Hereditary transthyretin amyloidosis

What is hATTR?

Hereditary transthyretin amyloidosis (hATTR) is a severe, rare, progressive, and fatal disease of autosomal dominant inheritance, characterized by the deposition of extracellular amyloid fibrils composed of transthyretin (TTR), a plasma transport protein for thyroxine and vitamin A that is produced predominantly by the liver.1,2 These amyloidogenic proteins are structurally dominated by β-sheet structures which can aggregate into rigid, nonbranching fibrils that abnormally accumulate in the extracellular spaces of body tissues.3

Deposition may be localized, where the defective protein can accumulate in a single organ, or systemic, where deposits can occur in multiple organs and tissues in the body.3 Amyloid protein accumulates as fibrils in tissues, including the peripheral nerves, heart, gastrointestinal system, eyes, and kidneys.2 This subsequently leads to organ dysfunction.4–6

The current classification of amyloidosis in medical practice is based on the amyloid protein type and are named according to the substitution or deletion in the mature protein.3 The amyloid is denoted by the letter “A” followed by an abbreviation of the protein type. In the case of hATTR, the amyloid is derived from the protein TTR.3 There are currently at least 36 different human proteins known to cause amyloidosis.3

The disease is progressive leading to death within approximately 10 years (ranging from 5 to 15 years) of symptom onset, depending on many factors.1,7

Find out more about the prognosis, symptoms, and management of hATTR in the short video below:

This video was developed and funded by PTC Therapeutics. All rights reserved.

What causes hATTR?

Transthyretin is a 55 kDs homotetrameric protein found in the plasma and cerebral spinal fluid. The main function of transthyretin is the transport of thyroxine and retinol bound to retinol-binding protein (RBP).8,9

hATTR is caused by autosomal dominant mutations in the TTR gene.10 Transthyretin is encoded by 7 kb of DNA spanning exons 1–4 of a single gene on the long arm (q) of chromosome 18 (18q12).11 The TTR gene, which encodes the 127 amino acids in the protein structure of TTR. hATTR is typically associated with the substitution of one amino acid for another in the protein structure of TTR, caused by a point mutation in the TTR gene.12

The amyloid aggregation of TRR occurs by dissociation of the tetrameric TTR into monomers; these partially unfold into amyloidogenic intermediates and self-associate into soluble oligomers and amyloid aggregates.13 Familial point mutations are known to destabilize the tetramer, resulting in increased dissociation and subsequent amyloid aggregation.13

Mechanism of TTR amyloid fibril formation

More than 130 mutations in the TTR gene have been identified.15 Specific genotypes are associated with predominant polyneuropathy or cardiomyopathy features; however, most mutations affect multiple organs and there is considerable heterogeneity in disease manifestations.16

The estimated prevalence of hATTR

Worldwide, approximately 50,000 individuals have hATTR, including:3

  • ~10,000 with predominant polyneuropathy17
  • ~40,000 with predominant cardiomyopathy17

Epidemiological estimates are affected by:18

  1. Underdiagnosis and misdiagnoses resulting from lack of disease awareness
  2. Clinical presentation involving non-specific clinical manifestations that are hallmarks of more common diseases

V122I is the most common mutation worldwide associated with hATTR with cardiomyopathy:17

  • In the United States, V122I is the most common mutation and primarily occurs in 3–4% of African Americans3,19

V30M is the most common mutation worldwide associated with hATTR with polyneuropathy:17

  • V30M is an endemic mutation found in Sweden, Portugal, and Japan2,3

Possible spectrum of genotype-phenotype correlations in transthretin-related amyloidosis

The signs and symptoms of hATTR

hATTR amyloidosis is characterized by substantial clinical heterogeneity. Cohorts from the three major endemic clusters (Sweden, Portugal, and Japan) present with an exclusive neurologic phenotype, whereas sporadic cases of hATTR are strictly cardiologic in presentation.2

Patients with hATTR amyloidosis often have a cluster of symptoms.21

Bilateral carpal tunnel syndrome (CTS) is a common presenting manifestation in patients with ATTR amyloidosis and can be diagnosed up to 10 years before confirmation of hATTR.22–25 Symptoms of CTS include numbness, weakness, or pain in the hand, wrist, or arm.25 In addition, most patients with CTS preceding hATTR diagnosis have systemic features with a median 7 years (range 0–35 years) between CTS symptoms and systemic symptoms.26 Recognizing systemic features at the time of CTS presentation may help in early diagnosis of hATTR amyloidosis.26

