Familial amyloid polyneuropathy (FAP), also called transthyretin familial amyloid polyneuropathy (TTR-FAP), is a group of disorders that is caused by mutations in the TTR gene. These mutations result in TTR protein aggregates or amyloids being deposited in various tissues, particularly the nerves and the heart, resulting in their damage.

Causes of FAP

The TTR protein is secreted by the liver and helps transport vitamin A and thyroxine to various tissues. For TTR to carry out its function, four such proteins must bind to each other and form a so-called tetramer.

Mutations in the TTR gene, of which more than 100 have been identified, impair the ability of the TTR protein to form tetramers and hence affect its function. These defective proteins often clump together and form aggregates or amyloids, which tend to accumulate in tissues such as the nerves and heart.

While mutations in the TTR gene are the most common cause of FAP, there are mutations in others such as the APOA1 (apolipoprotein A-1) and GSN (gelsolin) genes, which are associated with amyloid deposits.

Inheritance of FAP

FAP is inherited in an autosomal dominant manner. This means that one copy of the defective TTR gene is enough for the symptoms of the disease to appear. FAP is usually inherited from a parent or can occur by chance.

Each child has a 50 percent chance of being affected by FAP if either of the parents has mutations in the TTR gene and therefore has the disease. However, the severity of the symptoms depends largely on the type of mutation. FAP symptoms often develop later in life, and some people do not show any symptoms, despite carrying the defective gene.

Penetrance of TTR gene mutations

The penetrance of a mutation denotes the number of individuals who exhibit the traits associated with that mutation. In other words, a mutation that has a high penetrance is seen in a higher number of individuals than one that has low penetrance.

The most common TTR gene mutation implicated in FAP is the so-called Val30Met mutation where one of the amino acids, valine, is substituted with another amino acid, methionine, at position 30 in the protein. Amino acids are the building blocks of proteins, and mutations can result in impaired protein function.

Val30Met is the most prevalent TTR mutation, and has been documented well in Portugal, Japan, Brazil, France, and Sweden. However, differences exist between countries with respect to the penetrance of this mutation and, consequently, the age of onset and severity of symptoms. Increased age also presents a greater risk for the onset of FAP symptoms.

Penetrance of the mutations also varies depending on the gender of the person transmitting the defective TTR gene. In Swedish, Japanese, and Portuguese families, disease symptoms appear to start at a later age if the TTR mutation is inherited from the father, whereas there is a risk of early onset of symptoms if the mutation is inherited from the mother. The exact reasons for this are still being investigated.

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