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Verriello et al. Vessel Plus 2021;5:51 https://dx.doi.org/10.20517/2574-1209.2021.69 Page 3 of 11

Table 1. Inherited amyloid neuropathies and their clinical features
Type of Underlying mutation Precursor Main clinical features
amyloidosis protein
ATTRv Mutations in TTR gene Abnormal TTR Length-dependent sensory-motor axonal polyneuropathy with
dysautonomia
Rapidly progressive and disabling axonal polyneuropathy in the
elderly
Chronic inflammatory demyelinating polyneuropathy like (CIDP-
like)
Multifocal neuropathy with onset at upper limbs
Ataxic phenotype
Motor neuropathy
AApoA1 Mutations in apolipoprotein Abnormal ApoA1 The disease affects mainly kidneys, liver, and gastrointestinal tract
gene Gly26Arg mutation may cause a length-dependent polyneuropathy
Agel Mutations in gelsolin gene Abnormal gelsolin Cranial and peripheral neuropathy; cutis laxa and corneal lattice
dystrophy

Onset symptoms generally include sensory abnormalities due to damage of small fibers, such us numbness,
burning sensation and allodynia in the feet that often worsen at night. Neurological assessment reveals
predominant loss of thermal sensation and nociception.

With the progression of the disease, large sensory and motor nerve fibers are involved, inducing weakness
and reduction of vibration sense and proprioception. Furthermore, symptoms gradually spread from the
distal extremities to proximal lower limbs and upper limbs .
[9]

Given the involvement of small fibers, patients commonly present with autonomic dysfunctions .
[10]

Cardiovascular autonomic neuropathy may induce orthostatic hypotension and life-threatening
arrhythmias. Patients with orthostatic hypotension may complain of light-headedness, blurred vision, and
dizziness when standing.

Gastrointestinal autonomic symptoms, due to gastroparesis and dysmotility, include alternating post-
prandial diarrhea, severe constipation, early satiety, and crisis of vomiting.

Regarding genitourinary tracts, in the early stage of the disease, impairment of sacral parasympathetic fibers
may result in alteration of bladder sensation, urine retention, dysuria, and incomplete bladder emptying.
Then, when the motor sympathetic and somatic nerves are involved, urgency up to overflow incontinence
appears. In males, erectile dysfunction is the earliest finding.

There are over 100 TTR mutations that cause ATTRv, but not all of them determine the characteristic
clinical picture of ATTRv amyloidosis with polyneuropathy. The most common one is a point mutation
that leads to the substitution of methionine for valine at position 30 (Val30Met) . By the age at onset,
[11]
patients with Val30Met mutation are classified into two groups: early onset (< 50 years) and late onset (> 50
years).

Early onset ATTRV30M patients are seen in the endemic areas and they are characterized by onset before
50 years, high penetrance rate and classical clinical presentation, that is small fibers polyneuropathy with
marked autonomic dysfunction .
[8,9]