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This article has been co-authored by a patient living with hereditary transthyretin (ATTRv) amyloidosis and a neurologist, reflecting their experiences of the disease and its symptoms.

The patient describes his array of autonomic, neuropathic, and cardiovascular symptoms, the profound impact they have had on his life, and the struggles he faced with reaching a diagnosis of ATTRv.

The physician provides his perspective on the difficulties of identifying ATTRv due to its rarity and esoteric nature, and highlights the recent expansion of knowledge around this disease and its management.

There is an urgent need to increase awareness of the symptoms and treatment options for ATTRv among patients and physicians to aid diagnosis and treatment of the disease.

Digital Features

This article is published with digital features, including a video, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.26467951.

Patient’s Perspective

First Symptoms

I am a 74-year-old man, living with hereditary transthyretin (ATTRv) amyloidosis. The first symptoms appeared in my early 50s, 10 years before my diagnosis in 2018, and included tingling in my legs and feet, ruptured biceps, back pain, and autonomic symptoms such as erectile dysfunction (ED) and exercise intolerance. I also developed carpal tunnel syndrome. My symptoms worsened throughout the years, and were often attributed to aging, despite being only around 50 when they started. Although I’m older now, treatment has meant that I feel much better than I did at diagnosis.

Before my diagnosis, my symptoms were assessed by different specialists in isolation, meaning they weren’t noticed as being related. Neurologists suggested that neuropathic symptoms were due to pinched nerves, giving medications but no diagnosis. My symptoms progressed, then heart issues began to interfere with my life. Many cardiologists don’t have amyloidosis on their radar, and there were no treatments for ATTRv amyloidosis at the time; there did not seem to be success in identifying it from the symptoms I was presenting with. I have come to understand that, if you can catch the symptoms early and start the treatments that are now available, it could prevent the multiple organ damage that is associated with the disease.

Impact of Symptoms

My symptoms affected my relationship with my wife, as she also bore the burden of my limited abilities, and the symptoms impacted how we are able to spend our time together. ED (or sexual dysfunction) is one of the most frequently occurring symptoms in patients with ATTRv amyloidosis. However, people can be embarrassed to talk about it, even with their doctors. It takes away part of your relationship and can affect feelings of masculinity.

Beyond this, my ability to exercise, which I used to do daily, and my capabilities at work, were also diminished. Despite adapting to the symptoms that appeared gradually, I had to hire someone to help with the more manual side of my work as my symptoms progressed. The most alarming symptoms were those that stopped me doing normal activities, such as walking short distances or carrying things without having to rest, which greatly impacted my work and life in general. Other symptoms like numbness and impaired movement were bothersome, but I could adapt to them. However, I now live with the fact that every time something happens, like aches and pains, I do not know if it is normal or associated with my disease.

Diagnosis Experience

As my various symptoms arose over time, my general practitioner (GP) would send me to many specialists, such as neurologists, urologists, orthopedic doctors, and cardiologists. This meant that my symptoms were observed and managed independently and were therefore not noticed as related.

When I first saw a cardiologist, I was diagnosed with atrial fibrillation. My cardiac condition was rapidly getting worse, so I was prescribed cardioversion. However, the cardiologist who was to perform the procedure happened to be an expert in amyloidosis, and requested further testing, including a cardiac pyrophosphate scan, magnetic resonance imaging (MRI), and an echocardiogram. This finally led to my diagnosis of ATTRv amyloidosis, 10 years after the onset of my symptoms.

Being diagnosed by a physician who is an expert in amyloidosis meant that the disease was explained to me very well. It didn’t sink in at first, and the impact of hearing the prognosis without available treatments was hard, but I preferred that my doctor was honest with me and shared all the important information regarding this diagnosis. This cardiologist is now ‘the ruler of the ship’ in the management of my disease, working alongside other relevant specialists.

As every doctor is concerned with their own specialty, diagnoses unfortunately get missed. There seems to be either insufficient attention paid to ATTRv amyloidosis, or perhaps it is a difficult disease for non-experts to understand. My impression is that diagnosis is difficult because of low awareness by patients, doctors, and even some specialists. Even now, I am unsure whether my GP would know what amyloidosis is or be able to identify it.

