Amyloidosis, Transthyretin-Associated Familial, DNA Sequence, Blood
Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The systemic amyloidoses are a number of disorders of varying etiology characterized by extracellular protein deposition. The most common form is an acquired amyloidosis secondary to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) in which the amyloid is composed of immunoglobulin light chains. In addition to light chain amyloidosis, there are a number of acquired amyloidoses caused by the misfolding and precipitation of a wide variety of proteins. There are also hereditary forms of amyloidosis. Due to the clinical overlap between the acquired and hereditary forms, it is imperative to determine the specific type of amyloidosis in order to provide an accurate prognosis and consider appropriate therapeutic interventions.
The most common hereditary amyloidosis is familial transthyretin amyloidosis; an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene. The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic TTR protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Typically, TTR-associated amyloidosis is progressive over a course of 5 to 15 years and the most common cause of death is cardiomyopathy. Affected individuals may present with a variety of symptoms, including peripheral neuropathy, blindness, cardiomyopathy, nephropathy, autonomic nervous dysfunction, or bowel dysfunction.
More than 90 mutations have now been identified within the TTR gene which cause TTR-associated familial amyloidosis. Most of the mutations described to date are single base pair changes that result in an amino acid substitution. Some of these mutations correlate with the clinical presentation of amyloidosis. However, several different mutations have been identified which exhibit considerable clinical overlap.
It is important to note that this assay does not detect mutations associated with non-TTR forms of familial amyloidosis. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific mutation in the family before testing at risk individuals.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of transthyretin (TTR)-associated amyloidosis may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of TTR-associated amyloidosis. For carrier testing, it is important to first document the presence of a TTR gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Mutations in other genes, such as lysozyme, apolipoprotein AII, gelsolin, and others, have been shown to cause other forms of familial amyloidosis. Abnormalities in these genes are not detected by this assay.
DNA sequence analysis was performed on 196 specimens (17 patients with a known transthyretin mutation, 48 patients tested by mass spectrometry, 91 patients with amyloidosis, and 40 normal individuals).
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Benson MD: The hereditary amyloidoses. Best Pract Res Clin Rhematol 2003;17:909-927
2. Eneqvist T, Sauer-Eriksson AE: Structural distribution of mutations associated with familial amyloidotic polyneuropathy in human transthyretin. Amyloid 2001;8:149-168
3. Connors LH, Lim A, Prokaeva VA, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160-184