Familial amyloid polyneuropathy

Abstract

Familial amyloid polyneuropathy (FAP; also known as familiar amyloidosis and hereditary amyloidosis) is an autosomal dominant inherited disease due to mutations of the transthyretin (TTR) gene coding for the corresponding protein, consisting of 127 amino acids. The gene is located on chromosome 18q. More than 100 different mutations are known. Other mutant precursor proteins produced in the liver, such as apolipoprotein I and II, lysozyme and fibrinogen Aα, may be of etiological importance as well. Amyloidogenic mutations of the TTR gene lead to decreased stability of the corresponding protein and subsequently to extracellular deposition of amyloid in several tissues (peripheral and autonomic nerves, walls of the gastrointestinal tract, heart, etc.). The Val30Met mutation is the most prevalent cause of FAP worldwide. There are endemic regions in Portugal, Sweden and Japan. The onset of symptoms is usually between 25 and 35 years of age, but late-onset families are also known. The most common clinical symptoms are polyneuropathy of the lower limbs, rhythmological disturbances and diarrhea/obstipation. TTR amyloid is predominantly produced in the liver; only as few as 5% are synthesized in the retina and choroid plexus. Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms. Because of shortage of donor grafts, livers of FAP patients are used for domino liver transplantation. Last year, a new therapeutic option was approved by the European Medical Authority (EMA) for therapy of early-stage FAP. The first results of a multicenter-controlled trial have been published and show a benefit in patients with an early stage of disease regarding neurological symptoms as well as modified BMI. There are several other pharmacologic approaches that have been reported in the last years which may lead to stabilization of the TTR tetramer. Therefore, this might be the beginning of new therapeutic options with pharmacological therapies in patients with FAP.