Contributor: Gordon K. Klintworth
Familial amyloid polyneuropathy type I is one type of transthryretin amyloidosis caused by mutations in the transthyretin gene. Transthyretin is in normal constituent of human plasma and CSF. It is synthesized predominantly in the liver, but is also produced in the choroid plexusof the brain, and in the eye by the retinal pigment epithelium. This acidic protein displays an affinity for thyroxine and retinol binding protein and partakes in their plasma transportation. On electrophoresis it migrates in front of albumin, hence the older term prealbumin. It is made up of 4 identical subunits, each consisting of a known sequence of 127 amino acids. Approximately half of the amino acid chain forms a beta-pleated sheet. The gene encoding for transthyretin has been mapped to the long arm of human chromosome 18 (18q11.2-q12.1). Transthyretin is predominantly synthesized in the liver, but is also produced in the choroid plexus of the brain, and in the eye by the peripheral retinal pigment epithelium. More than 15 distinct point mutations in the transthyretin 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 amyloid polyneuropathy type I and familial amyloid polyneuropathy type II),the eye is not involved. A methionine substitution for leucine at position 111 in transthyretin does not cause familial amyloid polyneuropathy, 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.