As noted earlier in the discussion of acquired (primary) amyloidosis, amyloid is a descriptive term for any of the proteins that are deposited in filamentous beta-pleated sheets; it can be derived from a number of precursor protein sources. Peripheral neuropathy is a common and often the most prominent manifestation of amyloidosis. The polyneuropathies are of 2 main types—those associated with familial amyloidosis (referred to as FA) and the other associated with primary (nonfamilial) systemic deposition of amyloid (termed AL), which is derived from a circulating monoclonal protein. The acquired type has been discussed earlier. The most notable difference between these 2 types is the absence of a significant amount of paraprotein in the inherited forms (see further on). The amyloidosis that is secondary to chronic infectious or inflammatory disease, referred to as AA, is an increasingly rare condition and, in any case, does not affect the nerves.
In the following described most common familial amyloidoses, the amyloid is derived from an inherited abnormality of serum protein transthyretin (TTR, formerly called “prealbumin”). Several different amino acid substitutions have been identified in each type of amyloidosis. In the originally described Andrade type, methionine replaces valine at amino acid 30; therefore this has been referred to as transthyretin amyloidosis and as the TTR met 30 type. However, there are over 100 variants in the transthyretin gene that can give rise to amyloidosis.
The familial amyloid polyneuropathies comprise several distinct groups, as enumerated in Table 43-6. The pattern of inheritance in all types is autosomal dominant; males and females are affected with equal frequency. Although a descriptive classification based on the ethnic or geographic origin of affected families is still in use and is retained in the narrative categorization below, it is now possible to categorize the diseases according to their genetic causes and the corresponding chemical structure of the amyloid protein that is deposited in tissue. The recent cloning of many of the amyloid protein genes has made possible not only the detection of the common transthyretin mutation but also DNA tests for some of the other types of familial amyloidoses. Lachmann and colleagues (2002 and 2007) emphasize the high frequency of genetic defects in amyloid precursor proteins and the finding in one-quarter of cases of a low-level monoclonal gammopathy. Characteristic of all the amyloid polyneuropathies is the preferential involvement of small-diameter sensory and autonomic nerves and deposition of amyloid in various organs. Sensory loss, therefore, dominates the picture and pain and autonomic changes are prominent in most varieties of the disease.
The following are the main recognized types of familial amyloid neuropathies.
1. The Portuguese (Andrade) type. Andrade, in 1939, recognized that a chronic familial illness known as “foot disease” among the inhabitants of Oporto, Portugal, was a special type of amyloid polyneuropathy. He was not the first to have seen amyloid in degenerating nerve but deserves credit for identifying the disease as one of the heredofamilial polyneuropathies. By 1969 he had studied 148 sibships, comprising 623 individuals, among whom there were 249 with polyneuropathy. Descendants of this family have been traced to Africa, France, and Brazil. Other foci of the disease have been reported in Japan (Araki et al; Ikeda et al), the
United States (Kantarjian and DeJong), Germany (Delank et al), Poland, Greece, Sweden, and northwest Ireland (Staunton et al). As far as one can tell, these are separate, unrelated probands in different ethnic groups.