Help accelerate the diagnosis of hereditary ATTR amyloidosis

Consider hATTR amyloidosis in your differential diagnosis

Due to the rapid natural progression of the disease, patients with hATTR amyloidosis require an early and accurate diagnosis.1-3 Because the symptoms of hATTR amyloidosis may overlap with those of other diseases, detailed diagnostic history may help to identify patients with hATTR amyloidosis1,2,4,5

Diseases with symptoms that overlap with those of hATTR amyloidosis1,2,4,5
Clinical manifestation Potential diagnoses
Ataxia and foot numbness
  • CIDP
Motor involvement
  • ALS
  • Motor polyradiculoneuropathy
Upper limb neuropathy
  • Carpal tunnel syndrome
  • Idiopathic polyneuropathy
  • Paraneoplastic neuropathy
  • CIDP
  • Motor neuron diseases
Weakness in feet, ankles, legs
  • Charcot-Marie-Tooth disease
Pain and tingling with alcohol abuse
  • Alcoholic neuropathy
Polyneuropathy with diabetes
  • Diabetic neuropathy
Polyneuropathy with evidence of amyloid deposition
  • AL amyloidosis
  • AA amyloidosis
Clinical manifestation Potential diagnoses
Clinical manifestationAtaxia and foot numbness Potential diagnosis
  • CIDP
Clinical manifestationMotor involvement Potential diagnoses
  • ALS
  • Motor polyradiculoneuropathy
Clinical manifestationUpper limb neuropathy Potential diagnoses
  • Carpal tunnel syndrome
  • Idiopathic polyneuropathy
  • Paraneoplastic neuropathy
  • CIDP
  • Motor neuron diseases
Clinical manifestationWeakness in feet, ankles, legs Potential diagnosis
  • Charcot-Marie-Tooth disease
Clinical manifestationPain and tingling with alcohol abuse Potential diagnosis
  • Alcoholic neuropathy
Clinical manifestationPolyneuropathy with diabetes Potential diagnosis
  • Diabetic neuropathy
Clinical manifestationPolyneuropathy with evidence of amyloid deposition Potential diagnoses
  • AL amyloidosis
  • AA amyloidosis

For patients with neuropathic symptoms, the most common misdiagnosis previously received is CIDP.14

AA=amyloid A; AL=amyloid light chain; ALS=amyotrophic lateral sclerosis; CIDP=chronic inflammatory demyelinating polyneuropathy.
Diagnostic assessment Potential diagnoses
Left ventricular hypertrophy
Diastolic dysfunction
Heart failure with preserved ejection fraction
  • Hypertensive heart disease
  • Hypertrophic cardiomyopathy
  • Fabry disease
  • AL amyloidosis

For patients with cardiomyopathy, accurate diagnosis may be even more critical, as some medications for common cardiac conditions may be harmful. These medications may interact with amyloid fibrils and exert negative effects.15

Recognize the red-flag symptoms. Suspect hATTR amyloidosis.

Red-flag symptom clusters associated with hATTR amyloidosis

Progressive symmetric sensory-motor neuropathy and 1 of the following:

Bilateral carpal
tunnel syndrome

Nephropathy
(eg, proteinuria or renal failure)

Early autonomic dysfunction
(eg, sexual dysfunction
or postural hypotension)

Gastrointestinal complaints
(eg, vomiting, chronic diarrhea,
constipation, or
diarrhea/constipation)

Unexplained
weight loss

Cardiovascular manifestations
(eg, conduction block, cardiomyopathy, or arrhythmia)

Vitreous opacities

Positive family history

Additional signs: Rapid disease progression and failure to respond to immunomodulatory treatment

Adapted from Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9.

Clinical findings that may indicate hATTR amyloidosis

Historical and physical findings
Heart failure with a normal or preserved ejection fraction in the absence of hypertension, particularly in men
Hypotension in a person with previous hypertension
Evidence of right-sided heart failure:
loss of appetite, hepatomegaly, ascites, and lower extremity edema
Intolerance of commonly used cardiovascular medications: digoxin, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers
Bilateral carpal tunnel syndrome
Imaging findings
ECG
  • Low QRS voltage ± thick interventricular septum (low voltage to mass ratio)
  • Pseudo-infarction pattern
  • Progressive reduction in QRS voltage over time
Echo
  • Thick interventricular septum
  • Refractile myocardium (granular sparkling)
  • Low tissue Doppler velocities, strain, or strain rate
CMRI
  • Thick interventricular septum
  • Subendocardial late gadolinium enchancement
Scintigraphy Scan
  • Cardiac uptake of 99mTc-DPD or 99mTc-PYP
In addition, consider hATTR amyloidosis in a patient who has a family history of ANY of these symptoms
Adapted from Dharmarajan K, Maurer M. J Am Geriatr Soc. 2012;60(4):765-774.
ECG=electrocardiogram; CMRI=cardiac magnetic resonance imaging;
99mTc-DPD=technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-PYP=technetium-99m-pyrophosphate.

