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Key Points

  • Disease summary:

    • The hereditary systemic amyloidoses are a group of diseases caused by mutations in several structural proteins. The most common is transthyretin (TTR) amyloidosis, which is characterized mainly by peripheral neuropathy but also associated, in many cases, with restrictive cardiomyopathy. Systemic amyloidoses associated with mutations in fibrinogen Aα-chain, lysozyme, apolipoprotein A-I, and apolipoprotein A-II, are mainly associated with renal amyloidosis but may also affect other organ systems. As with all types of amyloidosis, organ dysfunction is caused by deposition of protein fibrils (∼10 nm in diameter) which, as they accumulate, displace normal tissue structures. As amyloid deposition progresses organ failure ensues often leading to death within a 10- to 15-year period. Since clinical diagnosis is often delayed until the disease is relatively advanced, death within 5 to 10 years after tissue diagnosis is not uncommon.

  • Differential diagnosis:

    • Some of the hereditary amyloidoses have overlapping clinical phenotypes while others have unique phenotypes which, when recognized, simplifies diagnosis. For those forms of hereditary amyloidosis with overlapping features it is very important to differentiate these from AL (Ig light-chain) and AA (reactive, secondary) amyloidosis. AL amyloidosis is most commonly associated with either nephrotic syndrome or cardiomyopathy. Both of these phenotypes are common with some forms of hereditary amyloidosis. AA amyloidosis, most commonly presents as nephrotic syndrome with progressive renal failure, a feature that is common to several hereditary amyloidoses.

  • Monogenic forms:

    • Each of seven types of hereditary amyloidosis arises from single gene mutations. The most common is transthyretin (TTR) amyloidosis, which is caused by mutations in the TTR gene (Table 92-1). Mutations in apolipoprotein A-I (APOA1), fibrinogen Aα-chain (FGA), lysozyme (LYZ), apolipoprotein A-II (APOA2), gelsolin (GSN), and cystatin C (CST3) genes also may cause systemic amyloidosis (Table 92-2). All forms of hereditary amyloidosis are inherited as autosomal dominant traits but the degree of penetrance in any one disease is variable.

  • Family history:

    • Since all of the hereditary amyloidoses are autosomal dominant, family history can be a very important factor in making a correct diagnosis. However, many patients, especially with TTR amyloidosis, present as sporadic cases without an informative family history. Often this is due to the fact that the disease is relatively late onset in any one particular family. A family history of a relative with blindness due to vitreous opacities is very suggestive of TTR amyloidosis.

  • Twin studies:

    • None

  • Environmental factors:

    • No definite environmental factors have been shown to be at play in hereditary amyloidosis. There is considerable variation within kindreds and geographic areas but these differences most likely are due to genetic background rather than environmental factors.

  • Genome-wide associations:

    • None

  • Pharmacogenomics:

    • None

Table 92-1Transthyretin Amyloidosis

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