What is the recommended screening approach for amyloidosis in individuals with a family history?

Screening for Amyloidosis with Family History

First-degree relatives and possibly other biologically related relatives of patients with hereditary transthyretin amyloidosis (ATTRv) should undergo genetic testing to determine their mutation carrier status, and if positive, begin surveillance approximately 10 years before the age of disease onset in affected family members. 1

Initial Genetic Screening Approach

Who Should Be Tested

• All first-degree relatives of patients with confirmed ATTRv amyloidosis should undergo genetic screening with TTR gene sequencing 1
• Extended biologically related relatives may also be considered for testing 1
• Do not offer genetic testing to minors, but it can be offered to young adults when results could guide lifestyle choices or reproductive planning 1
• For AL amyloidosis families, genetic screening is not routinely indicated as it is not hereditary 1

Cascade Screening Effectiveness

• Cascade screening of first-degree relatives identifies additional cases efficiently, with one study detecting 33 additional individuals (7 symptomatic and 26 presymptomatic carriers) among 84 first-degree relatives screened 2
• The detection rate in systematic screening can reach 10% in appropriately selected populations 2

Surveillance Protocol for Asymptomatic Carriers

When to Begin Monitoring

• Start surveillance approximately 10 years before the age of disease onset observed in affected family members 1
• Begin immediately if symptoms compatible with amyloidosis develop, regardless of predicted onset age 1
• The 2021 ESC recommendation to screen ≤10 years prior to predicted disease onset has an excellent negative predictive value of 97% 3

Frequency of Assessments

• Annual routine assessments are recommended for all asymptomatic carriers 4
• In-depth assessments every 3-5 years, with frequency increased as the predicted age of onset approaches 4
• Repeat bone scintigraphy every 3 years is critical, as 13% of relatives with ATTRv-CM show no signs on first-line diagnostic tests 3
• The yield of serial evaluation at 3-year intervals is approximately 9.4% 3

Specific Screening Tests

First-Line Diagnostic Tests (Performed Annually)

• Electrocardiogram (ECG) - look for low QRS voltage despite wall thickness, which suggests cardiac amyloidosis 1
• Echocardiogram with strain imaging - assess for left ventricular wall thickness ≥14mm and characteristic strain patterns 1
• Cardiac biomarkers: NT-proBNP and high-sensitivity troponin 1
• Targeted neurologic examination - assess for peripheral neuropathy (numbness, paresthesia, imbalance), autonomic dysfunction (orthostatic hypotension, GI symptoms), or carpal tunnel syndrome 1

In-Depth Assessments (Every 3-5 Years)

• Bone scintigraphy (99mTc-DPD preferred) - confirms presence of transthyretin cardiac amyloidosis without need for biopsy if positive and no monoclonal protein present 1
• Cardiac MRI with late gadolinium enhancement - particularly useful for certain mutations (p.Phe84Leu, p.Ser97Tyr) where bone scintigraphy may be negative 1
• Neurologic assessments if symptoms present: Neurologic Impairment Score (NIS), Small-Fiber Neuropathy Symptom Inventory Questionnaire (SFN-SIQ), EMG with nerve conduction studies 1

Critical Screening Considerations

• Important caveat: 13% of relatives with ATTRv-CM do not show any signs of cardiac involvement on first-line diagnostic tests, making serial bone scintigraphy essential 3
• Bone scintigraphy can be negative in some ATTRv mutations (p.Phe84Leu, p.Ser97Tyr), requiring CMR for diagnosis 1
• Male sex and infrequently identified variants are predictors for higher risk of ATTRv-CM 3

Red Flags Requiring Immediate Evaluation

Cardiac Red Flags

• Unexplained left ventricular wall thickness ≥14mm with fatigue, dyspnea, or edema 1
• Discordance between wall thickness on echocardiogram and QRS voltage on ECG 1
• Bilateral carpal tunnel syndrome, especially in context of cardiac symptoms 1
• Unexplained heart failure, particularly HFpEF 1

Neurologic Red Flags

• Progressive sensory-motor polyneuropathy with autonomic dysfunction 1, 2
• Unexplained weight loss associated with axonal polyneuropathy (highest predictive value) 2
• Gastrointestinal symptoms with polyneuropathy 2
• Lumbar spinal stenosis 2

Psychological Support and Counseling

• Provide psychological support throughout the screening process 1
• Offer genetic counseling before and after testing 1, 4
• Establish long-term therapeutic alliance with carriers for ongoing monitoring 1
• Counsel on usual presenting symptoms with instructions to return before scheduled visits if new symptoms arise 1

Critical Knowledge Gaps

• Major uncertainty exists regarding optimal methods (imaging vs biomarkers) for monitoring disease progression 1
• Timing of therapy initiation in asymptomatic ATTRv carriers with early disease signs remains unclear 1
• Current guidelines do not address how to treat mutation carriers with signs of disease who remain asymptomatic 1