Spinal canal stenosis has also been detected in patients with ATTR amyloidosis and is relate to the amount of transthyretin amyloid in the ligamentum flavum.27 Indeed, TTR amyloid deposits have been detected in as many as ~50% of surgical specimens from patients with lumbar spinal canal stenosis.27 Spinal canal stenosis is another common misdiagnosis in patients with hATTR.28

The signs and symptoms of hATTR are numerous and can affect many major organs.21 The majority of TTR mutations are associated predominantly with polyneuropathy or cardiomyopathy, however, most patients with hATTR amyloidosis have mixed clinical phenotypes.2

The polyneuropathy associated with hATTR amyloidosis is characterized by distal axonal degeneration and is described as progressive, symmetric, length-dependent, sensorimotor, and autonomic. Symptoms usually begin in the lower limbs (feet) and progress up the body to involve the ankles, legs, thighs, arms, and trunk.29,30

Cardiovascular manifestations
TTR amyloid fibrils may deposit in all structures of the heart, including the atrial and ventricular walls (myocardium), heart valves, the coronary and large arteries (e.g., aorta), and cardiac conduction system. Amyloid fibrils deposit extracellularly in the interstitium and impair tissue structure and function.31

hATTR is also associated with several other clinical manifestations which are influenced by genetic, epigenetic, or environmental factors other than the TTR mutation.21

Gastrointestinal (GI) disturbances
GI symptoms are present in approximately 60% of patients with ATTR.32 GI symptoms are more common in those with early-onset disease (<50 years old) versus late-onset disease (>50 years).32

Renal manifestations
These include albuminuria, azotemia and kidney failure.1,11 Albuminuria may be the first sign of kidney disease with progression to renal failure within ~5 years of detection.11 Albuminuria may arise before polyneuropathy and may appear as the presenting symptom of ATTR.11

  • Dialysis may improve prognosis, however progressive renal failure is a major cause of morbidity and mortality.33

Ophthalmologic manifestations
Ocular symptoms correlated to hATTR disease activity are common in patients dominated by polyneuropathy, and some evidence suggests that the prevalence of ocular symptoms increases with disease duration.34

The variation in clinical manifestiations of HaTTR

Determining a hATTR diagnosis

Patients with hATTR are frequently misdiagnosed, resulting in a significant delay between symptom onset and diagnosis.24 Lack of disease awareness and overlap of symptoms with other common conditions, such as hypertension and diabetes, hampers the diagnosis of hATTR.35

The resulting delay in diagnosis and misdiagnosis can negatively impact treatment approaches and outcomes.35 Therefore, establishing early diagnosis requires clinical suspicion.35

Red-flag symptom clusters may warn of hATTR diagnosis.10,21 Patients presenting with progressive, symmetric sensory length-dependent polyneuropathy or autonomic dysfunction, with one or more of the red flag signs and symptoms, should be tested for hATTR:10,36,21

Potential red flag symptom clusters that may warn of a diagnosis of hATTR

For patients without a family history of amyloidosis, diagnosis of hATTR amyloidosis should be considered if they have idiopathic progressive axonal polyneuropathy, or atypical CIDP.36

Rapid disease progression and failure to respond to immunomodulatory treatment are additional signs.10

Neurologic and physical examinations for hATTR
The diagnosis of hATTR involves neurologic and physical examinations, and several different types of diagnostic tests, including:

  • Genetic testing and DNA sequence analysis of the TTR gene10,36
  • Cardiac tests:36
    • Echocardiography37
    • Electrocardiogram (ECG)36,37
    • Scintigraphy36–38
    • Laboratory tests for cardiac biomarkers (troponin B-type natriuretic peptide)39,40
    • Cardiac magnetic resonance (CMR) imaging37
  • Neurophysiological tests:
    • Electrodiagnostic (EDx) testing including nerve conduction studies (NCS), needle electromyogram (EMG), and a variety of special studies42
    • Quantitative Sensory Testing (QST)43
    • Quantitative Sudomotor Axon Reflex Testing (QSART)44
    • Sympathetic Skin Response (SSR)45
  • Biopsy1,36

Following cardiac and neurologic testing, patients presenting with signs and symptoms of hATTR should undergo a tissue biopsy for obtaining evidence of amyloid deposits1

Algorithms for the diagnosis of both the polyneuropathy of cardiomyopathy of hATTR have been published:

hATTR with polyneuropathy diagnostic workup

Diagnostic workup when suspicion of amyloid in the heart

What is the burden of hATTR in patients?

