Last updated on: 11.08.2023

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Rare, hereditary amyloidosis with primary renal involvement characterized by interstitial and medullary amyloid deposition in the kidney, low plasma levels of apoA-1, and slow disease progression. Currently, more than 50 apoAI variants are known, 16 of which are associated with amyloidosis.

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Amyloidoses are a large group of heterogeneous diseases characterized by insoluble protein and peptide aggregates aligned in a β-sheet structure forming amyloid fibrils 10 to 12 nm in diameter. More than 30 different proteins that form amyloids have now been identified. Depending on histoanatomical distribution and quantity, amyloid can cause progressive and life-threatening organ dysfunction. Variants of transthyretin, apolipoprotein AI (apoAI), apolipoprotein AII, the Aα-chain of fibrinogen, gelsolin, and lysozyme are some of the proteins known to cause hereditary amyloidosis.

Basically, amyloid may be acquired or hereditary. Amyloid can be deposited locally or can be deposited in many different organs as a systemic disease. Because of the diversity of precursor proteins, between which there is no sequence homology, it has been impossible to find a common primary structural or functional motif that predicts the amyloidogenicity of a peptide or protein. In this regard, the hereditary amyloidoses are particularly interesting because they are caused by germline mutations that increase the propensity of the affected protein to form aggregates under certain circumstances. Important pathophysiological conclusions can be drawn from the genetic defect and the encoded "defective" protein.

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Hereditary AAPoA1 amyloidosis is caused by mutations in the APOA1 gene, a protein-coding gene located on chromosome 11q23.3. Mature ApoAI consists of 243 amino acids encoded by exons 3 and 4 of the APOA1 gene. ApoA1 protein is a plasma protein of 28 kDa synthesized by the liver and small intestine. It is the major protein of high-density lipoprotein particles and important for the formation and metabolism of high-density lipoprotein cholesterol esters. More than 50 ApoA1 variants have been described. Half of them are associated with decreased plasma levels of high-density lipoprotein apoA1. These ApoA1 variants either affect lecithin:cholesterol acyltransferase activity or promote amyloid formation. To date, 13 mutations are known to be associated with hereditary AApoA1 amyloidosis.

Clinical features
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AApo A-1 amyloidosis is the second most common cause of "hereditary" amyloidosis after ATTRv amyloidosis (transthyretin amyloidosis) and may also be associated with low high-density lipoprotein levels. The clinical manifestations of hereditary AApoAI amyloidosis often involve the liver, kidney, larynx, skin, and myocardium. The main clinical signs and symptoms are hypertension, proteinuria, hematuria, and edema due to chronic renal insufficiency leading to end-stage renal disease. Furthermore, hepatosplenomegaly, progressive cardiomyopathy, and involvement of the skin, testes, and adrenal glands (hypergonadotropic hypogonadism) have been reported.

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Amyloid shows a characteristic apple-green birefringence when viewed under polarized light after Congo red staining. The Abalgerungen are immunoreactive with antibodies against the ApoA1 amyloid.

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Apolipoprotein AI amyloidosis may also occur as a nonhereditary form with wild-type protein deposition in atherosclerotic plaques.

The organ distribution and clinical presentation of AApoAI amyloidosis appear to depend on the position of the mutation. Patients with alterations in codons 1 to 75 mostly develop hepatic and renal amyloidosis, whereas carriers of mutations in residues 173 to 178 mainly suffer from cardiac, laryngeal, and cutaneous amyloidosis.

ApoA1 mutations associated with AApoAI amyloidosis:

  • p.Gly26Arg: renal failure, gastrointestinal amyloid, peripheral neuropathy.
  • p.Trp50Arg: Renal failure
  • p.Leu60Arg: Renal failure
  • p.Leu64Pro: Renal failure
  • p.Leu60_Phe71delinsValThr: Liver failure
  • p.Glu70_Trp72del: Renal insufficiency
  • p.Asn74fs: Gastrointestinal amyloid, renal failure, amyloid detected in uterus, ovaries, pelvic lymph nodes
  • p.Leu75Pro:renal failure, hepatic amyloid, gastrointestinal amyloid 14, 15 Current report
  • p.Leu90Pro:cardiomyopathy, cutaneous amyloid 16
  • p.Lys107del: Intimal amyloid of the aorta 17
  • p.Ala154fs: Renal amyloid Current report
  • p.Leu170Pro: Amyloid in larynx Current report
  • p.Arg173Pro:Cardiomyopathy, cutaneous and laryngeal amyloid

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Amyloidosis hereditary; APOA2 gene;


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Last updated on: 11.08.2023