Raising Awareness Among Patients and Physicians

Motivated by the prognosis I had been given, I did my research so that I could be well-informed about ATTRv amyloidosis. This has allowed me to advocate for myself when interacting with physicians who didn’t know so much about the disease, which has been very important for how my disease has been managed.

We are the first generation of patients with ATTRv amyloidosis to have treatments available; therefore, I believe that patients have to advocate for themselves and be up to date with the latest research and treatment options, in case their doctor is not. Being involved in clinical trials can also help researchers to in turn help us.

My experiences have shown me that, generally, doctors do not know enough about this disease and how it presents. For example, patients with ATTRv amyloidosis often have high troponin levels. When I was in the intensive care unit being treated for COVID-19, the doctor mistook my high troponin as being a result of a cardiac event, even though I had made them aware of my ATTRv amyloidosis diagnosis. My wife was then incorrectly told that I had suffered a heart attack. This shows that not only cardiologists should be educated but that emergency room doctors, GPs, nurse practitioners and other physicians need to have ATTRv amyloidosis on their radar, so that they have some understanding when they treat patients with this disease.

Physician’s Perspective

First Symptoms

As a specialist in peripheral nerve diseases, I have seen tremendous progress in the understanding of ATTRv amyloidosis and its symptoms in recent years. Hereditary ATTRv amyloidosis is a rare, progressive disease caused by an inherited gene mutation, leading to dysfunction of multiple organs in the body [1]. Having seen over 200 patients with this rare disease, I have observed that people can have different ‘stories’ of how their early symptoms present. For many patients, small fiber neuropathy accounts for the initial symptoms, including pain, tingling, or numbness in the feet, as well as early autonomic symptoms such as gastrointestinal issues (constipation or diarrhea), wooziness when standing, or ED [2, 3]. For other patients, orthopedic issues or heart failure may arise as the early symptoms of the disease.

ATTRv amyloidosis is a rare disease, and early symptoms are often non-specific and can mimic other, more common conditions, such as diabetes [4]. As a result, ATTRv amyloidosis can be misdiagnosed. Early symptoms such as ED or tingling in the feet may be assumed to be diabetes, and, in fact, most of the time, such a diagnosis will be correct. However, one of the key clues that ATTRv amyloidosis may instead be the appropriate diagnosis is the clustering of different symptoms, such as ED in the absence of diabetes, plus tingling in the feet, plus carpal tunnel syndrome. It is important to make the connection between these different symptoms as early as possible. Disease awareness and education are making important strides in improving physicians’ awareness of this.

Impact of Symptoms

There is a spectrum of symptoms associated with ATTRv amyloidosis, and clinical manifestations of the disease often correlate with the specific mutation that a patient harbors, with multiple phenotypes reflecting the variability of the disease. Some mutations lead to ATTRv amyloidosis with polyneuropathy (ATTRv-PN), others result in ATTRv amyloidosis with cardiomyopathy (ATTRv-CM), and many mutations present as a mixed phenotype of both neuropathic and cardiac symptoms [5]. Table 1 shows the key symptoms associated with the ATTRv-PN and ATTRv-CM phenotypes. Different symptoms can affect patients in different ways, adding to the challenge of diagnosing ATTRv amyloidosis. Some patients experience general loss of vigor, blood pressure issues can cause fatigue and lack of strength or endurance, and gastrointestinal issues can range from being annoying to quite profound, as they can affect socializing and prevent people from going out. Additionally, sexual dysfunction is one of the most common symptoms in both male and female patients with ATTRv amyloidosis, affecting over 40% of patients [6]. The neuropathic aspects of the disease can also have a profound impact on daily life. Numbness in the feet can contribute to imbalance, and weakness in the legs can result in fatigue when walking and falling. Manual dexterity tasks can become more challenging, as a result of hand numbness and weakness. With time, these aspects can affect independence and the ability to work [4, 7].

