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Disease Overview

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hATTR amyloidosis is a multisystem, rapidly progressive, life-threatening disease1-3

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Hereditary transthyretin-mediated (hATTR)
amyloidosis is an autosomal dominant disease
caused by one of many possible mutations in the transthyretin (TTR) gene.3 An estimated 50,000 people are living with hATTR amyloidosis worldwide.4,5

How hATTR amyloidosis develops

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Formation of amyloid deposits1,2,6

Transthyretin (TTR) is produced in the liver

TTR TETRAMERS

TTR is primarily synthesized in the liver
and is secreted as a tetramer.

Transthyretin (TTR) tetramers dissociate into monomers

TTR MONOMERS

In hATTR amyloidosis, a genetic mutation causes the tetramer to become less stable, resulting in dissociation into monomers.

Monomers may misfold and aggregate into amyloid deposits

MISFOLDED TTR

TTR monomers misfold and aggregate into amyloid deposits.

Amyloid deposits cause damage and clinical symptoms

AMYLOID DEPOSITS

Amyloid is deposited
at multiple sites in the body, causing damage that leads to clinical symptoms.

Accumulation results in worsening symptoms

PROGRESSIVE SYMPTOMS

Accumulation of amyloid deposits over time results in worsening clinical symptoms.

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Another type of ATTR amyloidosis is called wild-type ATTR amyloidosis. The etiology is unknown, but is presumed to be associated with aging.1,7

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The multisystem nature of hATTR amyloidosis takes a toll on the whole body1

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Multisystem involvement and family history are red flags of hATTR amyloidosis and require urgent action.3 If your patient’s family has a history of the disease
or of its many symptoms, or your patient is experiencing a combination of multisystem symptoms, the cause could be hATTR amyloidosis.

Sensory-motor neuropathy1,3

  • Length-dependent neuropathic pain and numbness

  • Altered sensation

  • Weakness

  • Difficulty walking

  • Bilateral carpal tunnel syndrome

Autonomic neuropathy1,3

  • Orthostatic hypotension

  • Diarrhea, constipation, nausea and vomiting

  • Unintentional weight loss

  • Recurrent urinary tract infections

  • Sexual dysfunction

Cardiac manifestations8

  • Conduction abnormalities

  • Arrhythmias

  • Heart failure

  • Left ventricular hypertrophy

Additional findings3,8

  • Family history of hATTR amyloidosis symptoms or diagnosis

  • Rapid symptom progression

  • Failure to respond to immunomodulatory treatment

  • Intolerance of commonly used cardiovascular medications

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Disease progression leads to daily suffering and premature death9

Progression of sensory-motor neuropathy1,10-121,9-11

  • Sensory loss can reduce dexterity and temperature sensation

  • Motor deficits result in progressive weakness and impaired ambulation

  • Sensory-motor neuropathy progresses more than 10 times faster than diabetic neuropathy

Progression of autonomic neuropathy11-1910-19

  • Orthostatic hypotension can cause syncope and sudden falls

  • Gastrointestinal issues can cause patients to isolate themselves from social situations

  • Continuous weight loss
    leads to wasting and
    reduced survival

  • Autonomic neuropathy can induce fatal arrhythmias

Progression of cardiac manifestations8,20-228,20-22

  • Significant and measurable decline in cardiac function results in heart failure

  • Heart failure due to hATTR amyloidosis progresses
    more quickly than with other cardiac conditions

Disease progression leads to daily suffering and premature death22
Not a comprehensive list of all the symptoms associated with hATTR amyloidosis.
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Multisystem dysfunction is a reality for most patients1

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Although there is some association between mutation and symptom presentation, most patients suffer from overlapping symptoms of sensory-motor neuropathy, autonomic neuropathy, and cardiac manifestations.1 In the United States, the most common mutations (V122I, T60A, and V30M) are associated with both polyneuropathy and cardiomyopathy.1,19,23,241,18,23,24

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Symptom presentation of common mutations in the United States13,a,b12,a,b

Chart of hATTR amyloidosis symptom presentation of the V122I mutation Chart of hATTR amyloidosis symptom presentation of the V122I mutation

What you should know about V122I

  • V122I is the most common mutation in the United States and is found primarily in African Americans1,23

  • ~3–4% of African Americans carry the V122I mutation25

  • Individuals with a V122I mutation, historically associated with a predominantly cardiac presentation, are also at risk of being diagnosed with polyneuropathy23,26

  • In a global registry of patients with ATTR amyloidosis, 60% with the V122I mutation had sensory neuropathy1312

Chart of hATTR amyloidosis symptom presentation of the T60A mutation Chart of hATTR amyloidosis symptom presentation of the T60A mutation

What you should know about T60A

  • T60A is the second most common mutation in the US and is typically found in individuals of Irish descent23,27

  • It is associated with a mixed presentation of cardiac manifestations, autonomic neuropathy, and sensory neuropathy, and the median age of onset is 63 years13,2812,28

  • In a global registry of patients with ATTR amyloidosis, 91% of patients with the T60A mutation had cardiac complications, and 80% had sensory neuropathy13,2812,28

Chart of hATTR amyloidosis symptom presentation of the V30M mutation Chart of hATTR amyloidosis symptom presentation of the V30M mutation

