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

Diagnostic pitfalls and red flags
ATTRv amyloidosis with polyneuropathy is frequently diagnosed late, due to variable clinical presentations
that make the disease difficult to recognize.

Age at onset may vary, with a wide range from 20 to 80 years. Moreover, incomplete penetrance may be
responsible for cases without a positive family history.

Sporadic ATTRv amyloidosis with polyneuropathy is a diagnostic challenge. Some of the most frequent
misdiagnosis are: CIDP, idiopathic polyneuropathy, AL amyloidosis, diabetic neuropathy motor neuron
disease, and lumbar spinal stenosis [Table 2]. However, lumbar spinal stenosis, due to amyloid deposits
within the ligamentum flavum, may be an early manifestation of systemic ATTRv amyloidosis .
[33]

Some patients can have significant slowing of motor conduction velocity and sometimes fulfill EFNS/PNS
criteria for a definite CIDP. Furthermore, increased protein levels in CSF and negative biopsy contribute to
misdiagnosis [17-19] .

The sensitivity of tissue biopsy may be different within the various mutations and the sural nerve biopsy
may be unexpectedly negative as the deposition is often sporadic and random [34,35] .

Within the CIDP scenario, fast disease progression and immunomodulatory treatment failure are signs that
should suggest an alternative diagnosis, including ATTRv amyloidosis with polyneuropathy.

In the literature, patients with TTR-related amyloidosis who were diagnosed as affected by AL amyloidosis
have been described [36,37] , due to the concomitant presence of monoclonal gammopathy or mistakes in
immuno-labeling of amyloid aggregates.

This erroneous diagnosis may lead to inappropriate chemotherapeutic treatments; thus, the correct
identification of the amyloid precursor is mandatory.

Family history and multi-organ involvement are clues that should raise the clinical suspicion of ATTRv
amyloidosis with polyneuropathy.

Considering all available literature and expert opinions, ATTRv amyloidosis with polyneuropathy should be
suspected in case of a progressive sensory motor neuropathy associated with at least one of the following
“red flags”: family history of neuropathy, early autonomic dysfunctions (e.g., erectile dysfunction or postural
hypotension), weight loss not otherwise explained, bilateral CTS, cardiac signs and symptoms (e.g., heart
hypertrophy, arrhythmias, cardiomyopathy, or ventricular blocks), renal impairment (e.g., albuminuria),
[38]
and vitreous opacities [Figure 1].
Early diagnosis of ATTRv amyloidosis with polyneuropathy is important, considering currently available
therapies. The main investigation is the genetic test, by mean of the TTR gene sequencing to search for
amyloidogenic variants. Biopsy (e.g., salivary glands, sural nerve, or abdominal fat) allows detecting and
typing of the amyloid in the tissue.

Once the diagnosis has been made, assessing disease severity and monitoring its progression are crucial to
establish the indication for treatment.