Familial amyloid polyneuropathy (FAP) is a rare genetic condition that is difficult to diagnose because it shares symptoms with other neuropathic disorders, most of which are more common.
In regions where the disease is endemic, or in people with a family history of the disease, diagnoses typically occur within a year. In areas where FAP is less common, delays of three to four years in diagnosis can often happen.
Initially, the doctor will observe the patient for a period of time to understand their symptoms and examine their family history. The physician will then analyze the findings from physical and neurologic examinations and order additional tests to rule out other conditions that may cause similar symptoms.
Conclusive diagnostic tests
A conclusive diagnosis of FAP can be made only through genetic testing and tissue biopsy.
Genetic testing analyzes the sequence of the TTR gene to identify mutations that cause the disease. These mutations lead to a buildup of abnormal protein deposits, called amyloid fibrils, which damage the body’s tissues and organs.
The testing is usually performed on DNA extracted from blood samples drawn from a patient’s vein. There are more than 130 mutations in the TTR gene known to cause FAP, and different mutations have been associated with different symptoms and disease courses.
Since FAP is caused by mutations, genetic testing is essential for a conclusive diagnosis. However, to distinguish symptomatic patients from carriers — those who harbor a genetic mutation but have no symptoms of the disease — a tissue biopsy is needed to evaluate the presence of amyloid fibrils within body tissues.
Tissue biopsy is the “gold standard” test to detect amyloid fibrils. A small piece of an affected tissue or organ, such as a nerve or fat in the stomach area, is taken using a needle.
The sample is processed in the laboratory, usually with a dye called Congo red to stain and identify amyloid fibrils, and then examined under a microscope. If amyloid fibrils are present, then the sample has a characteristic “apple green” appearance, which changes to red as the plane of polarized light is rotated.
The presence of amyloid fibrils can be confirmed using specific antibody molecules (proteins) that are designed to bind, recognize, and distinguish different types of amyloid fibrils. Mass spectrometry can also be useful for differentiating types of amyloid fibrils.
Other diagnostic tests
Electromyography assesses the health of muscles and the nerves that control them. This test allows physicians to measure the electrical activity of patient muscle cells, by inserting a needle-like electrode into a specific muscle during a contraction. Electrical signals generated by muscle cells are recorded and then analyzed to assess muscle health.
Nerve conduction velocity test
The nerve conduction velocity test measures the strength and speed at which a nerve is able to transmit an electrical signal to other areas of the body. The 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, while the other records the nerve’s responses. Nerve conduction velocity is often decreased in FAP patients.
Tilt table test
This test monitors the response of blood pressure and heart rate to changes in posture and position. The patient lies flat on a table, and the upper part of the body is then tilted to the upright position. 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, a condition sometimes seen in those with FAP that occurs when the nerves that control involuntary bodily functions are damaged.
Thermoregulatory sweat test
This test measures the function of nerves controlling the body’s response to changes in temperature. It is usually done in a laboratory setting where temperatures can be carefully controlled. People with FAP may be less able to sense and respond to temperature changes.
These tests are used to check for abnormalities in digestion, such as slow digestion and delayed stomach emptying. Broadly, they involve having a person ingest a substance that can be detected at various points in the digestive tract. For example, some tests require patients to eat a light meal that contains a small amount of radioactive material. A scanner can then detect when the material leaves the stomach and determine whether digestion is taking place at a normal pace.
Quantitative sensory testing
Quantitative sensory testing comprises a battery of tests that are meant to evaluate a person’s ability to sense various stimuli normally, ranging from feeling vibrations and pressure, to sensing pain and heat.
Heart health assessments
Tests to evaluate heart health may include echocardiography to detect an enlargement of the heart caused by the buildup of amyloid deposits, as well as an electrocardiogram and Holter monitor to help detect abnormalities in the heart’s electrical activity. Magnetic resonance imaging can also be used to image the heart and detect abnormalities.
A blood test to measure the levels of NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) or troponin may be used to assess heart health since elevated levels can indicate heart injury.
In some cases, FAP can cause damage to the eyes. Thus, regular eye exams are recommended to monitor the course of FAP and help identify its presence.
Kidney health assessments
In some FAP patients, kidney health is also impaired. Impairments in kidney function can be assessed by measuring the levels of proteins and other substances in the urine, as well as through specific blood tests. Clinicians may use these tests to calculate the estimated glomerular filtration rate, which basically indicates how well kidneys are able to filter waste products from the bloodstream.
Bladder function tests
Autonomic neuropathy in FAP patients often results in improper bladder function. Bladder function tests, or urodynamics, may help evaluate the extent of bladder dysfunction in these cases. Doctors may suggest these tests to patients having certain symptoms, such as urine leakage, painful urination, sudden urges to urinate, or problems in completely emptying the bladder.
These tests include uroflowmetry to measure the speed and volume of urine, and cystometric tests to help determine the total amount of urine the bladder can hold, how full it is when patients have the urge to urinate, and the pressure inside the bladder.
Electromyography can be used to evaluate the electrical activity of muscles and nerves in and around the bladder. Bladder function can also be assessed using video urodynamic tests using X-rays or ultrasound to take pictures and record videos of the bladder while filling and emptying.
Last updated: Oct. 12, 2021
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