New transthyretin mutation V28M in a Portuguese kindred with amyloid polyneuropathy

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Abstract
A 62‐year‐old Portuguese man, with no history of familial amyloid polyneuropathy (FAP), and a 2½‐year history of tingling in the toes and sexual dysfunction was found neurophysiologically to have a sensory‐motor axonal polyneuropathy. Autonomic tests showed slight sympathetic and marked parasympathetic involvement. Heart, kidney, and eyes were normal. Single strand conformation polymorphism (SSCP) mutation analysis for the transthyretin (TTR) gene was performed. The SSCP pattern suggested the presence of a mutation in exon 2, but was different from the pattern observed for a control representing the most common TTR mutation associated with FAP, i.e., TTR V30M. DNA sequencing analysis revealed an A‐to‐G transition in the first base of codon 28 normally encoding a valine, giving rise to a methionine residue. The presence of this extra methionine was confirmed by peptide mapping and mass spectrometry analysis. Biopsy of nerve and skin of the propositus showed amyloid deposits that were immunoreactive for TTR. This is a new variant TTR related to late‐onset amyloid neuropathy with autonomic dysfunction. This case confirms that TTR mutation screening should be considered in patients with a clinical disorder consistent with amyloid neuropathy even in the absence of a family history. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1016–1021, 2000