Symptom Onset

  • Many initial signs and symptoms are vague and not specific to ATTR, and nonspecific symptoms may be mistaken for signs of aging, resulting in delayed diagnosis and treatment initiation​
  • With respect to wild-type ATTR (ATTRwt), cardiomyopathy (CM) is the hallmark – and known as ATTRwt-CM​
    • Patients commonly present with cardiac abnormalities, such as heart failure with preserved ejection fraction (HFpEF) and diastolic dysfunction, which are also characteristic of an elderly population
    • Amyloid deposits in the heart make the heart wall stiffen and work inefficiently; eventually this leads to congestive heart failure (HF), with symptoms such as shortness of breath, leg swelling, fatigue, nausea, and an irregular heartbeat or palpitation [6] ​
    • In a Japanese study, HF was both the most common initial symptom reported (49%) and the most common symptom leading to diagnosis (61%) [8]
    • HF is often preceded by carpal tunnel syndrome by 5-10 years [1], but it is often misdiagnosed [7]​
    • Peripheral and autonomic neuropathy can occur but are usually less severe than in patients with ATTRv and often manifest post-heart transplant [1] 
  • Compare hereditary ATTR (ATTRv):​
    • Patients may present with autonomic neuropathy, gastrointestinal impairment, cardiomyopathy, nephropathy, or ocular amyloid deposition [2] ​
    • Cardiac involvement develops in about half of ATTRv patients and usually presents as HF with normal systolic function, conduction blocks, ventricular arrhythmias or sudden cardiac death [3] ​
    • Classic neuropathic symptoms for early onset patients are related to small nerve fibers associated with pain and temperature; lower limbs usually precede observed symptoms in upper limbs [4]​
    • Late-onset patients may present with milder autonomic dysfunction; lower and upper limb symptoms may occur simultaneously [4]​
  • Depending on the symptom(s) experienced, ATTRwt patients may feel concerned or scared, or they may not worry that anything is seriously wrong
  • The patient experience at symptom onset is variable, as symptoms can differ in their nature and severity
    • Some patients describe suddenly noticing a problem they never noticed before, e.g., heart palpitations and dizziness in the middle of an exercise class
    • Other patients describe missing the signs for years, e.g., “For more than a decade, I experienced all the early indicators of ATTR-CM: bilateral carpal tunnel syndrome, ruptured biceps tendon, and lumbar stenosis”
  • Is something wrong?… A variety of symptoms are possible at onset, some of which emerge seemingly out of nowhere and others which may not be considered intrusive or concerning. This may lead some patients to dismiss their worry and possibly delay seeking care as they feel their symptoms are just a normal part of aging, while other patients seek care at the first sign
  1. Cruz Rodriguez JB, Tallaj JA. Narrative review of pharmacotherapy for transthyretin cardiac amyloid. Ann Transl Med. 2021;9(6):519.
  2. Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. The Lancet Neurology. 2011;10(12):1086-97.
  3. Finsterer J, Iglseder S, Wanschitz J, Topakian R, Loscher WN, Grisold W. Hereditary transthyretin-related amyloidosis. Acta Neurol Scand. 2019;139(2):92-105.
  4. Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6.
  5. ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck (ATTR deck, draft 3.0). 30_Acoradmidis deck v3. Citing: Muchtar E, et al. J Intern Med. 2021;289:268-292 & Koike H, Katsuno M. Neurol Ther. 2020;9:317-333. 
  6. Amyloidosis Research Consortium. Wild-type Amyloidosis. Accessed December 1, 2021.
  7. ALXN: Acoramidis ​for the Treatment of ATTR-CM: Training Deck (ATTR deck, draft 3.0). 30_Acoradmidis deck v3. Citing: Cuddy SAM, Faulk RH. Can J Cardiol. 2020;36:396-407.
  8. Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-37.