A NOVEL VARIANT OF TRANSTHYRETIN, 59(THR)-](LYS), ASSOCIATED WITH AUTOSOMAL-DOMINANT CARDIAC AMYLOIDOSIS IN AN ITALIAN FAMILY

Background Amyloidosis is a disorder of protein metabolism characteriz ed by extracellular accumulation of abnormal protein fibrils. Differen t proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Ca rdiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previo us perceptions, there is much recent evidence of effective treatment f or several different types of systemic and cardiac amyloidosis, includ ing the most common hereditary form caused by mutations in the transth yretin gene. Chemical and genetic typing of amyloid is therefore of co nsiderable clinical importance. Methods and Results Seven members in t wo generations of an Italian family presented with cardiac disease inh erited as an autosomal dominant and were found to have systemic amyloi dosis. Angina pectoris-like pain, an unusual feature in cardiac amyloi dosis, was a prominent symptom, possibly related to partial obliterati on of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropat hy, which are the usual features of hereditary amyloidosis, were prese nt in only two cases, and a diagnosis of acquired, immunoglobulin ligh t chain (AL type) amyloidosis was suspected in the index case before t he family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was a vailable were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-typ e Thr residue at position 59 in the mature protein. This mutation has not previously been reported. Conclusions We have identified a novel m utation in the transthyretin gene encoding 59(Thr-->Lys) associated wi th autosomal dominant hereditary systemic amyloidosis in an Italian ki ndred in whom cardiac involvement was the major feature. This family i llustrates the difficulty in diagnosis of cardiac amyloid, the variabl e clinical phenotype in hereditary amyloidosis even within a family, a nd the importance of precise fibril typing for correct management in t his condition.