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JMD 2007, Vol. 9, No. 1
Copyright © 2007 American Society for Investigative Pathology & Association for Molecular Pathology

Consultations in Molecular Diagnostics

Homozygous Transthyretin Mutation in an African American Male

Eapen K. Jacob^*, William D. Edwards^*, Mark Zucker, Cyril D’Cruz, Surya V. Seshan, Frank W. Crow^* and W. Edward Highsmith^*

From the Department of Laboratory Medicine and Pathology, * Mayo Clinic, Rochester, Minnesota; the Department of Cardiology, Newark Beth Israel Medical Center, Newark, New Jersey; Department of Laboratory Medicine and Pathology, Newark Beth Israel Medical Center, Newark, New Jersey; and Department of Pathology, Weill Medical College of Cornell University, New York, New York

Abstract

Cardiac amyloidosis of transthyretin type in the elderly may be senile or familial. The senile form is not typically associated with specific genetic changes. However, the familial form is and also occurs more frequently in African Americans than in the general population. One transthyretin mutation, V122I, is common in the African-American population, has a carrier frequency of 4%, and has marked cardiac specificity. Symptoms generally develop in the eighth and ninth decades. Here, we report the case of a 60-year-old African-American man who had a 2-year history of dyspnea and diffuse left ventricular wall thickening. Endomyocardial biopsy showed interstitial deposits of amorphous material confirmed as amyloid by Congo red staining and electron microscopy. Mass spectrometry showed a shift in protein mass of 14 d, indicative of transthyretin and confirming the production of abnormal protein. Bidirectional whole gene sequencing showed a homozygous mutation leading to a valine 122 isoleucine substitution (V122I). The 14-d mass shift observed using mass spectrometry is consistent with the V122I mutation. Homozygosity for the V122I mutation may be associated with earlier onset of cardiac disease. Transthyretin analysis should be considered for older African Americans with amyloid heart disease of transthyretin type.