Disease burden is high for patients with hATTR. The clinical manifestations impact multiple aspects of daily life, and the burden of disease increases rapidly as the disease progresses.48

Quality of life (QoL) particularly concerning physically-oriented QoL (e.g., the PCS on the SF‐12v2), whereas other studies have shown a burden on neuropathy‐related QoL, which increases with symptom duration.48
An analysis of neuropathy‐related QoL found that patients with hATTR amyloidosis experience:

  • A disease burden equivalent to that of patients with type 2 diabetes who have diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation48
  • The burden on physical functioning for patients with hATTR amyloidosis was worse than that of patients with Crohn’s disease, irritable bowel syndrome, and diabetic neuropathy, while comparable to that of patients with congestive heart failure and multiple sclerosis48

Symptoms experienced by patients with hATTR amyloidosis can interfere with their ability to work and complete typical household chores.49 Symptomatic patients frequently report being unable to work, and those who do continue to work commonly experience challenges with absenteeism and presenteeism.49

Findings from questionnaires completed by caregivers of patients with hATTR report substantial burden on caregivers, including work impairment, substantial time spent on providing care (mean 45.9 h/week), and poor mental health.50

Given the progressive and multisystemic nature of hATTR amyloidosis, the wide variety of clinical presentations often leads to misdiagnosis and diagnostic delays.51 This incorrect or delayed diagnosis severely impacts patient quality of life as a consequence of the progressive nature of hATTR amyloidosis that leads to significant disability and mortality.49,51

CMR, cardiac magnetic resonance; CTS, carpal tunnel syndrome; ECG, electrocardiogram; EDx, electrodiagnostic; EMG, electromyogram; GI, gastrointestinal; hATTR, hereditary transthyretin amyloidosis; HRdb, Heart Rate Response to Deep Breathing; q, long arm; QoL Quality of life; QSART, Quantitative Sudomotor Axon Reflex Testing; PCS, Physical Component Summary; QTS, Quantitative Sensory Testing; SF-12v2, Short Form Health Survey-version 2; SSR, Sympathetic Skin Response; NCS, nerve conduction studies; RBP, retinol-binding protein.


