Familial amyloid polyneuropathy (FAP) is a rare genetic condition caused by defects (mutations) in the TTR gene, possibly resulting in organ damage over time.

What is the TTR gene?

The TTR gene provides the instructions necessary for the production of a protein called transthyretin. This protein is mainly produced in the liver and transports vitamin A and a hormone called thyroxine throughout the body. To function correctly, four transthyretin proteins must be attached (bound) to each other, and form a so-called tetramer or four-unit complex.

What happens when the TTR gene is mutated?

Mutations in the TTR gene are thought to change the structure of the transthyretin proteins, impairing their ability to bind to each other and form a tetramer. Instead, the defective proteins gather forming amyloid fibrils that build up in tissues, particularly those of the nerves and heart, to cause symptoms of the disease.

What kind of mutations are there?

More than 100 different TTR gene mutations associated with FAP have been identified so far. Different mutations are associated with different patterns of organ involvement, age of onset, and disease progression.

The most common variant is the so-called TTR Val30Met variant. This genetic mutation causes one of the amino acids or building blocks of a protein, namely valine, to be substituted with another amino acid, methionine, at position 30 (hence the name Val30Met). This mutation is especially common among people in certain areas of Portugal, as well as in Japan and Sweden. Most patients who have this type of mutation first experience disease symptoms in their 30s. Peripheral and autonomic neuropathy are the main symptoms, and heart problems are rare.

Another TTR variant is called Thr60Ala, because the mutation causes the amino acid threonine to be replaced by the amino acid alanine at position 60, and is typically seen in people of Irish ancestry. In patients with this mutation, symptoms tend to start relatively late in life, between ages 45 and 78, and most often after age 60. The heart is almost always affected, and neuropathy is seen in about two-thirds of cases. Autonomic neuropathy symptoms such as diarrhea and/or constipation are more common than peripheral neuropathy.

Less common mutations in the apolipoprotein A-1 (APOA1) or gelsolin (GSN) genes are also associated with amyloid deposits and FAP.

How is FAP inherited?

TTR gene mutations are inherited in an autosomal dominant manner, meaning that getting one copy of the defective gene from either parent is sufficient for the disease to develop. This is because defective proteins produced by the mutated gene interfere with the correct formation of protein binding (tetramers) even if normal proteins being produced by the other, healthy gene.

Since FAP symptoms often appear later in life, a person carrying a TTR gene mutation may not know they have the disease. In fact, some people with FAP never show any symptoms but can pass the defective gene onto their children. A person with an autosomal dominant condition has a 50 percent chance of passing the disease-causing mutation to a child.

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