Onset in the seventh decade and lack of symptoms in heterozygotes for the TTR^Met30 mutation in hereditary amyloid neuropathy—type I (Portuguese, Andrade)

Abstract

In a Portuguese-American family with hereditary amyloid neuropathy (familial amyloidotic polyneuropathy), onset was in the seventh decade in all affected relatives. Another unusual characteristic was their origin from the Portuguese island of Madeira. In spite of this, the mutant transthyretin (TTRMet30) (the same variant prealbumin that is the circulating precursor of AFP protein in the classic Portuguese patients) could be found in the propositus' plasma. In addition, three other asymptomatic relatives (ages 90, 73, and 48) were shown to carry the mutation. Late onset and incomplete penetrance, at a clinical level, raise problems for presymptomatic detection of mutant TTR, as these tend to cluster in families. When counseling asymptomatic heterozygotes, we must consider intra-familial correlation in age-of-onset, and the distribution of age-of-onset including age of unaffected heterozygotes. This family poses interesting questions regarding pathogenesis of this degenerative process and the influence of other genetic factors, such as modifiers, epistasis, and polymorphism of the TTR genes or their regulators. A cis-effect of a gene linked to the mutant gene, decreasing the synthesis of the mutant TTR and keeping a sufficient amount of the normal one in circulation, or producing some cofactor for TTR, could also explain late onset and apparently incomplete penetrance; the occasional finding of classic forms in these families would be the result of recombinatory events.

Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M

“…Previous work from our group also confirmed that late-onset and aged-asymptomatic carriers aggregate in families, and that, as in Sweden, isolated cases with late-onset often descend from aged-asymptomatic carriers 4 8 9…”

The Neuromuscular Manifestations of Amyloidosis

“…30 Yet, there are Portuguese asymptomatic carriers older than age 70 and as old as 90 years. 31 Similarly, asymptomatic individuals have been described in Japanese kindreds who were as old as 81 years and had serum levels of variant TTR as high as those with polyneuropathy. 32 In view of this, it is not surprising that the family history has been found to be negative in one third of Portuguese cases in patients with FAP 33 and in over half of patients with FAP from other ethnic backgrounds.…”

Diagnosis of hereditary neuropathies in adult patients

“…In other neuropathies, onset occurs during adulthood, as in some cases of CMT (more frequently for the axonal variety CMT2), and in FAP, where disease onset may be delayed until the 7 th decade of life [104].…”