Table 1 Symptoms associated with the polyneuropathic and cardiac phenotypes of ATTRv amyloidosis
Full size table

Diagnosis Experience

It can be challenging for physicians to connect early symptoms of ATTRv amyloidosis with the disease to reach a diagnosis, as they are also associated with other, more common conditions. Gastrointestinal symptoms such as diarrhea might be attributed to irritable bowel syndrome, or an intolerance to specific foods. Symptoms of numbness and mild weakness in the hands and feet are often mistaken for diabetic neuropathy or peripheral neuropathy due to B12 deficiency or other causes. Autonomic symptoms are also often misunderstood [8]: patients may complain of fatigue that actually reflects low blood pressure, or autonomic symptoms can often be presumed to be associated with medication that a patient is receiving for other health issues. Rigorous assessment of autonomic function is also time-consuming and not routinely performed outside of academic centers because of the low likelihood of autonomic dysfunction in the general population.

Of the many physicians that a patient may interact with on their ATTRv amyloidosis diagnosis journey, it is often cardiologists who make the diagnosis. This is because they have extra tools that provide clues that can aid diagnosis, such as imaging or echocardiograms. Echocardiograms can prompt cardiologists to suspect amyloidosis when observing the associated cardiac issues, including left-ventricular wall thickening, diastolic dysfunction, and atrial dilation [9, 10]. Most neurological testing does not offer the same advantage. Additionally, as ATTRv amyloidosis is a genetic, hereditary disease, it is also important to enquire about family history of the disease when ATTRv amyloidosis is suspected, to aid diagnosis and disease management. Family history can go beyond the disease itself, and can include progressive polyneuropathy of unknown cause, cardiac failure or death, or arrhythmia [11].

As it is a rare disease, historically there has been little knowledge and few treatment options for ATTRv amyloidosis, so it was not at the forefront of physicians’ minds. Now that treatments are available, that approach has changed, and there is motivation to make the diagnosis and treat patients.

This article does not contain any new studies with human participants or animals performed by any of the authors.

Raising Awareness Among Patients and Physicians

The medical community is gaining better understanding of ATTRv amyloidosis and realizing the different footprints of how the disease presents. At this point in 2024, the disease is discussed routinely at medical meetings and awareness is increasing, but further progress is still needed. For instance, we need to educate physicians so that they can advocate for and support patients in finding a diagnosis. They should be aware of the symptoms and, although recognition of a combination of symptoms related to polyneuropathic or cardiac manifestations of ATTRv amyloidosis should raise suspicions of the disease early in its course, potential overlap in symptoms of the different phenotypes poses a substantial diagnostic challenge [4]. Therefore, identifying key signs and symptoms across the affected organs (including the most common presenting symptoms of peripheral neuropathy and/or congestive heart failure), rather than a specific combination of symptoms, is crucial [5]. Such symptoms can include progressive peripheral neuropathy, carpal tunnel, tendon ruptures, pain or history of surgery in the hip, shoulder, or knee, heart issues, heart failure, atrial fibrillation, lower back pain, dysautonomia, ED, light-headedness, loss of consciousness, and gastrointestinal symptoms [4]. Beyond improving awareness, facilitating the treatment of a patient at an amyloidosis center is also key, where they can receive expert, multidisciplinary care to address their array of symptoms [4].

Conclusions and Hopes for the Future

Symptoms of ATTRv amyloidosis present early in the disease journey, greatly impacting the relationships, work, and social lives of patients suffering with this disease. Due to the diffuse nature of symptom onset, the potentially siloed approach in which symptoms are often addressed, and a lack of disease awareness among patients and physicians, diagnosis of this disease can be difficult and delayed. Detecting key signs and symptoms across a range of organs and systems will facilitate earlier diagnosis of this disease.

In the last decade, the number of therapeutic options for and the awareness of ATTRv amyloidosis have increased [12]. This has altered disease progression and allowed patients to experience improved quality of life. Increased awareness has also facilitated a multidisciplinary approach to management of the disease, with a wider range of physicians now able to provide specialized care.

We, as a patient and a physician, hope that future therapies will be more accessible, offer better symptom management, and eventually provide a cure for the disease by not just stabilizing or preventing new amyloid deposition but reversing it. We also hope for accelerated processes for regulatory approvals of therapies for rare diseases like this, so that patients currently living with ATTRv amyloidosis can reap the benefits of new therapies as soon as possible.

We acknowledge that there are certain limitations to providing only one patient perspective and one physician perspective. However, the perspectives given here reflect the experiences of other patients and physicians found in the literature [8, 13, 14].