Herbert J, Soprano KJ, Schon EA, Goodman DS. Demonstration of transthyretin mRNA in the brain and other extrahepatic tissues in the rat. J Biol Chem. 1985;260(21):11793–8.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Cavallaro T, Martone RL, Dwork AJ, Schon EA, Herbert J. The retinal pigment epithelium is the unique site of transthyretin synthesis in the rat eye. Investig Ophthalmol Vis Sci. 1990;31(3):497–501.

    CAS  Google Scholar 

  7. 7.

    Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet. 1991;40(3):242–6.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995;268(5213):1039–41.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Sekijima Y. Recent progress in the understanding and treatment of transthyretin amyloidosis. J Clin Pharm Ther. 2014;39(3):225–33.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A. 2002;99(Suppl. 4):16427–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Kelly JW. Amyloid fibril formation and protein misassembly: a structural quest for insights into amyloid and prion diseases. Structure. 1997;5(5):595–600.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Damy T, Judge DP, Kristen AV, Berthet K, Li H, Aarts J. Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015;8(2):117–27.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Conceição I, Gonzalez-Duarte A, Obici L, Schmidt HH, Simoneau D, Ong ML, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733–48.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286–300.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Dharmarajan K, Maurer MS. Transthyretin cardiac amyloidoses in older North Americans. J Am Geriatr Soc. 2012;60(4):765–74.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 2012;98(21):1546–54.

    PubMed  Article  Google Scholar 

  19. 19.

    Algalarrondo V, Dinanian S, Juin C, Chemla D, Bennani SL, Sebag C, et al. Prophylactic pacemaker implantation in familial amyloid polyneuropathy. Heart Rhythm. 2012;9(7):1069–75.

    PubMed  Article  Google Scholar 

  20. 20.

    van den Berg MP, Mulder BA, Klaassen SHC, Maass AH, van Veldhuisen DJ, van der Meer P, et al. Heart failure with preserved ejection fraction, atrial fibrillation, and the role of senile amyloidosis. Eur Heart J. 2019;40(16):1287–93.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Coutinho MC, Cortez-Dias N, Cantinho G, Conceição I, Oliveira A, Bordalo e Sá A, et al. Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy. Circ Cardiovasc Imaging. 2013;6(5):627–36.

    PubMed  Article  Google Scholar 

  22. 22.

    Algalarrondo V, Antonini T, Théaudin M, Chemla D, Benmalek A, Lacroix C, et al. Cardiac dysautonomia predicts long-term survival in hereditary transthyretin amyloidosis after liver transplantation. JACC Cardiovasc Imaging. 2016;9(12):1432–41.

    PubMed  Article  Google Scholar 

  23. 23.

    Gonzalez-Duarte A. Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis). Clin Auton Res. 2019;29(2):245–51.

    PubMed  Article  Google Scholar 

  24. 24.

    Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T, Doden T, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58–63.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Sperry BW, Reyes BA, Ikram A, Donnelly JP, Phelan D, Jaber WA, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17):2040–50.

    PubMed  Article  Google Scholar 

  26. 26.

    Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid. 2018;25(1):8–10.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709–16.

    PubMed  Article  Google Scholar 

  28. 28.

    Rowczenio DM, Noor I, Gillmore JD, Lachmann HJ, Whelan C, Hawkins PN, et al. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat. 2014;35(9):E2403–12.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, et al. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol. 2016;29(Suppl. 1):S3–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013;34(7):520–8.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    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(1):63–76.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22–31.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Plante-Bordeneuve V, Carayol J, Ferreira A, Adams D, Clerget-Darpoux F, Misrahi M, et al. Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. J Med Genet. 2003;40(11):e120.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Mazzeo A, Russo M, Di Bella G, Minutoli F, Stancanelli C, Gentile L, et al. Transthyretin-related familial amyloid polyneuropathy (TTR-FAP): a single-center experience in Sicily, an Italian endemic area. J Neuromuscul Dis. 2015;2(s2):S39–48.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Alves-Ferreira M, Coelho T, Santos D, Sequeiros J, Alonso I, Sousa A, et al. A trans-acting factor may modify age at onset in familial amyloid polyneuropathy ATTRV30M in Portugal. Mol Neurobiol. 2018;55(5):3676–83.

