Amyloidosis, hereditary, transthyretin-related

Diagnosis and Testing

How do I get tested for hATTR amyloidosis?

Testing for hereditary transthyretin amyloidosis can happen through an examination with a doctor that would check for certain symptoms. Problems with the nerves outside of the central nervous system (peripheral neuropathy), pain that results from damage or injury to the nerves (neuropathic pain) and heart disease are common symptoms. Carpal tunnel syndrome, clouding of the gel-like substance of the eye (vitreous), and gastrointestinal issues like diarrhea or constipation are also possible signs. If a person has several of these symptoms, a doctor may order tests to check for hereditary transthyretin amyloidosis. If some of symptoms run in a family, a doctor is more likely to offer tests.

Tests that may be run include testing a tissue (biopsy) sample for the buildup of amyloid. The tissue sample is stained with a dye called Congo red, which allows doctors to see amyloid deposits under a special microscope. Doctors may also test a tissue sample for antibodies against transthyretin. To confirm a diagnosis, genetic testing may also be offered. These tests involve studying the TTR gene for changes (mutations).

If you believe that you or someone in your family has hATTR amyloidosis, you can request or seek out a referral to a genetics clinic that may be more familiar with these disorders. The Genetics and Rare Diseases Information Center provides information on how to find healthcare professionals with experience in specific conditions, specialty treatment centers, genetics clinics, and researchers who are studying a specific condition.

If you think that someone in your family has hATTR amyloidosis, you should also talk to a genetic counselor to learn more. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor."]http://www.nsgc.org/findageneticcounselor"]http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: www.alnylam.com/patients/alnylam-act.

References
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More Diagnosis and Testing Content

What tests support a diagnosis of hereditary transthyretin amyloidosis?

Who else in my family should I test for hereditary transthyretin amyloidosis?

Can hereditary transthyretin amyloidosis be found before birth?

What tests support a diagnosis of hereditary transthyretin amyloidosis with heart involvement?

Does everyone who has a mutation in the gene for hereditary transthyretin amyloidosis get the disease?

What tests support a diagnosis of hereditary transthyretin amyloidosis?

A doctor may suspect someone has hereditary transthyretin amyloidosis because of their symptoms. Problems with the nerves outside of the central nervous system (peripheral neuropathy), pain that results from damage or injury to the nerves (neuropathic pain) and heart disease are common symptoms. Carpal tunnel syndrome, clouding of the gel-like substance of the eye (vitreous), and gastrointestinal issues like diarrhea or constipation are also possible signs. The specific tests can be different. If a person only has heart problems, then the tests a doctor orders will be those that assess the function of the heart.

Hereditary transthyretin amyloidosis is caused by the buildup of a protein called transthyretin in various tissues of the body. Transthyretin is abnormal in people with hereditary transthyretin amyloidosis and forms clumps, called amyloid deposits, in various tissues of the body. Doctors will take a tissue sample, called a biopsy, and study it to see whether there are these amyloid deposits. They may stain the tissue sample with a dye called Congo red, which allows them to see these deposits under a special microscope.

The protein, transthyretin, can be found in the liquid portion of blood (serum). If an antibody against transthyretin is added to the serum sample, it can determine the levels of transthyretin. Antibodies are specialized proteins that react to specific substances.

To confirm a diagnosis, a doctor may offer genetic testing. These tests involve studying TTR gene for changes (mutations). This can include sequence analysis, where a part or sequence of DNA within a gene is examined; targeted mutation analysis, where specific changes (mutations) are looked for; or gene-targeted deletion/duplication analysis, where missing or extra regions of DNA are looked for within a specific gene. Molecular genetic testing must be done at specialized genetic testing laboratories.

Additional tests may be done before or after a diagnosis is made. These tests can include tests to see how well the heart is functioning or whether there is damage to the nerves.

To learn more about genetic testing, discuss it with your doctor or seek a referral to a genetic counselor. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors)

at http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: www.alnylam.com/patients/alnylam-act.

References
  • Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015;66(21):2451-66.
  • Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet Journal of Rare Diseases. 20138:31. Retrieved from https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-31
  • Sekigima Y, Yoshida K, Tokuda T. Familial Transthyretin Amyloidosis. GeneReviews website. Retrieved September 26, 2017 from https://www.ncbi.nlm.nih.gov/books/NBK1194
Who else in my family should I test for hereditary transthyretin amyloidosis?

In a family with hereditary transthyretin amyloidosis, tests can be done to see whether other family members are at risk or have the condition. Some people may not show any symptoms of the disorder. However, because the age when symptoms develop can vary, they may be tested to see whether they have an TTR gene change (or mutation), which causes the condition. This is called predictive genetic testing or presymptomatic genetic testing. The specific gene mutation in that family need to be known to perform such a test. If known, all siblings and other at-risk relatives can be offered testing. Molecular genetic testing, which are tests that look for changes to genes, can be performed.

Predictive or presymptomatic genetic testing in at-risk adults is available but the genetic testing process should include genetic counseling for both pre- and post-test guidance. Clinical evaluation of at risk family members can also provide information about any symptoms or signs of hereditary transthyretin amyloidosis. Genetic testing of adolescents under the age of 18 for hereditary transthyretin amyloidosis, a serious adult-onset disorder without a specific treatment, is not typically recommend by most medical professionals.