Whether patients present primarily with cardiomyopathy or polyneuropathy, obtaining a family history is an important step in the diagnostic process.1,2,16

Though patients may be unaware of hATTR amyloidosis in their family, inquiring about relatives who have experienced any of the symptoms, including symptoms different from their own, or who have died prematurely, can help identify a family history.

Are symptoms and family history leading you to suspect hATTR amyloidosis?Your patient may be eligible for Alnylam Act, a genetic testing and counseling program that can help confirm a diagnosis.
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Recognition of the red-flag symptom clusters may help physicians provide patients with an earlier diagnosis and determine appropriate treatment.1,2
Download a red-flag symptoms flashcard

Confirming an hATTR amyloidosis diagnosis

When you suspect hATTR amyloidosis, the diagnostic process may include1,4,15:

  • Cardiac and/or neurologic examination
  • Genetic testing
  • Tissue biopsy
  • Identification of the amyloid protein
Complete neurologic examination
Electromyography
Sympathetic skin response (SSR)
Heart rate deep breathing
Sudoscan assessment of electrochemical skin conductance
Medical history
Laboratory tests to exclude mimicking polyneuropathies

Genetic analysis to determine pathologic mutation

Tissue biopsy + Congo red staining
Salivary gland
Abdominal subcutaneous adipose tissue
Rectal mucosa
Sural nerve
Skin
Gastric

Identification of amyloid protein
Immunohistochemistry
Mass spectrometry
Cardiac examination
Electrocardiography
Echocardiography
Cardiac serum biomarkers
Cardiac magnetic resonance imaging
Nuclear scintigraphic imaging with 99mTc-DPD or 99mTc-PYP

Genetic analysis to determine pathologic mutation

Tissue biopsy + Congo red staining

Identification of amyloid protein
Immunohistochemistry
Mass spectrometry

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Alnylam Act

Third-party genetic testing and counseling programs offered at no charge

Genetic testing and counseling may help to:

  • Identify risk of disease for patients and their family members
  • Shorten the time to diagnosis and prevent misdiagnoses
  • Determine if patients are eligible to participate in clinical trials
  • Provide information about support resources such as patient advocacy organizations

The Alnylam Act program was developed to reduce barriers to genetic testing and counseling to help people make more informed decisions about their health. While Alnylam provides financial support for this program, tests and services are performed by independent third parties. Healthcare professionals must confirm that patients meet certain criteria to use the program. Alnylam receives de-identified patient data from this program, but at no time does Alnylam receive patient identifiable information. Alnylam receives contact information for healthcare professionals who use this program. Genetic testing is available in the U.S. and Canada. Genetic counseling is only available in the U.S. Healthcare professionals who use this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use or support any Alnylam product.

Visit Alnylam Act for more information on this program.

References:

  1. Adams D, Suhr OB, Hund E, et al. Curr Opin Neurol. 2016;29(Suppl 1):S14-S26.
  2. Conceição I, González-Duarte A, Obici L, et al. J Peripher Nerv Syst. 2016;21(1):5-9.
  3. Obici L, Kuks JB, Buades J, et al. Curr Opin Neurol. 2016;29(suppl 1):S27-S35.
  4. Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8:31.
  5. Ruberg FL, Berk JL. Circulation. 2012;126(10):1286-1300.
  6. Adams D, Théaudin M, Cauquil C, et al. Curr Neurol Neurosci Rep. 2014;14(3):435.
  7. Adams D, Lozeron P, Lacroix C. Curr Opin Neurol. 2012;25(5):564-572.
  8. Szigeti K, Lupski JR. Eur J Hum Genet. 2009;17(6):703-710.
  9. Zeng L, Alongkronrusmee D, van Rijn RM. J Pain Res. 2017;10:219-228.
  10. Shin SC, Robinson-Papp J. Mt Sinai J Med. 2012;79(6):733-748.
  11. Lalande S, Johnson BD. Drugs Today (Barc). 2008;44(7):503-513.
  12. Rapezzi C, Longhi S, Milandri A, et al. Amyloid. 2012;19(suppl 1):16-21.
  13. Linart A. In: Mehta A, Beck M, Sunder-Plassmann G (eds). Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 20.
  14. Cortese A, Vegezzi E, Lozza A, et al. J Neurol Neurosurg Psychiatry. 2017;88(5):457-458. doi:10.1136/jnnp-2016-315262.
  15. Dharmarajan K, Maurer MS. J Am Geriatr Soc. 2012;60(4):765-774.
  16. Tan BY, Judge DP. Circ Cardiovasc Genet. 2012;5(6):697-705.
  17. Castro J, Miranda B, Castro I, et al. Clin Neurophysiol. 2016;127(5):2222-2227.
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