    CAS  PubMed  Google Scholar 

  37. 37.

    Adams D, Lozeron P, Lacroix C. Amyloid neuropathies. Curr Opin Neurol. 2012;25(5):564–72.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Adams D, Lozeron P, Theaudin M, Mincheva Z, Cauquil C, Adam C, et al. Regional difference and similarity of familial amyloidosis with polyneuropathy in France. Amyloid. 2012;19(Suppl. 1):61–4.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Plante-Bordeneuve V, Ferreira A, Lalu T, Zaros C, Lacroix C, Adams D, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). Neurology. 2007;69(7):693–8.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Swiecicki PL, Zhen DB, Mauermann ML, Kyle RA, Zeldenrust SR, Grogan M, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123–31.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012;33(9):1120–7.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222–8.e1.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Miller AB, Januzzi JL, Neill BJ, Gundapaneni B, Patterson TA, Sultan MB, et al. Causes of cardiovascular hospitalization and death in the tafamidis in transthyretin cardiomyopathy clinical trial (ATTR-ACT). J Am Coll Cardiol. 2020;75(11 Suppl. 1):692.

    Article  Google Scholar 

  44. 44.

    Mariani LL, Lozeron P, Theaudin M, Mincheva Z, Signate A, Ducot B, et al. Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015;78(6):901–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry. 2012;83(2):152–8.

    PubMed  Article  Google Scholar 

  46. 46.

    Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847–54.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Plante-Bordeneuve V, Lozeron P, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Judge DP, Heitner SB, Falk RH, Maurer MS, Shah SJ, Witteles RM, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019;74(3):285–95.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Obici L, Kuks JB, Buades J, Adams D, Suhr OB, Coelho T, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29(Suppl. 1):S27-35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Conceição I, Damy T, Romero M, Galan L, Attarian S, Luigetti M, et al. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019;26:3–9.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Conceição I, Coelho T, Rapezzi C, Parman Y, Obici L, Galán L, et al. Assessment of patients with hereditary transthyretin amyloidosis—understanding the impact of management and disease progression. Amyloid. 2019;26(3):103–11.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Coutinho P, DeSilva AM, Lima JL, Barbosa AR. Forty years of experience with type I amyloid neuropathy: review of 483 cases. In: Glenner G, Costa P, de Freitas A, editors. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980. p. 88–98.

    Google Scholar 

  54. 54.

    Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Intern Med. 1994;235(5):479–85.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Dyck PJ, Boes CJ, Mulder D, Millikan C, Windebank AJ, Dyck PJ, et al. History of standard scoring, notation, and summation of neuromuscular signs. A current survey and recommendation. J Peripher Nerv Syst. 2005;10(2):158–73.

    PubMed  Article  Google Scholar 

  56. 56.

    Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord. 2013;6(2):129–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA, et al. Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014;344(1–2):121–8.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Dyck PJ, Kincaid JC, Dyck PJB, Chaudhry V, Goyal NA, Alves C, et al. Assessing mNIS+7IONIS and international neurologists’ proficiency in a familial amyloidotic polyneuropathy trial. Muscle Nerve. 2017;56(5):901–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Middleton A, Fritz SL, Lusardi M. Walking speed: the functional vital sign. J Aging Phys Act. 2015;23(2):314–22.

    PubMed  Article  Google Scholar 

  60. 60.

    Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39(2):142–8.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    van Nes SI, Vanhoutte EK, van Doorn PA, Hermans M, Bakkers M, Kuitwaard K, et al. Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology. 2011;76(4):337–45.

    PubMed  Article  Google Scholar 

  62. 62.

