Nerve impairment and heart problems are the hallmarks of familial amyloid polyneuropathy (FAP). However, because FAP is a multisystem disorder, it leads to a variety of symptoms, with a wide range of age at onset.
FAP is caused by the buildup of protein deposits, called amyloid fibrils, which gradually accumulate in different organs and tissues, causing the array of symptoms. The amyloid fibrils are usually due to mutations in the TTR gene, which provides instructions to make a protein called transthyretin.
Neuropathy, or nerve impairment, and heart problems are the disease’s most common symptoms. Moreover, heart failure caused by the buildup of amyloid deposits in the heart is the primary cause of death in these patients.
The age of symptom onset varies widely among patients, though the disease’s effects usually start after age 30. In some individuals, symptoms begin as early as 20, or as late as 80. The underlying genetic cause of the disease may affect its onset, as well as its course.
In individuals with early onset FAP, who usually have a family history of the disorder, the disease manifests before age 50, and patients tend to experience a rapid progression of symptoms. Conversely, in people with late-onset FAP, the disease generally doesn’t start until after age 50. Late-onset FAP generally progresses more slowly and, while it often involves the heart, it tends to cause fewer symptoms related to autonomic impairment. Autonomic dysfunction, or failure, refers to impairment of the body’s control of its heart rate, blood pressure, temperature control, digestion, and other functions.
Peripheral neuropathy symptoms
Peripheral nerves are those found outside the brain and spinal cord and are responsible for controlling sensation and movement in the arms and legs. In FAP, amyloid deposits accumulate and damage these nerves, leading to a condition known as peripheral neuropathy.
Typical symptoms of peripheral neuropathy include loss of sensation (numbness) or extreme sensitivity to touch, tingling or a pins-and-needles sensation in the feet and hands, lack of coordination, impaired thermal sensibility (inability to sense shifts in temperature), and muscle weakness. Feeling a sharp pain without a clear cause, or feeling pain in response to non-painful stimuli also is common. Paralysis also may occur if motor nerves — those responsible for controlling movements — are affected.
Carpal tunnel syndrome, a condition in which the median nerve — that running from the base of the neck to the hand, which is responsible for providing sensation to all fingers, apart from the little finger — becomes compressed, causing numbness, pain, and tingling, is one of the most common and early signs of peripheral neuropathy in FAP patients.
According to a 2019 study, symptoms of carpal tunnel syndrome may precede a formal FAP diagnosis by a decade. Yet, as carpal tunnel syndrome is a relatively common condition — with up to 6% of people in the general population estimated to have it at some point in life — its presence alone is insufficient to help identify FAP at an early stage. Nevertheless, when accompanied by other symptoms, such as diarrhea, constipation, and erectile dysfunction, it may prompt physicians to suspect of FAP and order specific tests to confirm its diagnosis.
Amyloid deposits in the heart can cause stiffening and thickening of the heart muscle, impairing the heart’s ability to efficiently pump blood through the body.
Symptoms may include fatigue, shortness of breath, palpitations and abnormal heart rhythm (arrhythmia), swelling in the legs, angina (chest pain), lightheadedness, and dizziness. Over time, patients also may develop heart failure, a condition in which the heart is no longer able to adequately pump blood throughout the body.
Autonomic neuropathy symptoms
Autonomic nerves are those that control bodily functions that do not require conscious thought, like breathing and digestion. These nerves regulate the function of internal organs, such as the heart, stomach, and intestines.
Amyloid deposits that damage these nerves may cause constipation, diarrhea, nausea, vomiting, urinary retention (inability to urinate), dysuria or painful urination, and erectile dysfunction. Postural hypotension — a condition in which a sudden drop in blood pressure after standing causes one to feel dizzy — and sweating excessively or not being able to sweat also are common.
Other organs also can be damaged by amyloid fibrils, leading, for instance, to vision problems — such as blurred vision and dry eyes — seizures, kidney failure, and abnormally high amounts of proteins in the urine.
Symptoms by TTR mutation
More than 130 different mutations in the TTR gene have been reported in medical literature. Specific mutations have been associated with varying types and severities of symptoms.
In patients with a Val30Met mutation, the most common FAP-causing mutation, neuropathy symptoms usually appear from the ages of 30 to 50. Heart disease is less common among people with the Val30Met mutation than in those with other mutations.
The mutations Ser50Arg and Ala97Ser are typically associated with neuropathy symptoms. In contrast, patients with Val122lle or Leu111Met mutations typically experience heart problems, and have little peripheral nerve involvement.
Individuals with the Thr60Ala mutation, which is most common in people of Irish ancestry, usually develop both neuropathy and symptoms of heart disease.
Last updated: Nov. 19, 2021
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