Hereditary amyloidosis is characterized by the extracellular accumulation of protein fibrils having β-pleated sheet structure. Actually, hereditary amyloidosis is only one of a number of forms of amyloidosis, each characterized by the protein that is the basic subunit of the amyloid fibril. Systemic hereditary amyloidosis (involving multiple organ systems) may be associated with variant forms of transthyretin, apolipoprotein A-I, gelsolin, cystatin C, fibrinogen, or lysozyme. Other forms of systemic amyloidosis, which are not hereditary, include immunoglobulin (amyloidosis of light chain (AL), primary) amyloidosis, in which the subunit protein is the variable portion of monoclonal immunoglobulin light chain; reactive (secondary) amyloidosis, in which the subunit protein is a degradation product—amyloid A (AA)—of a serum acute-phase protein—serum amyloid A (SAA); and β2-microglobulin (dialysis-associated) amyloidosis, in which the subunit protein is β2-microglobulin. All forms of amyloidosis cause illness and death by physical encroachment of the deposits on normal organ structures. In autosomal dominant hereditary amyloidosis, peripheral neuropathy is the most common finding, although infiltration of vital organs, such as heart, kidney, and bowel, give various syndromes, which usually lead to death.
Hereditary amyloidosis is a late-onset disease with clinical symptoms beginning in most kindreds within the third to seventh decades of life. The clinical disease usually progresses over 5 to 15 years and ends with death from cardiac failure, renal failure, or malnutrition. In some kindreds, heterozygotes with late-onset disease, however, have lived past age 90. Gene prevalence is not known, because there are a number of mutations in the genes for various plasma proteins, and many of the kindreds were characterized only recently. In the United States, the prevalence of variant transthyretin genes associated with amyloidosis varies with ethnic origin. In Caucasians, the prevalence is relatively low (perhaps 1 in 100,000). In Americans of African descent, as many as 1 in 25 may have one specific transthyretin variant (Val122Ile) that causes late-onset cardiomyopathy.
The primary defect in autosomal dominant transthyretin amyloidosis results from one of a number of mutations in the gene for transthyretin, which is a single-copy sequence on chromosome 18. To date, 73 single amino acid substitutions in the transthyretin molecule that could be associated with hereditary amyloidosis have been found. In addition, six mutations have been described in apolipoprotein A-I, two in gelsolin, four in fibrinogen A α-chain, two in lysozyme, and one in cystatin C, all of which are associated with systemic amyloidosis.
Direct DNA tests have been developed for many of the variant genes for transthyretin, apolipoprotein A-I, gelsolin, fibrinogen, lysozyme, and cystatin C. In addition, modern molecular biology techniques can provide easy detection methods for all of the demonstrated mutations. In many cases, restriction enzyme analysis of PCR amplification products has replaced Southern blot analysis. Direct DNA sequencing based on PCR technology is used in the discovery of new mutations. DNA tests have been established for certain protein variants, and these are used for genetic counseling.
Prenatal diagnosis has been developed for at least two forms of transthyretin amyloidosis based on PCR technology.
Autosomal dominant forms of amyloidosis that are localized to one organ system include familial Alzheimer disease, hereditary cerebral hemorrhage with amyloidosis-Dutch type (β-amyloid precursor protein [β-APP]), Gerstmann-Sträussler-Scheinker syndrome, Creutzfeldt-Jakob disease (prion), medullary carcinoma of the thyroid (procalcitonin), and various types of lattice corneal dystrophy (keratoepithelin).