Hereditary amyloid transthyretin (ATTR) amyloidosis is a rare disorder that develops due to a buildup of amyloid proteins in the body. ATTR is a type of amyloidosis in which the proteins can accumulate in the blood, bones, and even major organs, which causes a wide variety of complications. While hereditary ATTR amyloidosis is not curable, there are many treatments to manage this condition. However, diagnosis of this condition is challenging to begin with because the symptoms and causes mimic other types of conditions, including cardiovascular disease. At the same time, the symptoms also vary widely depending on the type of amyloidosis. Read on to find out how is hereditary ATTR diagnosed with the hereditary ATTR test, its use, and its procedure.
What is ATTR Amyloidosis, and How Many Types Are There?
ATTR amyloidosis stands for amyloid transthyretin (ATTR) amyloidosis. This is a rare type of disorder that happens when amyloid proteins start accumulating in the body. Amyloid proteins begin to accumulate in the blood, bones, and other major organs, causing a wide variety of complications. This is a complex condition, and there is no cure for ATTR amyloidosis. However, there are treatments available for the management of this condition.(1, 2, 3)
The symptoms of ATTR vary depending on which subtype of the disease you have but tend to include some common symptoms like:
- Weakness in the legs
- Extreme fatigue
- Swelling in the legs and ankle
- Heart palpitations, very common in ATTRwt
- Unintentional weight loss, usually due to a loss of appetite
- Low libido
- Loss of taste
- Ulcers and bleeding in the gastrointestinal tract
- Carpal tunnel syndrome
- Bowel and urinary problems, including diarrhea
- Low blood pressure or hypotension
- Decreased sweat production, especially in hATTR
When you have amyloidosis, you are at a higher risk of having heart disease, especially if you have wild-type ATTR. If you have wild-type ATTR, you may also experience some heart-related symptoms, including:(4)
ATTR is just one form of amyloidosis, but there are several subtypes of the disease that exist. These include:
- Hereditary ATTR (hATTR or ARRTm): Hereditary or familial ATTR is a type of amyloidosis that runs in families and has a genetic link. While amyloidosis tends to typically affect the kidneys, with hATTR, this is not usually the case.(5, 6)
- Acquired ATTR (ATTRwt): Acquired ATTR or non-hereditary ATTR is known as the wild-type ATTR or ATTRwt. Similar to other types of amyloidosis, this type of ATTR affects the heart and also increases the risk of developing congestive heart failure. ATTRwt is usually underdiagnosed, due to which the prevalence of this subtype of ATTR is not well researched and understood. This type of ATTR is usually linked with aging, but there is no evidence to show that it is also associated with other neurological diseases like dementia.(7, 8)
Hereditary ATTR Tests – Uses and Procedures
The first thing to keep in mind when you have ATTR is that this condition is challenging to diagnose because, firstly, the symptoms mimic other conditions, and secondly because the symptoms vary depending on what subtype of the disease you have.
If your doctor suspects ATTR amyloidosis, they will prescribe a large number of diagnostic tests. If there is a history of ATTR amyloidosis in your family, your doctor will first want to do genetic testing to check for the hereditary type of amyloidosis. Apart from your symptoms and your entire health history, genetic testing is the primary test used to diagnose hereditary ATTR.
According to data from the Amyloidosis Foundation, the wild type of ATTR is much more challenging to diagnose and detect in the initial stages because the symptoms mimic those of congestive heart failure.(9, 10, 11)
To confirm wild-type ATTR, your doctor might prescribe a biopsy of the heart tissues, as well as gene sequencing and protein analyses of the sample.(12) They may also order an ACG (echocardiogram) which is an imaging test of the heart that lets the doctor see what’s going on inside the heart.(13)
Hereditary ATTR amyloidosis is confirmed if the blood test shows there is a genetic mutation in the TTR gene. The genetic test also determines which variant of hereditary ATTR it is. In hereditary ATTR amyloidosis cases, doctors also recommend that other members of the family should also consider getting their genetic testing done.
If your doctor is more or less certain that you have ATTR, but there is no family history of the disease, your doctor will order tests to detect the presence of amyloids or the affected proteins in the body. One way this can be done is by conducting a nuclear scintigraphy scan.(14, 15) A nuclear scintigraphy scan searches for the TTR deposits in the bones. A blood test is also carried out to look for any deposits of TTR in the bloodstream.
