Familial amyloid polyneuropathy (FAP) is a rare genetic condition caused by mutations in the TTR gene, leading to the buildup of abnormal protein deposits that can result in organ and tissue damage over time.
What is the TTR gene?
The TTR gene provides the instructions necessary for the production of a protein called transthyretin, sometimes referred to as ATTR. 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, or bound, to each other to form a tetramer — a four-unit protein complex.
What happens when the TTR gene is mutated?
Disease-causing mutations in the TTR gene result in the production of transthyretin proteins with an abnormal structure that impairs their ability to bind to each other and form a tetramer. Instead, the defective proteins form abnormal clumps, called amyloid fibrils, that build up in different tissues, particularly those of the nerves and heart. The buildup of amyloid fibrils can cause tissue and organ damage, ultimately leading to the typical symptoms of the disease.
Any condition caused by mutations in TTR and the subsequent accumulation of amyloid fibrils is referred to as hereditary transthyretin amyloidosis, commonly abbreviated as either hATTR or ATTRv. FAP is a specific type of hATTR that is mainly characterized by polyneuropathy, or nerve damage, resulting in limb numbness, tingling, and weakness.
Sometimes, transthyretin amyloid fibrils can develop in people who have no mutation in the TTR gene, in which case the condition is called wild-type transthyretin amyloidosis.
What kind of mutations are there?
More than 130 different mutations in the TTR gene have been identified, and most are pathogenic (disease-causing). Different mutations are associated with different patterns of organ involvement, age of onset, and disease progression.
The most common pathogenic mutation in TTR is called Val30Met. Like all proteins, transthyretin is made up of a chain of building blocks called amino acids, which give the protein its specific structure. The Val30Met mutation causes one of these amino acids, called valine (Val), to be replaced by another amino acid called methionine (Met), at position 30 of the protein sequence — hence the name Val30Met. Other mutations follow the same naming pattern.
The Val30Met mutation is particularly common in people living 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 (damage to the nervous system) are the most common symptoms, while heart problems are comparatively rare.
Another common TTR mutation is Thr60Ala. This mutation is typically seen in people of Irish ancestry. In patients with this mutation, symptoms tend to start relatively late in life (most often after age 60). The heart is almost always affected, and neuropathy is seen in about two-thirds of the cases.
Other mutations are also more common in certain regions. These include Glu89Gln in Bulgaria, Ser50Arg in Mexico, Phe64Leu in Sicily, and Ala97Ser in Taiwan. The Ser77Tyr and Ser77Phe mutations are common in France.
These different mutations each tend to be associated with altered courses of disease. For instance, people with the Ser77Tyr mutation tend to have more rapid and severe disease progression than those with the Val30Met mutation.
How is FAP inherited?
Every person inherits two copies of the TTR gene, one from each biological parent. Pathogenic TTR gene mutations are inherited in an autosomal dominant manner, meaning that getting a mutated copy of the 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 tetramers, even if normal proteins are still being produced by the other non-mutated gene copy.
Since FAP symptoms often appear later in life, a person carrying a TTR gene mutation may not immediately know they have the disease. In fact, some people with these mutations may never show any symptoms of FAP, but can still pass the defective gene to their biological children. A person with an autosomal dominant condition has a 50% chance of passing the disease-causing mutation to their biological children.
Last Updated: June 3, 2021
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