What you should know about V30M

  • V30M is the most common mutation in the world, and is associated with 2 distinct clinical presentations1:

    • Early-onset V30M (<50 years) is characterized by progressive sensory-motor and autonomic neuropathy1,29

    • Late-onset V30M (≥50 years) is associated with sensory-motor neuropathy that begins in the lower limbs, with mild or no autonomic neuropathy, and has a more rapid disease course1,29

aNot representative of all possible TTR gene mutations.
bData collected by the THAOS registry.
THAOS=Transthyretin-Associated Amyloidosis Outcomes Survey.
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aNot representative of all possible TTR gene mutations.
bData collected by the THAOS registry.
THAOS=Transthyretin-Associated Amyloidosis Outcomes Survey.
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Patients with hATTR amyloidosis may already be in your practice

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In the profiles below, you will find examples of
different patient types, which may help you to
recognize patients in your practice who may
be at
risk of hATTR amyloidosis. Patient profiles are composites created through a review of published literature and are not of actual patients.

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Small-fiber
neuropathy

Cathy, 55 years old

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Polyneuropathy and
nephropathy

Mia, 48 years old

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HFpEF, autonomic
symptoms

Sam, 60 years old

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Atrial fibrillation,
intolerant to medication,
bilateral CTS

Charles, 66 years old

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Genetic testing is an essential step to confirming a diagnosis of hATTR amyloidosis.31,32

Learn more »
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References

References:

  1. Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8:31.
  2. Adams D, Coelho T, Obici L, et al. Neurology. 2015;85(8):675-682.
  3. Conceição I, González-Duarte A, Obici L, et al. J Peripher Nerv
    Syst
    . 2016;21(1):5-9.
  4. Plante-Bordeneuve V. J Neurol. 2014;261(6):1227-1233.
  5. Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med.
    2015;47(8):625-638.
  6. Kourelis TV, Gertz MA. Expert Rev Cardiovasc Ther.
    2015;13(8):945-961.
  7. Gertz MA. Am J Manag Care. 2017;23(suppl 7):S107-S112.
  8. Dharmarajan K, Maurer MS. J Am Geriatr Soc. 2012;60(4):765-774.
  9. Coutinho P, Martins da Silva A, Lopes Lima JL, et al. Excerpta
    Medica. 1980:88-98.
  10. Berk JL, Suhr OB, Obici L, et al. JAMA. 2013;310(24):2658-2667.
  11. Shin SC, Robinson-Papp J. Mt Sinai J Med. 2012;79(6):733-748.
  12. Koike H, Tanaka F, Hashimoto R, et al. J Neurol Neurosurg
    Psychiatry
    . 2012;83(2):152-158.
  13. Wixner J, Mundayat R, Karayal ON, et al. Orphanet J Rare Dis. 2014;9:61.
  14. González-Duarte A, Berk JL, Quan D, et al. J Neurol. 2019.
    https://doi.org/10.1007/s00415-019-09602-8.
  15. González-Duarte A. Clin Auton Res. 2019;29(2):245-251.
  16. Ando Y, Suhr OB. Amyloid. 1998;5(4):288-300.
  17. Suhr O, Danielsson A, Holmgren G, et al. J Intern Med. 1994;235(5):479-485.
  18. Low PA. Clin Auton Res. 2008:18(suppl 1):8-13.
  19. Castaño A, Drachman BM, Judge D, et al. Heart Fail Rev. 2015;20(2):163-178.
  20. Ruberg FL, Maurer MS, Judge DP, et al. Am Heart J.
    2012;164:222-228.
  21. Olivotto I, Cecchi F, Pogessi C, et al. Circ Heart Fail.
    2012;5(4):535-546.
  22. Drazner MH. Circulation. 2011;123(3):327-334.
  23. Coutinho P, Martins da Silva A, Lopes Lima JL, et al. Excerpta
    Medica. 1980:88-98.
  24. Maurer MS, Hanna M, Grogan M, et al. J Am Coll Cardiol. 2016;68(2):161-172.
  25. Parman Y, Adam D, Obici L, et al. Curr Opin Neurol. 2016;29(suppl 1):S3-S13.
  26. Jacobson D, Tagoe C, Schwartzbard A, et al. Am J Cardiol. 2011;108(3):440-444.
  27. Parker MM, Damrauer SM, Rader DJ, et al. Presented at: AANEM Annual Meeting; October 10-13, 2018.
  28. Reilly MM, Staunton H, Harding AE, et al. J Neurol Neurosurg
    Psych
    . 1995;59(1):45-49.
  29. Sattianayagam PT, Hahn AF, Whelan CJ, et al. Eur Heart J. 2012;33:1120-1127.
  30. Adams D, Ando Y, Beirao JM, et al. J Neurol. 2019.
    https://doi.org/10.1007/s00415-019-09688-0.
  31. Gillmore JD, Maurer MS, Falk RH, et al. Circulation.
    2016;133(24):2404-2412.
  32. Maurer MS, Elliott P, Comenzo R, et al. Circulation.
    2017;135(14):1357-1377.
  33. Adams D, Suhr OB, Hund E, et al. Curr Opin Neurol. 2016;29(suppl 1):S14-S26.