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Page 4 of 11 Verriello et al. Vessel Plus 2021;5:51 https://dx.doi.org/10.20517/2574-1209.2021.69

On the other hand, late-onset Val30Met patients are seen in non-endemic areas, with onset after 50 years,
low penetrance rate, male predominance, and no family history. Clinically, they show sensorimotor
symptoms, beginning in the distal lower extremities, with loss of all sensory modalities and mild autonomic
[8,9]
dysfunction. In late-onset ATTRV30M, amyloid cardiomyopathy is frequently encountered .

Carpal tunnel syndrome (CTS) is often seen in ATTRv amyloidosis with polyneuropathy, caused by the
focal amyloid deposit in the transverse carpal ligament.

In recent case series, CTS occurred in two-thirds of patients with neuropathy related to ATTRv and,
frequently, preceded the diagnosis by a decade [12,13] .

The main symptoms of CTS are numbness, tingling, and pain in the fingers, especially the thumb, the index,
and the middle fingers. At onset, these symptoms often wake up the patient from sleep, then the numbness
may become constant over time. At the later stage, the patient may experience grip weakness.

Although CTS is commonly found in the general population, it tends to be bilateral, asynchronous and
more severe in patients with ATTRv amyloidosis with polyneuropathy than in subjects with idiopathic CTS.

Moreover, some specific TTR mutations, such as Leu58Arg , Ile84Ser , and Tyr114His , can present
[15]
[14]
[16]
with CTS as the only neurological manifestation in addition to other systemic symptoms.
Patients with ATTRv and atypical phenotypes of neuropathy have been described in non-endemic areas.
They are all late-onset cases and their clinical presentation includes: length-dependent all-fiber
sensorimotor polyneuropathy mimicking chronic inflammatory demyelinating polyneuropathy
[21]
(CIDP) [17-19] , multifocal neuropathy with onset in upper limbs , ataxic phenotype , and motor
[20]
neuropathy [22,23] . This clinical heterogeneity may frequently cause misdiagnosis.
One of the most frequent misdiagnoses of ATTRv amyloidosis with polyneuropathy is CIDP [17-19,24-27] . The
main factors leading to this misdiagnosis, in sporadic late-onset ATTRv amyloidosis with polyneuropathy,
are demyelinating features on nerve conduction study and mild elevation of cerebrospinal fluid (CSF)
proteins. However, patients with ATTRv amyloidosis with polyneuropathy frequently present severe pain
not restricted to lower limbs, while in case of CIDP, pain is rare and mild or moderate. Furthermore,
dysautonomic features are not a distinctive characteristic of CIDP and they provide a clue toward the
diagnosis of ATTRv amyloidosis with polyneuropathy, although they are less common in late-onset forms.
Thus, pain and dysautonomia, in patients with demyelinating polyneuropathy not responding to immune
therapy, are predictors of demyelinating ATTRv amyloidosis with polyneuropathy [19,24] .

Another atypical phenotype, in non-endemic area, is represented by multifocal neuropathy with onset in
[20]
upper limbs . Therefore, it is important to propose early molecular analysis of TTR gene in patients with
idiopathic upper limb neuropathies.

Ataxic phenotype, with a rapid course and sensory loss involving mainly vibration and joint position, has
been reported in France and Germany associated with Tyr77Ser mutation [21,26] .

Finally, predominantly motor neuropathies have been described in association with different
mutations [22,28-31] . In these cases, bulbar signs (dysarthria, dysphagia, and tongue atrophy) may be
encountered, mimicking amyotrophic lateral sclerosis [23,32] .