A genetic counselor or a physician with experience in hereditary transthyretin amyloidosis can provide advice about how a confirmed diagnosis can affect other family members. In the U.S., medical geneticists can be found through the American College of Medical Geneticists.

In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: www.alnylam.com/patients/alnylam-act.

References
  • Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet Journal of Rare Diseases. 20138:31. Retrieved from https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-31
  • Sekigima Y, Yoshida K, Tokuda T. Familial Transthyretin Amyloidosis. GeneReviews website. Retrieved September 26, 2017 from https://www.ncbi.nlm.nih.gov/books/NBK1194
  • Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29 Suppl 1:S27-35.
Can hereditary transthyretin amyloidosis be found before birth?

Parents who have a family history of hereditary transthyretin amyloidosis (or if one parent has the TTR gene change or mutation that causes the disorder) may choose to have their child tested for the disorder before the child is born. This is known as prenatal diagnosis. If the gene change(s) that causes TTR are known in a family, genetic testing (to detect these mutations) can be used for prenatal diagnosis. Prenatal testing for genetic conditions that commonly present in adulthood is uncommon and need careful consideration and genetic counseling is recommended.

Preimplantation genetic diagnosis (PGD) in which embryos can be genetically tested is also available. During this process, embryos are created through in vitro fertilization (IVF) by taking eggs from the mother and sperm from the father. The two are then combined in the laboratory. A few cells are removed from the embryo and are then tested to determine whether or not that specific embryo inherited the altered TTR gene. Then, the family can choose to only have the embryos without hereditary transthyretin amyloidosis transferred to create the pregnancy.

To learn more about the option of genetic testing and what is involved, please seek out a referral to see a genetic counselor.

In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

References
  • Sekigima Y, Yoshida K, Tokuda T. Familial Transthyretin Amyloidosis. GeneReviews website. Retrieved September 26, 2017 from https://www.ncbi.nlm.nih.gov/books/NBK1194
  • Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29 Suppl 1:S27-35.
What tests support a diagnosis of hereditary transthyretin amyloidosis with heart involvement?

Hereditary transthyretin amyloidosis can cause heart disease. The disorder is caused by changes (mutations) in a gene called TTR. This gene produces the protein transthyretin. Because of the mutation in this gene, the transthyretin it produces does not work properly and is known as amyloid. Amyloid begins to clump together and build up in tissues of the body.

Sometimes, amyloid builds up in the heart. Some people will only have heart involvement, while other people may have other organs affected. If other organs are involved, a diagnosis of hereditary transthyretin amyloidosis may be made and the heart will be evaluated to see whether amyloid is building up there.

In people with only heart involvement, a family history of the disorder will lead to earlier diagnosis. If there is no family history, a diagnosis may be delayed. A diagnosis of the heart form of hereditary transthyretin amyloidosis is based on identifying the clinical symptoms and then specialized testing including looking for certain markers in the blood (biomarkers) and noninvasive imaging studies.

Biomarkers are substances that can be tested for that suggest a person has a specific disorder or that there is damage to an organ. There are specific biomarkers that suggest people have heart disease caused by amyloidosis. These biomarkers do not distinguish among the different types of amyloidosis.

Noninvasive imaging can include an electrocardiogram (ECG), transthoracic echocardiogram (TTE), or a cardiac MRI (magnetic resonance imaging). An electrocardiogram records the heart's electrical impulses and may reveal abnormal electrical patterns that suggest heart disease due to amyloid deposits. A transthoracic echocardiogram creates images of the heart using high frequency sound waves. This test can show distinctive changes in the heart in people with cardiac amyloidosis like abnormal thickness of the lower left chamber of the heart. An MRI uses a magnetic field and radio waves to produce images of particular organs. When an MRI is used to create a picture of the heart (cMRI), it can reveal changes or abnormalities in the heart (including deposits of amyloid).

A newer test called scintigraphy can be used to detect amyloid deposits in the heart, distinguish between different types of amyloidosis, monitor the progression of the disease, and assess the response to treatment. Scintigraphy is a form of nuclear medicine. An individual will swallow a radioactive material that will accumulate in a specific area (e.g. the heart). A special camera will be used to detect the levels of radiation producing an image of the heart.

References
  • Mohty D, Damy T, Cosnay P, et al. Cardiac amyloidosis: updates in diagnosis and management. Arch Cardiovasc Dis. 2013;106(10):528-40.
  • Arbustini E, Merlini G. Early identification of transthyretin-related hereditary cardiac amyloidosis. JACC Cardiovasc Imaging. 2014;7(5):511-4.
  • Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 20151;66(21):2451-66.
  • Bokhari S, Shahzad R, Castaño A, Maurer MS. Nuclear imaging modalities for cardiac amyloidosis. J Nucl Cardiol. 2014;21(1):175-84.
Does everyone who has a mutation in the gene for hereditary transthyretin amyloidosis get the disease?

Gene changes (mutations) in the TTR that causes hereditary transthyretin amyloidosis have decreased penetrance. Penetrance is the chance that someone with a mutation in a gene will actually develop symptoms of the disease. If a genetic disease has a 100% penetrance, that means that everyone who inherits a mutation in that gene will develop the disease. However, in hereditary transthyretin amyloidosis, there is decreased penetrance. This means that not everyone who has the gene change will develop symptoms of the disease. Some research suggests that the penetrance is affected by the region of the world. If you do not have symptoms but know you have a gene mutation in the TTR gene, a genetic counselor or medical geneticist can help you understand your risks. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

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