Boston Medical Center is the primary teaching affiliate of the Boston University School of Medicine. Transthyretin (TTR) Amyloidosis Frederick L. Ruberg, MD Amyloidosis Center and Section of Cardiovascular Medicine Boston University School of Medicine Boston Medical Center Boston, MA
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Boston Medical Center is the primary teaching affiliate
of the Boston University School of Medicine.
Transthyretin (TTR) Amyloidosis
Frederick L. Ruberg, MD
Amyloidosis Center and Section of Cardiovascular Medicine
Boston University School of Medicine
Boston Medical Center
Boston, MA
OVERVIEW OF TTR AMYLOIDOSIS
• Amyloidosis is a disorder of protein folding
• Classification of amyloid type by precursor protein
• Transthyretin (TTR) aka prealbumin 55 k-Da protein
synthesized by liver > 100 known SNPs
• Mutations alter thermodynamic properties of protein to favor
mis-folding and aggregation as amyloid fibrils
– Variant TTR amyloidosis
– Autosomal dominant inheritance pattern (50% likelihood of
transmission)
Connors, Amyloid 2003
KEY POINTS TO REMEMBER 1. Variant TTR amyloidosis results from single nucleotide
polymorphisms (SNPs) that cause nerve, cardiac, and soft tissue amyloid fibril deposition (alone or in combination)
2. Mutations vary by geographic distribution thus ancestry can predict mutation
3. Penetrance is incompletely understood however there are clear gender and age associations with phenotypic expression
4. Clinically it can be difficult to distinguish variant TTR from ATTRwt, but easier to differentiate from AL
5. Novel approaches using TTR stabilization or suppression agents hold great promise to treat variant TTR disease
TTR STRUCTURE AND FIBRIL FORMATION
Bulawa et al. PNAS 2012
CLINICAL MANIFESTATIONS OF VARIANT TTR
AMYLOIDOSIS
Variant TTR amyloidosis
Restrictive Cardiomyopathy
(FAC)
V122I
T60A
Autonomic and peripheral
Neuropathy (FAP) V30M
Mutation
Ruberg, Circulation 2012
FEATURES OF TTR CARDIAC AMYLOIDOSIS
DIAGNOSIS OF VARIANT TTR CARDIAC
AMYLOIDOSIS 1. Clinical suspicion and recognition!
2. Tissue biopsy to identify amyloid by Congo red stain – Abdominal fat aspirate (20-25% sensitive for ATTRwt, 50-75%