Clinical Information

The amyloidoses are a group of diseases that result from the abnormal deposition of amyloid in various tissues of the body. They have been classified into 3 major types: primary, secondary, and hereditary. The most common form of amyloidosis (AL) is a disease of the bone marrow called primary systemic AL (immunoglobulin light chain). Secondary AL usually occurs in tandem with chronic infectious or inflammatory diseases, such as rheumatoid arthritis, tuberculosis, or osteomyelitis. Familial or hereditary AL is the least common form. Determining the specific type of AL is imperative in order to provide both an accurate prognosis and appropriate therapies.

Familial or hereditary transthyretin AL is an autosomal dominant disorder caused by variants in the transthyretin gene (TTR). The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic transthyretin (TTR) protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Affected individuals may present with a variety of symptoms including sensorimotor and autonomic neuropathy, vitreous opacities, cardiomyopathy, nephropathy, and gastrointestinal dysfunction. TTR-associated AL is progressive over a course of 5 to 15 years and usually ends in death from cardiac or kidney failure or malnutrition. Orthotopic liver transplantation is a treatment option for some patients who are diagnosed in early stages of the disease. Other treatment options include the use of TTR tetramer stabilizer medications and gene-silencing therapies (RNA interference/RNAi) approved for use in several countries including the United States.

Mayo Clinic Laboratories recommends a testing strategy that includes both protein analysis by mass spectrometry (MS) and TTR gene analysis by DNA sequencing for patients in whom TTR-associated familial AL is suspected. The structure of TTR protein in plasma is first determined by MS. The presence of a disease-causing variant in the TTR gene leads to conformational changes in the TTR protein. This ultimately disrupts the stability of the mature TTR protein tetramer, leading to increased amounts of pro-amyloidogenic TTR monomers in the plasma of affected individuals. MS technology can identify the mass difference between wildtype TTR and variant TTR protein. Only the transthyretin (also known as prealbumin) is analyzed for amino acid substitutions. Other proteins involved in other less common forms of familial amyloidosis are not examined. If no alterations are detected, gene analysis will not be performed unless requested by the provider (ie, when the diagnosis is still strongly suspected; to rule out the possibility of a false-negative by MS). In all cases demonstrating a structural change by MS, DNA sequence analysis will be performed on the TTR gene to identify and characterize the observed alteration (disease-causing or benign variant). More than 90 variants that cause TTR-associated familial AL have now been identified within the TTR gene. Most of the variants described to date are single base pair changes that result in an amino acid substitution. Some of these variants correlate with the clinical presentation of AL.

For predictive testing in cases where a familial variant is known, testing for the specific variant by DNA sequence analysis (FMTT / Familial Variant, Targeted Testing, Varies) is recommended. These assays do not detect alterations associated with non-TTR forms of familial AL. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific alteration in the family before testing at-risk individuals.