Homozygous transthyretin Leu64: a very rare transthyretin mutation associated with amyloidosis but not with euthyroid hyperthyroxinemia

Transthyretin (TTR) or prealbumin is a tetrameric thyroid hormone (TH) plasma transport protein, but is also one of the fibrillar proteins associated with specific forms of amyloidosis. Typically, patients with TTR- associated amyloidosis are heterozygous for a point mutation in the TTR gene and suffer from peripheral polyneuropathy with or without other symptoms/signs (e.g., erectile dysfunction). Here we report a Sicilian patient, born from unknown parents, who harbored a biallelic T→C mutation at nucleotide 3871 of exon 3 of the TTR gene. This point mutation caused Phe64 to be replaced by Leu. There was no change in thyroid hormone levels because the mutation occurred far from the C-terminal TH binding domain. Only one other patient with TTR-associated amyloidosis due to the Phe64→ Leu mutation has been described thus far. He was also Italian but heterozygous, so that the disease started appearing about two decades later than in our homozygous patient. This rare case of homozygosity for a very rare TTR variant indicates that a relatively conservative amino acid change in the β turn which separates β strands D (aa 53-55) and E (aa 67-74) causes conformational changes that lead to the enhanced precipitation of TTR in the form of amyloid fibrils without distorting the thyroid hormone binding cavity.