Diagnosis of adult individuals suspected of having TTR-associated

familial amyloidosis

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

MGUS (monoclonal gammopathy of unknown significance) 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.

An interpretive report will be provided.

The identification of a TTR mutation is consistent with the diagnosis of

familial transthyretin amyloidosis.

A small percentage of individuals who are carriers or have a diagnosis of

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.

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