  1. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8(1):1–18.
  2. Luigetti M, Romano A, Di Paolantonio A, et al. Ther Clin Risk Manag 2020;16:109–123.
  3. Picken MM. Acta Haematol 2020;143(4):322–334.
  4. Yarlas A, Gertz MA, Dasgupta NR, et al. Muscle & Nerve 2019;60(2):169–175.
  5. Benson MD, Buxbaum JN, Eisenberg DS, et al. 2018;25(4):215–219.
  6. Taber’s Medical Dictionary. Amyloidosis. Available at: (Last accessed May 2021).
  7. Baker KR, Rice L. Methodist Debakey Cardiovasc J 2012;8(3):3–7.
  8. Sharma M, Khan S, Rahman S, Singh LR. Front Physiol 2019;10(5):1–8.
  9. Buxbaum JN, Reixach N. Cell Mol Life Sci  2009;66(19):3095–3101.
  10. Sekijima Y, Ueda M, Koike H, et al. Orphanet J Rare Dis 2018;13(1):1–17.
  11. Lobato L, Rocha A. Clin J Am Soc Nephrol  2012;7(8):1337–1346.
  12. Ruberg FL, Berk JL. Circulation 2012;126(10):1286–1300.
  13. Saelices L, Johnson LM, Liang WY, et al. J Biol Chem 2015;290(48):28932–28943.
  14. Bulawa CE, Connelly S, Devit M, et al. Proc Natl Acad Sci USA 2012;109(24):9629–9634.
  15. Ueda M, Ando Y. Transl Neurodegener 2014;3(1):1–10.
  16. Maurer MS, Hanna M, Grogan M, et al. J Am Coll Cardiol  2016;68(2):161–172.
  17. Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med 2015;47(8):625–638.
  18. Schmidt HH, Waddington-Cruz M, Botteman MF, et al. Muscle & Nerve 2018;57(5):829–837.
  19. Castaño A, Drachman BM, Judge D, et al. Physiol Behav 2015;176(5):139–148.
  20. Rapezzi C, Quarta CC, Obici L, et al. Eur Heart J 2013;34(7):520–528.
  21. Conceição I, González-Duarte A, Obici L, et al. J Peripher Nerv Syst 2016;21(1):5–9.
  22. Lousada I, Maurer M, Warner M, et al. Orphanet J Rare Dis 2017;12(Suppl 1):165.
  23. Wininger AE, Phelps BM, Jessica TL, et al. BMC Musculoskelet Disord 2021;22(51):1–10.
  24. Cortese A, Vegezzi E, Lozza A, et al. J Neurol Neurosurg Psychiatry 2017;88(5):457–458.
  25. Shin SC, Robinson-Papp M. Mt Sinai J Med 2012;23(1):1–7.
  26. Karam C, Diana D, Christ M, Neurol Clin Pract 2019;9(4):309–313.
  27. Yanagisawa A, Ueda M, Sueyoshi T, et al. Mod Pathol 2015;28(2):201–207.
  28. Westermark P, Westermark GT, Suhr OB, et al. Ups J Med Sci 2014;119(3):223–228.
  29. Chung T. Neuroimaging Clin N Am 2014;23(1):1–7.
  30. Coelho T, Ericzon B, Falk R, et al. A guide to transthyretin amyloidosis. 2016. Available at (Last accessed May 2021).
  31. Rapezzi C, Quarta CC, Riva L, et al. Nat Rev Cardiol 2010;7(7):398–408.
  32. Wixner J, Mundayat R, Karayal ON, et al. Orphanet J Rare Dis 2014;9(1):1–9.
  33. Lobato L. Orphanet J Rare Dis 2015;10(Suppl 1): I12.
  34. Beiraõ JM, Malheiro J, Lemos C, et al. Amyloid 2015;22(2):117–122.
  35. Vaxman I, Gertz M. Acta Haematol 2020;143(4):304–311.
  36. Adams D, Ando Y, Beirão JM, et al. J Neurol 2020.
  37. Siddiqi OK, Ruberg FL. Trends Cardiovasc Med 2019;28(1):1–28.
  38. Cytawa W, Teodorczyk J, Lass P. Pol J Radiol 2019;79:222–227.
  39. Gertz MA, Benson MD, Dyck PJ, et al. J Am Coll Cardiol 2015;66(21):2451–2466.
  40. Mythili S, Malathi N. Biomed Rep 2015;3(6):743–748.
  41. Cruz MW. Clin Auton Res 2019;29(s1):19–24.
  42. Sonoo M, Menkes DL, Bland JDP, et al. Clin Neurophysiol Pr 2018;3:78–88.
  43. Mücke M, Cuhls H, Radbruch L, et al. Quantitative sensory testing (QST). English version. Schmerz. 2016. Available at (Last accessed May 2021).
  44. Novak P. Quantitative autonomic testing. J Vis Exp 2011;53:1–24.
  45. Sympathetic Skin Response. Vitalscan. Available at: (Last accessed May 2021).
  46. Carvalho A, Rocha A, Lobato L. Liver Transpl 2015;21(3):282–292.
  47. Nativi-Nicolau J, Maurer MS. Curr Opin Cardiol 2018;33(5):571–579.
  48. Yarlas A, Gertz MA, Dasgupta NR, et al. Muscle Nerve 2019;60(2):169–175.
  49. Lovley A, Raymond K, Guthrie SD, et al. J Patient Rep Outcomes 2021;5(3):1–10.
  50. Stewart M, Shaffer S, Murphy B, et al. Neurol Ther 2018;7(2):349–364.
  51. Gertz MA. Am J Manag Care 2017;23(7 Suppl):S107–S112.

GL-hATTR-0201 | September 2021
Sign in or register to access exclusive content on this site 

Welcome to MEDhub

A website for healthcare professionals, provided by PTC Therapeutics

This educational website provides you with the latest scientific data and expert
insights on the diagnosis and management of a range of rare diseases across the neuromuscular system, central nervous system, and other areas

This content is protected. To view it please enter your email address below:

Register here to access the content on the site
MED-ALL-CORP-2200029 | December 2022


The content you are trying to access is not currently available.

We will be updating the MEDhub site regularly to provide you with up-to-date, insightful expert-led content. To be notified when new additions become available, register now.