A 73-year-old man with biventricular diastolic heart failure, spinal stenosis, chronic kidney disease, cirrhosis, hypertension, and bilateral carpal tunnel syndrome, was referred to the clinic for suspected cardiac amyloidosis. An echocardiogram revealed an abnormal global averaged left ventricular longitudinal peak systolic strain at −7% (normal = ≤−18%), apical sparing pattern. Green birefringence on Congo red-stained cardiac tissue was observed under cross-polarized light (A). Liquid chromatography tandem mass spectrometry on peptides extracted from Congo red-positive, microdissected areas of the specimen detected a peptide profile consistent with ATTR (transthyretin)-type amyloid deposition (B). However, Sanger sequencing of the TTR gene did not reveal a pathogenic missense alteration (C).
The correct answer is ...
Histology, mass spectrometry, and sequencing results are consistent with a diagnosis of wild-type ATTR (transthyretin)-type amyloidosis.
Correct. Congo red positivity on cardiac specimen indicates the patient does have amyloid fibrils in the heart. Mass spectrometry analysis confirms these are TTR-type amyloid fibrils. A negative Sanger sequencing result is most consistent with wild-type or age-related TTR-type amyloidosis.
Sanger sequencing data confirms this patient does not have an ATTR (transthyretin)-type Amyloidosis. Incorrect — The negative Sanger sequencing results simply provides evidence that this patient is less likely to have an inherited or familial form of Transthyretin (TTR)-type Amyloidosis. Congo red positivity and mass spectrometry indicate that this patient does have TTR-type cardiac amyloidosis.
Based on Congo red stain and mass spectrometry alone we can conclude this patient has Familial ATTR (transthyretin)-type Amyloidosis TTR-associated. Incorrect — Congo red stain positivity and the mass spectrometry results indicate that this patient does have TTR-type cardiac amyloidosis but does not specify familial or wild-type (age-related) forms.(1)
Sanger sequencing is unable to identify the most common pathogenic TTR variants and follow up gene-targeted deletion/duplication analysis should be recommended. Incorrect — More than 99% of pathogenic TTR variants are sequence variants, generally detectable by standard Sanger sequencing analysis. Gene-targeted deletion duplication analyses are extremely low yield, as these types of alterations (i.e., exon or whole-gene deletions/duplications) are not typically reported in familial TTR-type amyloidosis.(2)
Laura Thompson, Ph.D.
Fellow, Laboratory Genetics and Genomics
Linda Hasadsri, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomics
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science