Familiar amyloid polyneuropathy (FAP) is a rare genetic condition that shares symptoms with other neuropathic disorders, most of which are much more common than FAP. Because of that, it is difficult to diagnose FAP. Delays in diagnosis are not uncommon, and range from one to five years, depending on the possible presence of a positive family history.
First, the doctor will observe the patient for a period of time to understand their complaints and take their family history. The physician then will analyze the findings from physical and neurologic examinations and conduct further clinical tests to rule out other possible causes of the symptoms.
Tests that can help diagnose FAP
Tests that may help diagnose FAP include:
- Electromyogram and nerve conduction studies, to confirm peripheral neuropathy.
- Tilt-table test, thermoregulatory sweat test, gastric-emptying tests, and bladder function tests to investigate autonomic neuropathy.
An electromyogram assesses the health of the muscles and the nerves that control them. It measures the electrical activity of muscle cells and looks for any muscle damage. A needle-like electrode is inserted into a muscle and the electrical signals generated during muscle contraction are recorded.
Nerve conduction velocity (NCV) test
The nerve conduction velocity (NCV) test measures the speed and strength of a nerve to transmit an electrical signal to other areas of the body. The NCV test is performed by placing electrodes on the surface of the skin at various points over a nerve. One electrode delivers small electrical shocks to the nerve and the other records the nerve’s responses. NCV often is decreased in FAP patients.
This test monitors the response of blood pressure and heart rate to changes in posture and position. The patient lies flat on a table, with the upper part of their body tilted. Normally, blood vessels become narrower and heart rate increases to compensate for the drop in blood pressure. This response may be slowed or abnormal if the patient has autonomic neuropathy.
Thermoregulatory sweat test
This test measures the function of nerves controlling the response to changes in temperature.
These tests are used to check for digestive abnormalities such as slow digestion and delayed emptying of the stomach.
Bladder function tests
These are a series of urine tests that can evaluate bladder function in patients with bladder or urinary symptoms.
If these tests confirm peripherical neuropathy and there is a known family history of the condition, with or without autonomic manifestations, doctors may suspect FAP.
In cases where no family history of the disease is reported, peripheral and autonomic neuropathy appearing together, carpal tunnel syndrome (a condition that mainly causes numbness, tingling in the hand and arm), and neuropathy together with heart disease, could indicate FAP.
Tests for conclusive FAP diagnosis
This is the “gold standard” test to detect amyloid fibril deposits, the hallmark of FAP. A small piece of an affected organ, especially a nerve or the stomach area (abdominal fat biopsy), is taken using a needle.
The sample is processed in the laboratory using staining with a dye called “Congo red” for identifying amyloid fibrils and then examined under a microscope. If amyloid fibrils are present it has a characteristic “apple green” appearance, which changes to red as the plane of polarized light is rotated.
Confirmation of amyloid fibrils is made using specific antibody molecules (proteins) that are designed to bind, recognize and distinguish different types of amyloid fibrils.
Genetic testing analyzes the sequence of the TTR gene to identify defects (mutations) known to be responsible for the disease. The test is performed on DNA extracted from blood samples drawn from the patient’s vein.
There are more than 100 mutations in the TTR gene known to cause FAP, and the different mutation identified may provide information about the likely clinical course of the disease. For example, the most common mutation worldwide, which results in the production of the Val30Met TTR protein variant, usually leads to amyloid deposition affecting only the nerves and not the heart. In contrast, the mutation that results in the production of the Thr60Ala TTR protein variant, typically seen in patients of Irish descent, may lead to disease affecting the nerves and the heart.
Imaging studies of the heart
If heart disease is suspected, cardiac investigations must be performed and include echocardiography to detect an enlargement of the heart caused by amyloid deposits, and electrocardiogram and Holter recording, for early detection of intracardiac conduction abnormalities.
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