Familial amyloid polyneuropathy (FAP) is the name given to a class of rare genetic diseases characterized by the accumulation of abnormal protein deposits called amyloid fibrils in the peripheral nervous system and other tissues. This results in severe nerve damage, which can be life-threatening. It is difficult to diagnose FAP just by looking at symptoms, so late diagnosis is common.
Genetics of FAP
FAP is caused by mutations in the TTR gene, which encodes for the transthyretin protein. There are more than 100 other mutations that have been identified within the TTR gene. One of the most common mutations leads to a so-called Val30Met variant of the TTR protein, where the amino acid valine is substituted with the amino acid methionine at position 30. (Amino acids are building blocks of proteins). The Val30Met variant affects mostly Portuguese, Japanese, and Swedish populations.
How can genetic testing help early diagnosis?
Properly targeted genetic testing offers opportunities for early and reliable diagnosis of FAP, especially since the penetrance (percentage of people carrying a dysfunctional protein in a given population) and age of disease onset vary dramatically around the world, even for the same mutation. Early diagnosis by genetic testing can significantly improve life expectancy by helping clinicians to initiate treatment early or recommend clinical trials for a patient to join.
Guidelines and timing for FAP genetic testing
In FAP patients, genetic testing is recommended at two stages of the disease: presymptomatic testing (PST) based on family history, and as a follow-up for symptomatic diagnosis.
Specific guidelines are beginning to emerge that can help clinicians to diagnose FAP. Two roundtable European expert meetings titled “Optimising the Management of TTR-FAP in Europe” were conducted in November 2012 and March 2014, which attempted to draw out guidelines for FAP genetic testing. These guidelines were based on many parameters such as patient demographics (age, sex, ethnic origin), results of clinical examinations, sensitivity in the feet and legs, quantitative sensory testing, sympathetic skin response, biopsy evidence of amyloid, and results from heart and kidney function tests.
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