    Denier C, Ducot B, Husson H, Lozeron P, Adams D, Meyer L, et al. A brief compound test for assessment of autonomic and sensory-motor dysfunction in familial amyloid polyneuropathy. J Neurol. 2007;254(12):1684–8.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Lefaucheur JP, Zouari HG, Gorram F, Nordine T, Damy T, Plante-Bordeneuve V. The value of electrochemical skin conductance measurement using Sudoscan® in the assessment of patients with familial amyloid polyneuropathy. Clin Neurophysiol. 2018;129(8):1565–9.

    PubMed  Article  Google Scholar 

  64. 64.

    Castro J, Miranda B, Castro I, de Carvalho M, Conceição I. The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy. Clin Neurophysiol. 2016;127(5):2222–7.

    PubMed  Article  Google Scholar 

  65. 65.

    Shields RW Jr. Heart rate variability with deep breathing as a clinical test of cardiovagal function. Cleve Clin J Med. 2009;76(Suppl. 2):S37–40.

    PubMed  Article  Google Scholar 

  66. 66.

    Koike H, Nakamura T, Hashizume A, Nishi R, Ikeda S, Kawagashira Y, et al. Cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy. J Neurol. 2017;264(11):2293–302.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Delahaye N, Le Guludec D, Dinanian S, Delforge J, Slama MS, Sarda L, et al. Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated hearts by familial amyloid polyneuropathy. Circulation. 2001;104(24):2911–6.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Azevedo Coutinho MDC, Cortez-Dias N, Cantinho G, Conceição I, Guimarães T, Lima da Silva G, et al. Progression of myocardial sympathetic denervation assessed by (123)I-MIBG imaging in familial amyloid polyneuropathy and the effect of liver transplantation. Rev Port Cardiol. 2017;36(5):333–40.

    PubMed  Article  Google Scholar 

  69. 69.

    Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012;87(12):1196–201.

    PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68(10):1014–20.

    PubMed  Article  Google Scholar 

  71. 71.

    Balke B. A simple field test for the assessment of physical fitness. Rep 63–6. Rep Civ Aeromed Res Inst US. 1963;1–8.

  72. 72.

    New York Heart Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston: Lippincott Williams and Wilkins; 1994.

    Google Scholar 

  73. 73.

    Eliahou L, Chequer R, Ou P, Algalarrondo V, Antonini T, Slama M, et al. Multi-modality imaging in cardiac ATTR amyloidosis: agreement between echocardiography, MRI and DPD-scintigraphy. Orphanet J Rare Dis. 2015;10(1):O17.

    PubMed Central  Article  Google Scholar 

  74. 74.

    Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al. Role of 99mTc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging. 2011;4(6):659–70.

    PubMed  Article  Google Scholar 

  75. 75.

    Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, et al. Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis. JAMA Cardiol. 2016;1(8):880–9.

    PubMed  Article  Google Scholar 

  76. 76.

    Martinez-Naharro A, Treibel TA, Abdel-Gadir A, Bulluck H, Zumbo G, Knight DS, et al. Magnetic resonance in transthyretin cardiac amyloidosis. J Am Coll Cardiol. 2017;70(4):466–77.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Haaf P, Garg P, Messroghli DR, Broadbent DA, Greenwood JP, Plein S. Cardiac T1 mapping and extracellular volume (ECV) in clinical practice: a comprehensive review. J Cardiovasc Magn Reson. 2016;18(1):89.

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799–806.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Law S, Petrie A, Chacko L, Cohen OC, Ravichandran S, Gilbertson JA, et al. Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage. ESC Heart Fail. 2020;7(6):3942–9.

    PubMed Central  Article  Google Scholar 

  80. 80.

