Transthyretin Amyloidosis: Shining a Light on a Rare but Rising Threat
May 2025 – Rare Disease Today — Once considered obscure and underdiagnosed, Transthyretin Amyloidosis (ATTR) is now gaining clinical and research attention worldwide. With advancements in genetic screening, imaging, and novel therapies, ATTR is emerging as a key focus area in the fight against rare and progressive systemic diseases.
What Is Transthyretin Amyloidosis?
Transthyretin Amyloidosis (ATTR) is a progressive condition caused by the misfolding of transthyretin (TTR), a protein primarily produced in the liver. When TTR becomes unstable, it forms amyloid fibrils that accumulate in various organs — most commonly the heart and peripheral nerves.
There are two main forms of ATTR:
Hereditary ATTR (hATTR): Caused by a TTR gene mutation; inherited in an autosomal dominant pattern.
Wild-type ATTR (wtATTR): Occurs without genetic mutation, typically in older adults, and was historically referred to as senile systemic amyloidosis.
Clinical Presentation and Challenges
ATTR can present with a wide range of symptoms, making diagnosis challenging and often delayed:
Cardiac ATTR (ATTR-CM)
Heart failure with preserved ejection fraction (HFpEF)
Arrhythmias
Thickened ventricular walls (mimicking hypertrophic cardiomyopathy)
Neurological ATTR (ATTR-PN)
Peripheral neuropathy (numbness, tingling, pain)
Carpal tunnel syndrome
Autonomic dysfunction (e.g., gastrointestinal, bladder issues)
Misdiagnosis is common due to symptom overlap with more prevalent conditions like diabetic neuropathy or hypertensive heart disease.
Advancements in Diagnosis
The last few years have seen significant progress in non-invasive diagnostics, including:
99mTc-PYP scintigraphy: A nuclear imaging test that helps identify cardiac ATTR without biopsy.
Genetic testing: Confirmatory for hereditary ATTR and valuable for family screening.
Mass spectrometry cardiac MRI: Used in specialized centers to confirm amyloid type and organ involvement.
Earlier and more accurate diagnosis has opened doors to timely intervention and treatment optimization.
Emerging Therapies and Hope for Patients
Until recently, treatment options were limited. However, recent FDA and EMA approvals have transformed the landscape.
Approved Treatments:
Tafamidis (Vyndaqel®, Vyndamax®) – Stabilizes TTR, slowing progression of ATTR-CM.
Patisiran (Onpattro®) and Vutrisiran (Amvuttra®) – RNA interference therapies that reduce TTR production, approved for ATTR-PN.
Inotersen (Tegsedi®) – An antisense oligonucleotide also used for ATTR-PN.
Pipeline Innovations:
CRISPR-based gene editing therapies (in early trials) aim for a one-time cure by knocking out mutant TTR production.
Monoclonal antibodies targeting amyloid fibrils for clearance from tissues.
Oral TTR silencers offering greater convenience and accessibility.
Global Awareness and Market Trends
As awareness increases among cardiologists, neurologists, and general practitioners, the diagnosis rate of ATTR is rising, particularly in North America, Europe, and Japan. Global patient advocacy groups have played a key role in increasing visibility and support.
The global ATTR therapeutics market is projected to exceed $6 billion by 2030, fueled by:
Expanded label indications for RNA-based therapies
Aging populations prone to wild-type ATTR
Advances in precision medicine and companion diagnostics
Final Thought
Transthyretin Amyloidosis is no longer a hidden disease. Thanks to innovations in molecular diagnostics and targeted therapies, what was once a fatal, underdiagnosed condition is now being addressed with precision and hope. Continued education, genetic counseling, and early screening are key to ensuring patients benefit from the treatments now reshaping this rare disease landscape.
