Amyloidosis hereditaryE85.2

Group of autosomal-dominantly inherited, rare diseases with clinical and genetic heterogeneity characterized by deposits of insoluble protein and peptide aggregates that form aligned, amyloid fibrils 10 to 12 nm in diameter in a β-sheet structure. The nondegradable amyloids deposit in numerous organs and, with increasing mass, interfere with organ function. In systemic amyloidoses, the deposition occurs extracellularly. In terms of fine tissue, amyloid is characterized by:

• Blue staining after contact with and dilute sulfuric acid.
• Eosinophilia in conventional HE staining
• Green-yellowish to red staining and birefringence in polarized light after staining with Congo red
• Electron microscopy by a meshwork of unbranched fibrils and by a non-fibrillar component (serum amyloid P component) common to all types of systemic and localized amyloid
• Beta-fold sheet structure, detectable by X-ray diffraction
• Differently associated protein types (detectable by laser microdissection of amyloid deposits followed by mass spectrometry)

The classification is based on the mutated "amyloid" proteins and the clinical symptoms:

• Transthyretin amyloidosis (ATTRv/caused by mutations in the transthyretin gene on chromosome 18q12.1)
  • Familial amyloid polyneuropathy of the Portuguese type (caused by mutations in the transthyretin gene; clinical: polyneuropathy)
  • Familialcardiomyopathy (caused by mutations in the FAC gene; clinically progressive cardiomyopathy)
• Apolipoprotein A1amyloidosis (AApo A1/caused by mutations in the APOA1 gene; clinically: nephro-, polyneuro-, hepatopathy, rarely skin amyloidosis)
• Apolipoprotein A2 amyloidosis (AApo A2/caused by mutations in the APOA2 gene; clinically like AAPoA1)
• AGel amyloidosis (Gelsolin, causative mutations in GSN gene; clinical: corneal opacities, polyneuropathy, cutis laxa)
• AFib amyloidosis (fibrinogen alpha, caused by a mutation in the FGA gene (FGA stands for "fibrinogen alpha chain") which encodes the alpha chain of fibrinogen; clinical: nephropathy and petechiae)
• Alys amyloidosis (caused by mutations in the lysozymegene/LYZ gene); clinical: the nutated lysozyme causes nephropathy, sicca symptoms, petechiae)
• ABeta amyloidosis (also "hereditary cerebral hemorrhage with amyloidosis - Dutch type"; caused by mutations in the integral membrane protein 2B/ITM2B gene)
• ACys amyloidosis (also "hereditary cerebral hemorrhage with amyloidosis - Icelandic type"; caused by mutations in the cystatin gene/CST3 gene)
• ABRI/Dan amyloidosis (also "Hereditary cerebral hemorrhage with amyloidosis-British/Danish type; caused by mutations in the integral membrane protein 2Bgene (ITM2B gene, also known as BRI2)).

• Familial primary localized cutaneous amyloidosis (caused by pathogenic heterozygous missense mutations in the OSMR gene encoding oncostatin M receptor beta (OSMRbeta), a cytokine receptor of the interleukin (IL)-6 family).

Rare group of diseases occurring all over the world. Commonly found in Portugal, Japan, Sweden, Spain, Finland and France. Hereditary systemic amyloidosis affects 5% of the total systemic amyloidosis population.

The classification of all systemic and thus also hereditary aymloidoses is based on the biochemical structure of the amyloid fibrils. These are formed by polymerization of specific precursor proteins. So far, > 30 different such precursor proteins have been identified. Typical protein representatives are variants of:

• Transthyretin
• Apolipoprotein AI (ApoAI)
• apolipoprotein AII
• the Aα-chain of fibrinogen
• Gelsolin
• Lysozyme
• Cystatin C.

The clinical presentation of hereditary amyloidoses (as with acquired systemic amyloidoses) is variable and depends on the particular precursor protein, its mutations, and the localization of the amyloid deposits. Depending on histoanatomic distribution and amount, amyloid can cause progressive and life-threatening organ dysfunction, affecting different organs depending on the amyloid variant.

For example, in the most common hereditary amyloidosis, TTR amyloidosis, the following symptoms are prominent: polyneuropathy, carpal tunnel syndrome, impotence, diarrhea, constipation, cardiomyopathy, and vitreous opacities. In other mutatiton types are found: nephropathies (Afib), cardiomyopathies (FAC), petechiae, polyneuropathies (AGel), corneal opacities (AGel) and cerebral hemorrhages (Acys, Abeta).

Orthotopic liver transplantation.

Experimental: drug stabilization of the TTR tetramer.

1. Adams D et al (2000) The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain 123: 1495-1504
2. Almeida MR et al (2000) Screening and biochemical characterization of transthyretin variants in the Portuguese population. Hum Mutat 9: 226-233
3. Buxbaum J (2006) The genetics of the amyloidoses: interactions with immunity and inflammation. Genes and Immunity 7: 439-449
4. Hund E et al (2001) Transthyretinassociated neuropathic amyloidosis. Neurology 56: 431-435