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

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, erectile dysfunction
or postural hypotension)

Gastrointestinal complaints
(eg, 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.

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

Alnylam-sponsored, third-party genetic screening and counseling programs for hATTR amyloidosis offered at no charge

When hATTR amyloidosis is suspected, genetic counseling can help patients understand the potential diagnosis, the genetic screening process, and the implications of the disease.

The Alnylam Act (formerly known as Alnylam Assist) program was created to potentially enable diagnosis through genetic screening and to provide genetic counseling to help people make more informed decisions about their health. Genetic counseling is available before, during, and after genetic screening through this program. These services are available only in the United States. While Alnylam provides financial support for this program, all tests and services are performed by independent third parties. At no time does Alnylam receive patient identifiable information. Alnylam receives contact information for health care providers who sign up for this program.

References:

  1. Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29(Suppl 1):S14-S26.
  2. Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.
  3. Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29(suppl 1):S27-S35.
  4. Ando Y, Coelho T, Berk JL, et al. Guidelines of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
  5. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300.
  6. Adams D, Théaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep. 2014;14(3):435.
  7. Adams D, Lozeron P, Lacroix C. Amyloid neuropathies. Curr Opin Neurol. 2012;25(5):564-572.
  8. Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009;17(6):703-710.
  9. Zeng L, Alongkronrusmee D, van Rijn RM. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US. J Pain Res. 2017;10:219-228.
  10. Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748.
  11. Lalande S, Johnson BD. Diastolic dysfunction: a link between hypertension and heart failure. Drugs Today (Barc). 2008;44(7):503-513.
  12. Rapezzi C, Longhi S, Milandri A, et al. Cardiac involvement in hereditary-transthyretin related amyloidosis. Amyloid. 2012;19(suppl 1):16-21.
  13. Linart A. The heart in Fabry disease. 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. Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy (published online. J Neurol Neurosurg Psychiatry. 2017;0(0). doi: 10.1136/jnnp-2016-315262.
  15. Dharmarajan K, Maurer MS. Transthyretin cardiac amyloidosis in older North Americans. J Am Geriatr Soc. 2012;60(4):765-774.
  16. Tan BY, Judge DP. A clinical approach to a family history of sudden death. Circ Cardiovasc Genet. 2012;5(6):697-705.
  17. Castro J, Miranda B, Castro I, et al. The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy. Clin Neurophysiol. 2016;127(5):2222-2227.