Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Amyloidosis, familial type [E85.1] [E85.2]

OMIM numbers: 105210, 176300 (TTR)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Wolfgang Rupprecht,
Prof. Dr. Reinhold P. Linke

Scientific Background

Amyloidosis is a heterogenous group of diseases that are characterized by the deposition of misfolded proteins in the extracellular matrix as insoluble amyloid fibrils. The constant deposition leads to a progressive loss of function of different organs and premature death. Generalized amyloidosis is almost always fatal. The particular protein that is deposited as amyloid determines the amyloid class — currently there are more than 25 classes described. Even within a class there are different types, making the amyloidosis a group of complex diseases. There are local, organ-limited and generalized types, each requiring an individual therapy due to their different pathogenesis. Therefore, precise diagnostics is esssential prior to a specific therapy.

Besides the acquired types of amyloidosis (e.g. as result of a malignoma or a chronic inflammatory disease) there are inherited types with mostly autosomal dominant inheritance. Two common conditions associated with localized amyloidosis are Alzheimer's disease and type 2 diabetes. Among the generalized types the most frequent are amyloidosis related to monoclonal gammopathies (ALλ, ALκ, AHγ) and transthyretin-related amyloidosis (ATTR). ATTR amyloidosis is divided into senile systemic amyloidosis (SSA), especially characterized by cardiac symptoms, and hereditary ATTR amyloidosis which generally shows an earlier onset and is associated with familial amyloid polyneuropathy with progressive sensorimotor and autonomic neuropathy, cardiomyopathy, cardiac arrhythmias, diarrhea and malabsorption. The causes of AA amyloidosis are chronic inflammations and amyloid is mainly found in the parenchymal organs like spleen, kidney, liver and intestines. 

Diagnostic procedure is conducted in three steps:

  • Detection of amyloid in a tissue sample by Congo red staining. Tissue is acquired by excision, or more frequently by biopsy of organs (e.g. heart, kidney, intestines, rectum, skin or liver) or by aspiration of subcutaneous fat tissue. If the presence of amyloid is identified via green birefringence in polarized light the second step follows.
  • Immunohistochemical classification of amyloidosis by special antibodies. Please contact amYmed for services and products.
  • Molecular genetic analysis of the identified protein

Transthyretin amyloidosis (ATTR) is the most common hereditary type of amyloidosis. It is caused by mutations in the TTR gene and follows autosomal dominant inheritance. The most common mutation is the point mutation V30M (Portuguese-/Japanese-type). The TTR gene encodes the serum protein transthyretin (prealbumin). So far more than 80 mutations have been identified which can cause amyloidosis. As the liver is the main production site of transthyretin a liver transplantation has been the only effective therapy of ATTR so far. Diagnosis and indication for a transplantation have to be made as early as possible since remission of manifested symptoms can be expected to a limited extent only. In 2011, a pharmaceutical (Vyndaqel®) for the treatment of transthyretin-related familial amyloid polyneuropathy was approved by the European Medicines Agency (EMA).