    Rousseau A, Kaswin G, Adams D, Cauquil C, Théaudin M, Mincheva Z, et al. Ocular involvement in familial amyloid polyneuropathy. J Fr Ophtalmol. 2013;36(9):779–88.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Martins AC, Rosa AM, Costa E, Tavares C, Quadrado MJ, Murta JN. Ocular manifestations and therapeutic options in patients with familial amyloid polyneuropathy: a systematic review. Biomed Res Int. 2015;2015:282405.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Beirao JM, Malheiro J, Lemos C, Beirao I, Costa P, Torres P. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. Amyloid. 2015;22(2):117–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Reynolds MM, Veverka KK, Gertz MA, Dispenzieri A, Zeldenrust SR, Leung N, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthalmol. 2017;183:156–62.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007–16.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    González-Duarte A, Berk JL, Quan D, Mauermann ML, Schmidt HH, Polydefkis M, et al. Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. J Neurol. 2020;267(3):703–12.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Obici L, Berk JL, González-Duarte A, Coelho T, Gillmore J, Schmidt HH, et al. Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. Amyloid. 2020;27(3):153–62.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357–77.

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Dittrich T, Benner A, Kimmich C, Siepen FAD, Veelken K, Kristen AV, et al. Performance analysis of AL amyloidosis cardiac biomarker staging systems with special focus on renal failure and atrial arrhythmia. Haematologica. 2019;104(7):1451–9.

    PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Jadhav V. Advances in RNAi therapeutics platform. In: 3rd International conference on the long and the short of non-coding RNAs; 18–23 June 2019; Chania, Crete, Greece.

  90. 90.

    McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Investig. 2018;128(8):3558–67.

    PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Alnylam Pharmaceuticals Inc. Clinical trial: HELIOS-B: a study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. 2020. Available from https://clinicaltrials.gov/ct2/show/NCT04153149?term=NCT04153149&draw=2&rank=1. Accessed 1 July 2021.

  92. 92.

    Ionis Pharmaceuticals Inc. Clinical trial: CARDIO-TTRansform: a study to evaluate the efficacy and safety of AKCEA-TTR-LRx in participants with transthyretin-mediated amyloid cardiomyopathy (ATTR CM). 2019. Available from https://clinicaltrials.gov/ct2/show/NCT04136171?term=NCT04136171&draw=2&rank=1. Accessed 1 July 2021.

  93. 93.

    Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743–9.

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

Administration of the questionnaire and editorial assistance was provided by Ed Childs, PhD of Adelphi Communications (Macclesfield, UK) in accordance with the Good Publication Practice guidelines.

Funding

Unconditional financial support for article processing fees, administration of the questionnaire, and editorial assistance was given by Alnylam Pharmaceuticals (Cambridge, MA, USA).

Author information

Affiliations

Authors

Contributions

All authors contributed their clinical opinions, designed the tables and figures, and wrote and revised the report. All authors approved the submitted version. The views and opinions expressed in the manuscript are solely those of the authors. All authors read and approved the final manuscript.

Authors' information

David Adams is a neurologist at the Centre Hospitalier Universitaire (CHU) Bicêtre, at Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Saclay. DA is Head of the Neurology Department and the French Reference Center for hereditary amyloidosis with polyneuropathy (ATTRv) and other rare peripheral neuropathies. He was also involved in building the European Network for ATTR amyloidosis and the development of the main disease-modifying therapies. DA’s main areas of expertise are peripheral neuropathies, including ATTRv amyloidosis. He is the president of the French Society of Peripheral Neuropathy and member of the Scientific Panel on Neuropathies of EAN.

Vincent Algalarrondo is a cardiologist at the Centre Hospitalier Universitaire (CHU) Xavier Bichat Claude-Bernard hospital, at Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris. VA is part of the Centre de Compétence Amyloses Cardiaques, Member of the French National Reference Center for Familial Amyloid Polyneuropathy (CRMR-NNERF). VA’s research interests include cardiac amyloidosis, cardiac arrhythmias, and chronic heart failure.

Michael Polydefkis is a neurologist at Johns Hopkins University School of Medicine, Baltimore. He received his medical degree from Johns Hopkins University in 1993 and completed a Fellowship in Neurology at the same institution. MP is Co-Director of the Cutaneous Nerve Laboratory. His expertise includes nerve conduction studies, electromyography, and nerve, skin, and muscle biopsy reading. MP’s research focuses on neuromuscular diseases, particularly peripheral nerve diseases including ATTRv amyloidosis and diabetic and HIV-associated peripheral neuropathy. In 2019 MP received the Donlin M. Long Award.

