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Polyneuropathy Symptoms
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Polyneuropathy Symptoms
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Disease Overview

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hATTR amyloidosis is a multisystem, rapidly progressive, often fatal disease1-3

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Hereditary transthyretin-mediated (hATTR)
amyloidosis is an autosomal dominant disease
caused by one of many possible variants 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 variant 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 neuropathy
Autonomic neuropathy
Cardiac manifestations
Additional findings

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 manifestations3,8

  • 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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Progression of polyneuropathy leads to significant disability22

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 can progress more than 10x 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

Progression of polyneuropathy leads to significant disability22

Not a comprehensive list of all the symptoms associated with hATTR amyloidosis.
Each patient may not experience all of these symptoms or may not experience them at the same time.

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Recognize the signs.
Download the Symptoms Guide.
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Multisystem dysfunction is a reality for most patients1

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Although there is some association between variant 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 variants (V122I, T60A, and V30M) are associated with both polyneuropathy and cardiomyopathy.1,19,23,241,18,23,24 Polyneuropathy may precede or coincide with cardiomyopathy, even in patients with the V122I variant.25

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

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

What you should know about V122I

  • V122I is the most common variant in the United States and is prevalent in ~4% of African Americans1,23,26

  • A majority of individuals with a V122I variant have polyneuropathy symptoms, including sensory, motor, and gastrointestinal symptoms12,23,27

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

Learn more about V122I »
Chart of hATTR amyloidosis symptom presentation of the T60A variant Chart of hATTR amyloidosis symptom presentation of the T60A variant

What you should know about T60A

  • T60A is the second most common variant in the US and is typically found in individuals of Irish descent23,28

  • It is associated with a mixed presentation of cardiac manifestations, autonomic neuropathy, and sensory neuropathy, and the median age of onset is 63 years13,2912,29

  • In a global registry of patients with ATTR amyloidosis, 91% of patients with the T60A variant had cardiac complications, and 80% had sensory neuropathy13,2912,29

Learn more about T60A »
Chart of hATTR amyloidosis symptom presentation of the V30M variant Chart of hATTR amyloidosis symptom presentation of the V30M variant

What you should know about V30M

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

    • Early-onset V30M (<50 years) is characterized by progressive sensory-motor and autonomic neuropathy1,30

    • 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 course1,30

Learn more about V30M »
aNot representative of all possible TTR gene variants.
bData collected by the THAOS registry.
THAOS=Transthyretin-Associated Amyloidosis Outcomes Survey.
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aNot representative of all possible TTR gene variants.
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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Cathy, 55 years old, small-fiber neuropathy

Small-fiber
neuropathy

Cathy, 55 years old

View more »
Mia, 48 years old, polyneuropathy and nephropathy

Polyneuropathy and
nephropathy

Mia, 48 years old

View more »
Sam, 60 years old, autonomic neuropathy symptoms, HFpEF

Autonomic neuropathy symptoms, HFpEF

Sam, 60 years old

View more »
Charles, 66 years old, bilateral CTS, atrial fibrillation, intolerant to medication

Bilateral CTS, atrial fibrillation, intolerant to medication

Charles, 66 years old

View more »
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Download the patient profiles

Genetic testing can help confirm a diagnosis of hATTR amyloidosis.32,33

Learn more »
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Resources for your patients
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Patient Resources

Intro to hATTR Amyloidosis
A Closer Look at hATTR Amyloidosis
Patient Symptom Tracker

Family Resources

An Overview of Genetic Counseling and Testing
Family Discussion Guide
Family Health Tree

Information and Support Groups

Patient Information and Resources
Amyloidosis Support Groups
Amyloidosis Foundation
Amyloidosis Research Consortium
Cece's Story: Finding Answers
The Importance of Genetic Testing
Inheritance of hATTR Amyloidosis
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References

References:

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  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. Berk JL, Suhr OB, Obici L, et al. JAMA. 2013;310(24):2658-2667.
  10. Shin SC, Robinson-Papp J. Mt Sinai J Med. 2012;79(6):733-748.
  11. Koike H, Tanaka F, Hashimoto R, et al. J Neurol Neurosurg
    Psychiatry    . 2012;83(2):152-158.
  12. Wixner J, Mundayat R, Karayal ON, et al. Orphanet J Rare Dis. 2014;9:61.
  13. González-Duarte A, Berk JL, Quan D, et al. J Neurol. 2020;267(3):703-712.
  14. González-Duarte A. Clin Auton Res. 2019;29(2):245-251.
  15. Ando Y, Suhr OB. Amyloid. 1998;5(4):288-300.
  16. Suhr O, Danielsson A, Holmgren G, et al. J Intern Med. 1994;235(5):479-485.
  17. Low PA. Clin Auton Res. 2008:18(suppl 1):8-13.
  18. Castaño A, Drachman BM, Judge D, et al. Heart Fail Rev. 2015;20(2):163-178.
  19. Ruberg FL, Maurer MS, Judge DP, et al. Am Heart J.
    2012;164:222-228.
  20. Olivotto I, Cecchi F, Pogessi C, et al. Circ Heart Fail.
    2012;5(4):535-546.
  21. Drazner MH. Circulation. 2011;123(3):327-334.
  22. Coutinho P, Martins da Silva A, Lopes Lima JL, et al. Excerpta
    Medica. 1980:88-98.
  23. Maurer MS, Hanna M, Grogan M, et al. J Am Coll Cardiol. 2016;68(2):161-172.
  24. Parman Y, Adams D, Obici L, et al. Curr Opin Neurol. 2016;29(suppl 1):S3-S13.
  25. Grogan M, Hawkins PN, Kristen AV, et al. Poster presented at: 23rd Annual Meeting of the Heart Failure Society of America (HFSA); September 13-16, 2019; Philadelphia, PA.
  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. 2021;268(6):2109-2122.
  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.