Diagnosing hATTR-PN
SNAPSHOT OF CANADIAN GUIDELINES FOR DIAGNOSING hATTR-PN1
Screening
Recommended in patients with idiopathic peripheral neuropathy
and ≥1 multi-systemic “red flag” symptom
and ≥1 multi-systemic “red flag” symptom
↓
Rapid progression
Weight loss
Bilateral carpal tunnel syndrome
Autonomic neuropathy
Unexplained heart failure and/or cardiac arrhythmias
Family history of neuropathy, cardiomyopathy, carpal tunnel syndrome
Gastrointestinal symptoms
Vitreous opacities
Any unexplained renal insufficiency or nephrotic syndrome
↓↓↓↓↓↓↓↓↓
Diagnostic workup and patient assessment
↓
Confirmatory testing
NCS and EMG to confirm and characterize large-fiber nerve involvement
➕
Skin punch biopsy may be performed to assess small-fiber involvement when clinical presentation is not convincing*
➕
Cardiologist referral to assess for cardiac amyloidosis
↓
Genetic testing†
↓
hATTR-PN
Adapted from the 2021 hATTR-PN Canadian Guidelines by Alcantara M, et al.1
* Other quantitative tests of small-fiber function may complement the diagnostic workup.1
† Recommended when there is clinical suspicion or a positive family history (with or without suggestive symptoms).1
💡
Post-diagnosis monitoring should include screening for sensory, autonomic, and cardiac involvement, as well as effects on quality of life1
Explore the paths you can take to achieve an accurate ATTR diagnosis:
Diagnosing ATTR-CM
SNAPSHOT OF CANADIAN RECOMMENDATIONS FOR DIAGNOSING ATTR-CM2
Clinical suspicion
Based on standard HF work-up, including cardiac imaging with either echocardiography and/or cardiac magnetic resonance, troponin, and BNP/NTproBNP
Monoclonal light-chain testing*
Using serum and urine protein electrophoresis with immunofixation or serum free light chain assay
Negative (monoclonal protein absent)
Cardiac scintigraphy
With Tc-99m-PYP scan†
Positive (ATTR confirmed)
Genetic testing
Positive (presence of TTR variant)
Negative (absence of TTR variant)
hATTR-CM
ATTRwt-CM
Adapted from the 2020 Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on ATTR-CM.2
* To rule out AL amyloidosis by screening for plasma cell dyscrasia.2
† If unavailable, perform endomyocardial biopsy with mass spectrometry or immunohistochemistry if positive. Tissue biopsy analysis includes Congo red staining for amyloid deposits.2
As mixed-phenotype disease is common in those with hATTR, all patients with hereditary cardiac amyloidosis should be referred to a neurologist for polyneuropathy screening3
Mixed-phenotype diagnosis
RECOMMENDED PATHWAY FOR SCREENING, DIAGNOSIS, AND MONITORING OF MIXED-PHENOTYPE hATTR3
hATTR confirmed
Screening for mixed-phenotype hATTR amyloidosis
Assessment by both a cardiologist AND a neurologist recommended for all hATTR patients to understand the extent of amyloid deposition/organ involvement
Cardiovascular assessments
- Symptoms/medical history
- 12-lead electrocardiogram
- Echocardiogram
- Cardiovascular MRI
- Nuclear scintigraphy scan with bone-seeking radiotracer (99mTc-PYP)
- Serum troponin and BNP/NT-proBNP
Neurologic assessments
- Symptoms/medical history
- Nerve conduction studies
- Small fiber tests
- Postural blood pressure
- Other autonomic neuropathy tests
Multidisciplinary consultation to determine next steps
With referral to other specialists as needed (e.g., ophthalmologist, gastroenterologist)
Ongoing routine monitoring by both cardiologist and neurologist
Follow patients every 6-12 months to monitor for progression
Key cardiology assessments: NYHA class, KCCQ QoL, 6MWT, hospitalizations, serum markers, echocardiography, ECG
Key neurology assessments: Gait, PND score, grip strength, NCS, NIS score, autonomic tests, PROs (R-ODS, SFN-SIQ, CADT, COMPASS-31)
Adapted from the 2025 Canadian Perspective on Mixed-Phenotype hATTR.3
Multi-disciplinary consultation is crucial given that mixed-phenotype hATTR can be expected in up to 80% of patients depending on mutation, with increasing incidence as the disease progresses3,4
Common misdiagnoses
The journey toward diagnosis has its challenges
Patients with ATTR often face diagnostic challenges due to low clinical suspicion and nonspecific symptoms that may mimic other more common conditions. This results in underdiagnosis and frequent misdiagnosis. 5,6
PATIENTS WITH ATTR FACE A DIAGNOSTIC DELAY OF
>3
YEARS7
~60% OF PATIENTS SAW
3+
PHYSICIANS
BEFORE RECEIVING THE CORRECT DIAGNOSIS OF ATTR6
COMMON MISDIAGNOSES AND OVERLAPPING CONDITIONS5
Neurologic
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
- Paraproteinemic peripheral neuropathy (e.g., monoclonal gammopathy-associated)
- Toxic peripheral neuropathy
- Vasculitic peripheral neuropathy
- Idiopathic axonal polyneuropathy
- Paraneoplastic neuropathy
- Diabetic neuropathy
- Alcoholic neuropathy
- Motor neuron disease (e.g., amyotrophic lateral sclerosis)
- Fibromyalgia
- Light chain amyloidosis
Cardiac
- Heart failure with preserved ejection fraction (HFpEF)
- Hypertensive cardiomyopathy
- Aortic stenosis
- Hypertrophic cardiomyopathy
- Light chain amyloidosis with cardiac involvement
- Idiopathic restrictive cardiomyopathy
- Iron overload
- Other infiltrative cardiomyopathies (e.g., Fabry disease)
Adapted from Nativi-Nicolau JN, et al.5
When there is any doubt in the initial diagnosis and/or clinical suspicion of hATTR, refer the patient for genetic testing1
Multi-systemic symptoms are a red flag for hATTR, with autonomic dysfunction present in almost all mutations1,8
Multi-systemic symptoms are a red flag for hATTR, with autonomic dysfunction present in almost all mutations1,8
ATTR is a systemic, progressive, and fatal disease caused by misfolded TTR, a protein produced by the liver1,3,10
ATTR is a systemic, progressive, and fatal disease caused by misfolded TTR, a protein produced by the liver1,3,10
