HEREDITARY AMYLOIDOSIS

TTR Cardiac Amyloidosis — a treatable cause of heart failure hiding in plain sight, where tafamidis reduces mortality by 30% but requires TTR genotyping that most cardiologists have not yet ordered.

Whole genome sequencing identifies all TTR variants — including Val122Ile (carried by 3-4% of African Americans) and Val30Met (the most common hereditary ATTR variant) — providing the molecular diagnosis that unlocks tafamidis therapy.

About this condition

Hereditary Amyloidosis — ATTR Wild-Type & Variant

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by misfolding and deposition of transthyretin (TTR) protein as amyloid fibrils in the myocardium, producing restrictive cardiomyopathy with heart failure. Two forms exist: hereditary ATTR (hATTR, caused by >130 known TTR pathogenic variants) and wild-type ATTR (wtATTR, previously called 'senile cardiac amyloidosis,' caused by age-related misfolding of normal TTR protein). Combined prevalence is dramatically higher than previously recognized — studies suggest ATTR-CM is present in 6-13% of patients with heart failure with preserved ejection fraction (HFpEF) and 5-16% of patients undergoing transcatheter aortic valve replacement.

The TTR Val122Ile variant (p.Val142Ile using current nomenclature) is carried by approximately 3-4% of African Americans — among the most common pathogenic variants of any gene in any population. Val122Ile causes late-onset cardiac amyloidosis, typically presenting after age 60 with progressive heart failure, conduction abnormalities, and carpal tunnel syndrome. It is frequently misdiagnosed as hypertensive heart disease or idiopathic HFpEF in African American patients. The Val30Met variant (p.Val50Met) is the most common hereditary ATTR variant globally, prevalent in Portugal, Sweden, and Japan, and causes both polyneuropathy and cardiomyopathy.

Tafamidis (Vyndamax/Vyndaqel), a TTR stabilizer that prevents tetramer dissociation and amyloid fibril formation, was FDA-approved in 2019 for ATTR cardiomyopathy. The ATTR-ACT trial demonstrated that tafamidis reduced all-cause mortality by 30% and cardiovascular hospitalization by 32% compared to placebo — one of the largest mortality benefits of any heart failure therapy. However, tafamidis requires confirmed ATTR-CM diagnosis, and molecular TTR genotyping is essential to distinguish hereditary from wild-type ATTR (both are treated with tafamidis, but hereditary ATTR has implications for family screening). Gene-silencing therapies (patisiran, inotersen, vutrisiran) are approved for hATTR polyneuropathy.

3-4% of African Americans carry TTR Val122Ile — making it one of the most common pathogenic variants in any population. Late-onset heart failure in African Americans should prompt TTR genotyping.

Gene locus: TTR (18q12.1) — >130 pathogenic variants; Val122Ile (3-4% African Americans), Val30Met (most common globally)

ATTR-CM is treatable with tafamidis (30% mortality reduction) but is missed in the majority of affected patients. Adding TTR genotyping to heart failure evaluation identifies a treatable subset currently dying of 'idiopathic' heart failure.

30% mortality reduction with tafamidis — but only patients with confirmed ATTR-CM diagnosis receive it

The ATTR-ACT trial demonstrated that tafamidis produces a 30% reduction in all-cause mortality in ATTR cardiomyopathy — among the largest mortality benefits in heart failure therapeutics. Yet autopsy studies suggest that ATTR-CM is present in 20-25% of elderly patients with heart failure who were never diagnosed during life. The gap between treatable disease and actual treatment is enormous. TTR genotyping identifies the hereditary component, and nuclear scintigraphy (99mTc-PYP/DPD scan) diagnoses ATTR-CM non-invasively without biopsy. WGS identifies TTR variants as part of a comprehensive genomic evaluation, flagging ATTR-CM risk before clinical heart failure develops.

Hereditary ATTR requires family cascade screening — all first-degree relatives should be genotyped and monitored

When a TTR pathogenic variant is identified, all first-degree relatives have a 50% chance of carrying the same variant. Presymptomatic carriers benefit from regular cardiac surveillance (echocardiography, cardiac biomarkers, nuclear scintigraphy) to detect subclinical amyloid deposition before heart failure develops — enabling early tafamidis initiation when treatment is most effective. Without molecular TTR diagnosis, the proband is diagnosed with 'cardiac amyloidosis' but family members are not screened, missing the opportunity for presymptomatic intervention.

TTR Cardiac Amyloidosis — a treatable cause of heart failure hiding in plain sight, where tafamidis reduces mortality by 30% but requires TTR genotyping that most cardiologists have not yet ordered.

Hereditary Amyloidosis — ATTR Wild-Type & Variant

ATTR-CM is treatable with tafamidis (30% mortality reduction) but is missed in the majority of affected patients. Adding TTR genotyping to heart failure evaluation identifies a treatable subset currently dying of 'idiopathic' heart failure.

30% mortality reduction with tafamidis — but only patients with confirmed ATTR-CM diagnosis receive it

Hereditary ATTR requires family cascade screening — all first-degree relatives should be genotyped and monitored

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