Nitasha Sarswat is an assistant professor of medicine and cardiologist at the University of Chicago. She received her medical degree from Northwestern University (2005) and completed fellowships in Cardiovascular Disease at UMDNJ Hospitals and in Advanced Heart Failure and Transplantation at Montefiore Medical Center and Massachusetts General Hospital. She is Director of the Infiltrative Cardiomyopathy Program at University of Chicago Hospital and Section Head of Advanced Heart Failure at NorthShore University Hospital. NS has particular expertise in cardiac amyloidosis and sarcoidosis and has published over 50 articles on advanced heart failure, mechanical circulatory support, and transplantation.

Michel S. Slama is a professor of cardiology at Xavier Bichat Claude-Bernard hospital and Université Paris-Saclay. He is Head of the Centre de Compétence Amyloses Cardiaques and Member of the French National Reference Center for Familial Amyloid Polyneuropathy (CRMR-NNERF) since 2005. His group has published research on multimodality imaging for early detection of amyloid cardiomyopathy, prophylactic pacing for conduction disorders, and the diagnostic and prognostic value of sympathetic and parasympathetic denervation. MSS took part in the Phase III studies of new disease-modifying therapies, focusing on the assessment of their cardiac effects, including tafamidis, inotersen, patisiran, and revusiran.

Jose Nativi-Nicolau is a board-certified heart failure cardiologist at the University of Utah. He received his medical degree from the University of Panama, and completed Fellowships in Cardiology at the University of Utah and in Advanced Heart Failure and Transplantation at the Mayo Clinic. He is the Cardiovascular Director of the Amyloidosis Program at the University of Utah and Huntsman Cancer Institute. JN-N’s research interests include cardiac amyloidosis, heart failure, mechanical circulatory support, and heart transplantation. JN-N is a co-author in major clinical trials and scientific statements in the field of amyloidosis.

Corresponding author

Correspondence to Jose Nativi-Nicolau.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

DA acknowledges consultancy fees and institutional grants from Alnylam Pharmaceuticals and Pfizer Inc., and symposium honoraria from Pfizer Inc. outside the submitted work. VA reports consultancy fees from Pfizer Inc. and consultancy fees and institutional grants from Alnylam Pharmaceuticals outside the submitted work. JN-N’s institution received funding for clinical trials for Pfizer Inc., Akcea Therapeutics, and Eidos, and educational grants from Pfizer Inc., and received consulting income from Pfizer Inc., Eidos, Akcea Therapeutics, and Alnylam Pharmaceuticals outside the submitted work. MP reports consultancy and principal investigator fees from Alnylam Pharmaceuticals in relation to this work and from Alnylam Pharmaceuticals, Ionis Pharmaceuticals, and Pfizer Inc. outside the submitted work. NS reports funding for clinical trials for Pfizer, Akcea/Ionis, Alnylam, and Eidos, and consulting income from Pfizer, Akcea, and Alnylam. MSS acknowledges personal consultancy fees and symposium honoraria from Alnylam Pharmaceuticals and Pfizer Inc. outside the submitted work. The authors were not paid for their work developing the manuscript. The sponsor initially contacted the authors to ascertain their interest in writing the manuscript but had no role in the design, execution, interpretation, or writing of the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1.

Survival of patients with ATTRv amyloidosis.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Adams, D., Algalarrondo, V., Polydefkis, M. et al. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis 16, 411 (2021). https://doi.org/10.1186/s13023-021-01960-9

Download citation

Keywords

  • hATTR amyloidosis
  • ATTRv amyloidosis
  • Amyloid neuropathies
  • Amyloid cardiomyopathies
  • Familial
  • Diagnostic techniques and procedures
  • Disease progression
  • Transthyretin