FAP: investigation for early diagnosis and differentials

In this second episode of PEBMED in partnership with Pfizer, Marcelo Gobbo and Viviane Carvalho discuss further the investigation of the rare FAP disease, familial amyloid polyneuropathy, for early and differential diagnosis.

In the first podcast of this series, we talk about the DPF, its definition, history, presentation and warning signs. Today we will talk a little more about research for early diagnosis and also about differential diagnoses.

Discover the first episode of the series

How is the initial approach to these patients made?

Well, the first step is to suspect the diagnosis and I want to stress that here, as a doctor, you need to know the signs and symptoms of the disease in order to suspect FAP. Recalling here a bit what we talked about in the last podcast, facing a patient with polyneuropathy, who presents warning signs, which are¹:

– Polyneuropathy, sometimes with an early dysautonomic component;

Progressive and severe character of the neuropathy

– Family history of neuropathy or heart disease;

– bilateral carpal tunnel syndrome;

– Early erectile dysfunction without known cause;

– Diarrhea or constipation, which can be alternated;

– Weight loss without known cause;

– Ophthalmological alterations such as vitreous opacities;



-Hypertrophic cardiomyopathy

– Lack of response to immunoglobulin (e.g. CIDP not responding to immunoglobulin)¹

Well, now, in front of a patient with that kind of suspicion, you should investigate, right? How is it done?

Exactly. Now, faced with a compatible history and clinic, let’s proceed with the investigation.

In general, in our clinical practice as a neurologist, the first step is what we call laboratory screening for neuropathies. This helps us strengthen our hypothesis and/or rule out other possibilities.

In this lab screening, we usually do a complete blood count; dosage of vitamin B12; Glycated hemoglobin; thyroid hormones (TSH, T4L); hepatogram and assessment of renal function. In addition, a very useful and important test for neuropathies is protein electrophoresis with immunofixation and measurement of free light chains.¹.

In this case, in the face of this suspicion and based on your physical examination, you will follow the screening according to the manifestations of your individual patient. So there is a logic, but it is not a cake recipe. For example, you should also be careful and investigate heart, eye, skin, gastrointestinal, etc. problems. In addition, an examination that helps the neurologist a lot in neuropathies is electroneuromyography.

And here I would like to stop to point out that electroneuromyography, although very useful, does not change in every neuropathy. Like any complementary examination, it has its limits. And the main limitation of electroneuromyography is that it does not assess fine fibers² well.

As I mentioned in the previous podcast, in early FAP, the patient may initially have a neuropathy consisting solely of fine, free-standing fibers. In this case, the ENMG will be normal1. In addition to skin biopsy, some more specific tests can be used, although they are not widely available in clinical practice. Among them we can mention the QST (QST – Quantitative Sensory Testing) analyzes perception in response to an external stimulus of controlled intensity; corneal confocal microscopy (which visualizes C-type fibers that originate from the trigeminal nerve and travel to Bowman’s membrane in the cornea); microneurography which assesses the activity of sympathetic fibers and type C nociceptors; CHEPS, which assesses the potential evoked by contact with heat; the QSART which assesses the sudomotor axonal reflex and peripheral nerve ultrasound³.

Biopsy of affected tissues can be used to demonstrate amyloid deposits. Preferred sites for biopsy are the salivary gland and abdominal subcutaneous fatty tissue, as they are less invasive. But it can also be done for the nerves, heart, kidneys and gastrointestinal tract. But it is important to know that a negative biopsy does not exclude the diagnosis of ATTRv amyloidosis, because amyloid deposits have a multifocal distribution.4,5,6.

Scintigraphy with rbone diotracers also demonstrate good sensitivity and specificity for ATTR cardiomyopathy, especially in patients who do not have monoclonal gammopathy¹.

In addition, we are currently using genetic testing more frequently. In this test, it is possible to perform TTR gene sequencing and identify pathogenic variants.

Currently, excluding other causes, and from a compatible history and clinic, and with gene sequencing identifying a pathogenic variant, it is possible to obtain the diagnosis of PAF. Despite this, it is recommended to perform a minimally invasive biopsy in the initial investigation due to the variable penetrance of TTR mutations.¹.

In short, the more information that supports your diagnosis, the better.

You talked about excluding other causes. If so, what would be the main differential diagnoses?

Well, regarding the differential diagnoses, we can highlight: chronic inflammatory demyelinating polyneuropathy (CIDP or CIDP); spinal canal stenosis; Charcot-Marie-Tooth disease (CMT); diabetic neuropathy; ethyl deficiency neuropathy; vasculitis; and leprosy1.7.

Specifically here in Brazil, it is important to draw attention to diabetic neuropathy with a dysautonomic component, such as patients with advanced stages or with diabetic cachexia and also leprosy; since I often see these conditions in our population. (professional experience).

Also, CIDP or PIDC is a condition that can be quite confused with FAP. Although typically characterized by predominantly demyelinating sensory-motor neuropathy, once extensive, length-dependent axonal damage is present, the electrophysiological features of TTR-PAF may resemble those seen for CIDP, due to axonal damage to conduction nerve fibers faster or due to secondary damage. demyelination1.7.

Additionally, there may be some degree of proteinorachia in patients with FAP (due to increased levels of TTR protein in CSF), although usually less marked than that seen in CIDP. Also, when a negative biopsy is obtained, some professionals believe that the diagnosis of FAP should be completely excluded and CIDP should be considered, and as we have already seen, a negative biopsy does not invalidate the diagnosis.8.9.

What would you like to leave as a last message to our listeners?

We know that early diagnosis is essential in these patients, because it is through diagnosis that these patients will have access to earlier treatment. We are living in a new phase in which we have greater access to diagnostic methods, and in a less invasive way, such as genetic sequencing.

We are talking here about a multisystem disease, serious, progressive and potentially fatal. Today, we are able to offer patients a much better prognosis and quality of life through early treatment.

That’s why this space here is so important for spreading knowledge, and I appreciate this opportunity.

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In this second episode of PEBMED in partnership with Pfizer, Marcelo Gobbo and Viviane Carvalho discuss further the investigation of the rare FAP disease, familial amyloid polyneuropathy, for early and differential diagnosis.
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