The myriad of mutations identified in the TTR gene translates into distinct phenotypes among patients with hereditary transthyretin amyloidosis (hATTR), even within the same family. Some mutations are more often associated with either polyneuropathy or cardiomyopathy, but in most patients, the disease manifests as a mix of cardiac and neuropathic symptoms.

The diversity in hATTR-associated symptoms can make diagnosis difficult. Cardiovascular signs and symptoms in hATTR can overlap with iron overload and cardiovascular diseases, such as heart failure with preserved ejection fraction, hypertensive cardiomyopathy, aortic stenosis, hypertrophic cardiomyopathy, light chain amyloidosis with cardiac involvement, idiopathic restrictive cardiomyopathy, and other infiltrative cardiomyopathies (eg, Fabry disease).

Neurologic symptoms in hATTR may overlap with chronic inflammatory demyelinating polyneuropathy, paraproteinemic peripheral neuropathy, toxic peripheral neuropathy, vasculitic peripheral neuropathy, idiopathic axonal polyneuropathy, paraneoplastic neuropathy, diabetic neuropathy, alcoholic neuropathy, motor neuron disease, fibromyalgia, and light chain amyloidosis.

As a consequence of misdiagnosis, patients can receive inappropriate treatments (eg, chemotherapy for light-chain amyloidosis and intravenous immunoglobulins or steroids for immune polyneuropathies). The delay in providing appropriate treatment may affect a patient’s quality of life and result in the worsening of symptoms.

Read more about hATTR differential diagnosis

“Because ATTR amyloidosis is now a treatable disease, recognizing the constellation of associated signs and symptoms, including those that are neurologic and musculoskeletal, is important because early treatment will make a meaningful impact on a patient’s quality of life, autonomy, and physical function,” said Nativi‑Nicolau et al in a review article recently published in Heart Failure Reviews.

Recognizing ATTR Symptoms

Though symptoms of cardiomyopathy and/or progressive polyneuropathy are usually predominant in patients with ATTR, other manifestations may occur. These include musculoskeletal symptoms, orthostatic hypotension, erectile dysfunction, gastrointestinal abnormalities, unexplained weight loss, ocular manifestations, and symptoms of nephropathy.

Therefore, according to Nativi‑Nicolau et al, “ATTR amyloidosis should be considered in patients with signs and symptoms associated with cardiac, neurologic, or musculoskeletal manifestations, particularly when the constellation of those symptoms suggests that multiple organs are affected.”

Cardiovascular Symptoms

Cardiac ATTR, as explained by Nativi‑Nicolau et al, “is characterized by increased ventricular wall thickness, increased valve thickness, and interatrial and interventricular septum thickness that present as restrictive cardiomyopathy and progress to heart failure—initially in the setting of preserved ejection fraction, conduction system disturbances, and arrhythmias—with resulting impaired functional capacity, syncope, or palpitations.”

Hence, clinicians should suspect ATTR-associated cardiomyopathy in the presence of heart failure with predominant right-sided symptoms; heart failure with preserved ejection fraction (especially in men); intolerance to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, or beta-blockers; or unexplained atrial arrhythmias, conduction system disease, or need for a pacemaker.

Heart failure in patients with ATTR worsens over time, with patients experiencing declines in diastolic dysfunction and functional capacity (~26 m decrease in 6-min walk distance every 6 months), decreases in left ventricular ejection fraction (~3% every 6 months), enhanced restrictive filling pattern, and increased troponin or N-terminal pro–B-type natriuretic peptide levels.

Neurologic Symptoms

Polyneuropathy in ATTR is mainly characterized by symmetrical length-dependent peripheral neuropathy. Distal and occasionally proximal limb weakness might also be obvious in patients with certain TTR mutations.

Neuropathic ATTR is a very heterogeneous disease, as clinical manifestations depend on the class of nerve fiber affected. Early examination of nerve fiber involvement may reveal degeneration of unmyelinated and small myelinated nerve fibers, rather than large myelinated fibers. At this stage, patients may complain of burning pain. Older patients may also experience numbness and loss of pain and temperature sensation, but they usually keep the ability to perceive touch pressure and joint position.

As the disease progresses, muscle weakness increases, with patients presenting with progressive lower limb numbness, weakness, and gait imbalance. The progressive nature of polyneuropathy in ATTR and the tendency for distal limb weakness distinguish it from diabetic polyneuropathy.

Ohashi et al investigated the electrophysiological demyelinating features in patients with hATTR (n=102, 85 with Val30Met mutation). They concluded that “patients with [hATTR] occasionally show electrophysiological demyelinating features without conduction block following severe axonal degeneration.”

Autonomic dysfunction can precede motor impairment in ATTR. It can manifest as orthostatic hypotension (evidenced by dizziness or fainting when standing up, blurred vision, confusion, and/or light-headedness), recurrent urinary tract infection, erectile dysfunction, and/or gastrointestinal disturbances (eg, nausea, vomiting, constipation, diarrhea, fecal incontinence, and/or unintentional weight loss). In severe cases with reduced sympathetic function, autonomic dysfunction can mask the signs and symptoms of heart failure.

A recent study conducted by Kleefeld et al revealed differences in the neurological presentation of hATTR and wild-type ATTR (ATTRwt). “Compared to [hATTR], the severity of polyneuropathy in ATTRwt amyloidosis is milder and without relevant motor involvement,” they said.

Musculoskeletal Manifestations

A history of musculoskeletal syndromes or procedures (eg, carpal tunnel syndrome, lumbar spinal stenosis, spontaneous distal bicep tendon rupture, or shoulder, knee, or hip surgery) together with cardiovascular signs and symptoms should raise suspicion of ATTR. In fact, musculoskeletal manifestations may arise 5 to 15 years prior to other symptoms.

Carpal tunnel syndrome is the most common noncardiac manifestation in patients with cardiac ATTR. About 10% of patients with bilateral carpal tunnel syndrome showed amyloid deposits. The coexistence of carpal tunnel syndrome and trigger finger was reported in members of a Japanese family with hATTR.

Moreover, spontaneous distal bicep tendon rupture (also known as Popeye sign) can be an early sign of amyloidosis and should raise suspicion of ATTR in patients older than 50 years.

Evidence suggests that patients with cardiac ATTR are more likely to need orthopedic surgery than the general population. For instance, almost 10% of ATTR patients underwent rotator cuff repair. Arthroplasty typically occurs 6-8 years before ATTR diagnosis.

“It can be challenging to identify ATTR amyloidosis given the diversity of diagnostic clues that can manifest in a patient over time (across many years),” acknowledged Nativi‑Nicolau et al. Therefore, patient assessment, diagnosis, and management should be performed by a multidisciplinary team. Also, clinicians should be aware of noncardiac symptoms potentially associated with ATTR.


Nativi-Nicolau JN, Karam C, Khella S, Maurer MS. Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2022;27(3):785-793. doi:10.1007/s10741-021-10080-2

Kleefeld F, Scherret E, Knebel F, et al. Same same, but different? The neurological presentation of wildtype transthyretin (ATTRwt) amyloidosis. Amyloid. 2022;29(2):92-101. doi:10.1080/13506129.2021.2014448

Ohashi N, Kodaira M, Morita H, Sekijima Y. Electrophysiological demyelinating features in hereditary ATTR amyloidosis. Amyloid. 2019;26(1):15-23. doi:10.1080/13506129.2018.1564903