Page 120 - Read Online

Page 6 of 11 Scirpa et al. Vessel Plus 2022;6:52 https://dx.doi.org/10.20517/2574-1209.2021.74

may help to avoid unnecessary testing and procedures, guide recommendations for medical treatment and
screening, and offer accurate genetic counseling (including risk assessment) for the family. Similarly, in the
evaluation of ATTR, genetic testing may be considered to confirm a suspected diagnosis of ATTRv and
determine carrier status for a known familial mutation. Identification of patients whose amyloidosis is of
genetic origin is of utmost importance, as it affects treatment decisions.

[6]
The diagnosis of cardiac ATTR is a challenge in daily clinical practice. According to Gillmore’s algorithm ,
in the presence of clinical suspicion of cardiac amyloidosis, it is mandatory to rule out a monoclonal
gammopathy by means of three tests: serum-free light chains (sFLC), serum, and urine immunofixation
electrophoresis. Moreover, a scintigraphy with bone avid tracers technetium pyrophosphate ( Tc-PYP),
99m
99m
99m technetium 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), and 99m technetium
hydroxymethylene diphosphonate (99mTc-HMDP) should be performed; if the results are positive, this
allows making a cardiac-ATTR diagnosis without the need of an endomyocardial biopsy [6,41,42] . In particular,
cardiac ATTR can be diagnosed when all of the following criteria are met: heart failure with an
echocardiogram or cardiac magnetic resonance (CMR) that is suggestive of amyloidosis; grade 2 or 3
99m
cardiac uptake on a radionuclide scan with Tc-PYP, Tc-DPD, or Tc-HMDP; and absence of a
99m
99m
detectable monoclonal protein despite sFLC, serum, and urine immunofixation electrophoresis assay .
[6,7]
Histological confirmation is needed in all cases of suspected cardiac amyloidosis in which these criteria are
not met . The first cause of false positive scans is AL amyloidosis which should obligatorily be excluded.
[6,7]
On the contrary, false negative scans may occur in the presence of some ATTRv mutations such as
Phe64Leu that is characterized by low or absent myocardial bone tracer uptake; therefore, in such cases, in
the presence of high clinical suspicion, a multimodal approach with CMR, cardiac biopsy, and/or genetic
[43]
testing should be sought .

Once the diagnosis of cardiac amyloidosis has been made, genetic testing has to be performed in all patients,
regardless of the presence of family history, in order to distinguish ATTRwt amyloidosis from the mutated
form [7,44-46] . The genetic test has a fundamental role even if the proband is old, given that certain specific
mutations are characterized by a late clinical onset [7,44-46] .

Genetic testing of TTR mutations should also be offered to patients with neurological symptoms suggestive
of ATTR: unexplained dysautonomia, progressive sensory length-dependent polyneuropathy, or rapidly
progressive sensory-motor axonal neuropathy in the absence of other possible causes (such as diabetes,
alcohol abuse, monoclonal gammopathy, vitamin B12 deficiency, or hypothyroidism) .
[47]

When a diagnosis of hereditary amyloidosis has been established and the mutation identified, genetic study
of relatives can determine who needs to be monitored and who does not. In particular, genetic screening
should be offered to the proband’s siblings, who are at higher risk for developing a clinical disease in the
immediate future. Usually, the timing between the diagnosis of the index patient and the offer of genetic
testing to its relatives should be flexible and should consider the specific mutation penetrance, as well as the
age of onset and the severity of the disease both in the proband and in the other affected relatives [48,49] .
Genetic studies in those under 18 years of age are not recommended, given that the result would not affect
the clinical approach, while it could have possible negative psychological consequences for the minors and
those around them [44,46] . Participation in genetic screening must be an autonomous personal choice, and
long-term clinical monitoring can be offered to those who refuse to undergo genetic testing.

Doing the genetic test in asymptomatic relatives presents the potential psychological consequence of
knowing to be at risk for developing a degenerative disease. Therefore, it should always be considered that