Contributor: Gordon K. Klintworth
The transthryretin amyloidoses are types of amyloidosis caused by mutations in the TTR gene which encodes for transthyretin. The transthyretin amyloidoses include: familial amyloid polyneuropathy type I, familial amyloid polyneuropathy type II. More than 15 distinct point mutations in the TTR gene have been identified and most of them are associated with systemic deposits of amyloid. Mutations in positions 30(Val-30-Met), 58(Leu-58-His), 60(Thr-60-Ala), or 84(Ile-84-Ser) cause a familial polyneuropathy [amyloid polyneuropathy type I]. It is noteworthy that the substitution of alanine for threonine in position 60 results in familial polyneuropathy with major deposits in the heart (unlike the other mutations), and in contrast to many other transthyretin related amyloidoses (including familial polyneuropathy type I and familial polyneuropathy type II), the eye is not involved. A methionine substitution for leucine at position 111 in transthyretin does not cause FAP, but produces amyloid to deposit predominantly in the heart. Senile systemic amyloidosis occurs when isoleucine replaces valine in position 127. Moreover, a valine substitution for tyrosine at position 116 of transthryrein has no pathologic consequences. A characteristic manifestation of transthyretin amyloidosis is a polyneuropathy sometimes becoming first manifest with a carpal tunnel syndrome. A cardiomyopathy is often associated and may cause the death of the patient. Vitreous deposits of amyloid are features of some mutations in transthyretin. All forms of transthyretin amyloid have autosomal dominant modes of transmission.