Familial amyloid polyneuropathy (FAP) is a multisystem disorder caused by deposits of amyloid fibrils in the nerves and organs, commonly due to mutations in the TTR gene.

Because amyloid fibrils gradually accumulate in different organs and tissues FAP can lead to many different symptoms, with heart enlargement and irregular heartbeats being the most serious and the primary cause of death.

Peripheral neuropathy symptoms

Peripheral nerves control sensation and movement in the arms and legs. IN FAP, abnormal deposits of amyloids occur mainly in peripheral nerves, causing their deterioration. Peripheral neuropathy symptoms include:

  • Loss of sensation (numbness)
  • Limb weakness and pain
  • Tingling
  • Pins-and-needles in the feet and hands
  • Impaired thermal sensibility in the feet

Autonomic neuropathy symptoms

Autonomic nerves control the function of internal organs such as the heart, stomach, and intestines. Amyloid deposits may occur in these nerves, leading to one or more of the following symptoms:

  • Postural hypotension when blood pressure drops upon standing, leading to dizziness or fainting
  • Disturbed bowel function, nausea, and vomiting
  • Urinary retention
  • Sexual dysfunction
  • Reduced sweating
  • Weight loss

Cardiac symptoms

Amyloid deposits in the heart can cause stiffening and thickening of the heart muscle, so the heart cannot pump the blood through the body as efficiently. Symptoms include:

  • Shortness of breath after mild exertion, or even when lying flat
  • Palpitations and abnormal heart rhythms, most frequently atrial fibrillation
  • Fatigue
  • Fainting, which may occur after exertion, or after eating
  • Angina (chest pain).

The disease usually worsens over five to 15 years and can end with death from heart failure.

Other symptoms depend on the body region where protein accumulation occurs. and can include blurred vision, blindness, protein loss via the urine, kidney failure, and goiter (swelling of the thyroid).

Symptoms by TTR mutation

More than 100 different defects (mutations) in the TTR gene have been reported in medical literature, and the severity of symptoms varies depending on the type of mutation.

In patients with a Val30Met mutation (the most common FAP-causing mutation), neuropathy symptoms usually appear between ages 30 and 50 years.

Heart disease is less common among people with the Val30Met mutation than with other mutations. In contrast, patients with the Val122lle mutation typically present with cardiac disease only and have little involvement of the peripheral nerves.

The Thr60Ala mutation is most common in people of Irish ancestry, who usually develop both neuropathy and heart disease.

Age of onset of the symptoms

The age of onset of the first FAP symptoms varies widely among affected individual. Although they usually occur after age 30, they may sometimes arise as early as age 20, or as late as age 80. The underlying genetic cause of the disease may affect the age of onset of the symptoms, as well as disease course.

In patients with early-onset FAP, usually with a positive family history, the disease occurs before age 50 and progresses quickly because of autonomic dysfunction and rapid progression of the peripheral deficit. Conversely, in many patients with late-onset FAP, the disease occurs after age 50 and progresses slowly, often with cardiac involvement, but with less autonomic dysfunction.

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