Page 19 - Read Online

Page 2 of 11 Verriello et al. Vessel Plus 2021;5:51 https://dx.doi.org/10.20517/2574-1209.2021.69

All amyloid fibril proteins are called protein A plus an abbreviated form of the precursor protein name as a
suffix. Therefore, amyloid fibrils protein AL comes from immunoglobulin light chains and the disease is
known as AL amyloidosis, while TTR stands for transthyretin and the disease is ATTR amyloidosis. Further
details can be reported after the protein name, for instance ATTRwt or ATTRv (wt: wild-type and v:
variant). Moreover, the specific mutation can replace the “v”, e.g., ATTRV30M (p. TTRV50M) .
[2]
Many organs/systems may be affected by systemic amyloidosis, including heart, kidneys, liver,
gastrointestinal tract, and nervous system. Peripheral neuropathy is among the most frequent
complications. Its clinical presentation varies according to the affected nerves and their level of structural
involvement .
[3-5]

The most common phenotype is a length-dependent sensorimotor polyneuropathy, but there are many
[3]
atypical presentations that often lead to delayed diagnosis .
In this review, we describe the clinical features of neuropathy in hereditary and acquired forms of
amyloidosis, emphasizing the clinical aspects that should induce the clinicians to consider amyloidosis in
their differential diagnosis.

INHERITED FORMS OF AMYLOID NEUROPATHY
Hereditary amyloid neuropathy includes a group of autosomal dominant diseases, due to extracellular
accumulation of variant proteins, damaging somatic and autonomic peripheral nervous fibers.

The most common hereditary form of amyloid neuropathy is ATTR amyloidosis .
[3]

Other mutated proteins, like gelsolin and apolipoprotein A, may lead to amyloid neuropathy whose specific
clinical characteristics are summarized in Table 1.

Hereditary transthyretin amyloidosis
Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disease, due to a mutation in
[3]
transthyretin (TTR) gene, located on chromosome 18 . TTR is responsible for the transport of thyroxin and
retinol binding protein complex. TTR consists of a tetrameric protein with four identical subunits, and it is
primarily synthesized by the liver. Point mutations induce destabilization and dissociation of the TTR
[6]
tetramer into monomers, which aggregate into amyloid fibrils in different organs at the extracellular level .

Some mutations are associated predominantly with peripheral and autonomic neuropathy, others with
prevalent cardiomyopathy. Finally, there are mutations causing a mixed phenotype .
[7]

Clinical features
ATTRv amyloidosis with polyneuropathy phenotype depends on geographic location, causative gene
mutation, and age of onset. Moreover, for each specific mutation in the TTR gene, the phenotype may be
various, even within the same family.

In endemic areas (e.g., Portugal, Sweden, Japan, and Brazil), the most frequent phenotype is a length-
dependent small-fibers polyneuropathy with dysautonomia .
[8,9]