Of course, while this is not always the case, but in some cases, co-occurring conditions known as comorbidities can also be observed with amyloidosis, including:(16)
- Autoimmune diseases like lupus, ankylosing spondylitis, or rheumatoid arthritis
- Early onset of Alzheimer’s Disease
- Multiple myeloma
- Crohn’s disease
Some other tests that can be ordered to diagnose ATTR amyloidosis include:
- Electrocardiogram (ECG)
- Bone scan, known as bone scintigraphy to, look for amyloid deposits
- Heart biopsy
- Blood tests to search for any changes in the TTR gene
- Cardiac imaging tests like ECG, MRIs, and positron emission tomography (PET) scans
In rare cases, your doctor may also order some scans like mass spectrometry and immunohistochemistry to differentiate between ATTR and other types of amyloidosis.
Treatment of Hereditary ATTR Amyloidosis
Until a few years ago, the only treatment for hereditary ATTR amyloidosis was a liver transplant. Since TTR is primarily manufactured by the liver and a liver transplant reduces the production of the abnormal TTR protein. However, in recent years, many medications have become available for the treatment of hereditary ATTR, though some of them are still under trial with the Food and Drug Administration. These treatments have various approaches to treat the condition and basically work to stabilize the TTR protein, remove the amyloid deposits, and also stop the production of the TTR protein.(17, 18)
Remember that there is no cure for ATTR amyloidosis, but there are many evolving clinical trials that might help develop new treatment approaches in the future. If you want to get yourself enrolled in a clinical trial, you should talk to your doctor about finding out if you would be a good fit.
Just like with other forms of amyloidosis, there is no cure for hereditary ATTR. Diagnosing hereditary ATTR can be challenging as the symptoms mimic other conditions and also vary depending on what subtype of the condition you have. Treatment can help slow down the progression of the disease, as well as help with symptom management, which can improve your overall quality of life.
- Sekijima, Y., 2015. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. Journal of Neurology, Neurosurgery & Psychiatry, 86(9), pp.1036-1043.
- Ihse, E., Rapezzi, C., Merlini, G., Benson, M.D., Ando, Y., Suhr, O.B., Ikeda, S.I., Lavatelli, F., Obici, L., Quarta, C.C. and Leone, O., 2013. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid, 20(3), pp.142-150.
- Gonzalez-Duarte, A. and Ulloa-Aguirre, A., 2021. A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis). International Journal of Molecular Sciences, 22(23), p.13158.
- Amyloidosis (2020) NORD (National Organization for Rare Disorders). Available at: https://rarediseases.org/rare-diseases/amyloidosis/ (Accessed: October 5, 2022).
- Gertz, M.A., 2017. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care, 23(7 Suppl), pp.S107-S112.
- Swiecicki, P.L., Zhen, D.B., Mauermann, M.L., Kyle, R.A., Zeldenrust, S.R., Grogan, M., Dispenzieri, A. and Gertz, M.A., 2015. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid, 22(2), pp.123-131.
- Wild-type (2021) Amyloidosis Foundation. Available at: http://amyloidosis.org/facts/wild-type/ (Accessed: October 5, 2022).
- Mohamed-Salem, L., Santos-Mateo, J.J., Sanchez-Serna, J., Hernández-Vicente, Á., Reyes-Marle, R., Sánchez, M.I.C., Claver-Valderas, M.A., Gonzalez-Vioque, E., Haro-del Moral, F.J., García-Pavía, P. and Pascual-Figal, D.A., 2018. Prevalence of wild type ATTR assessed as myocardial uptake in bone scan in the elderly population. International journal of cardiology, 270, pp.192-196.
- Sekijima, Y., Yazaki, M., Ueda, M., Koike, H., Yamada, M. and Ando, Y., 2018. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid, 25(1), pp.8-10.
- Ladefoged, B., Dybro, A., Povlsen, J.A., Vase, H., Clemmensen, T.S. and Poulsen, S.H., 2020. Diagnostic delay in wild type transthyretin cardiac amyloidosis–a clinical challenge. International Journal of Cardiology, 304, pp.138-143.
- Bruno, M., Castaño, A., Burton, A. and Grodin, J.L., 2021. Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges. Heart failure reviews, 26(1), pp.35-45.
- Wild-type (2021) Amyloidosis Foundation. Available at: http://amyloidosis.org/facts/wild-type/#diagnosis (Accessed: October 5, 2022).
- Muchtar, E., Dispenzieri, A., Magen, H., Grogan, M., Mauermann, M., McPhail, E.D., Kurtin, P.J., Leung, N., Buadi, F.K., Dingli, D. and Kumar, S.K., 2021. Systemic amyloidosis from A (AA) to T (ATTR): a review. Journal of Internal Medicine, 289(3), pp.268-292.
- Brownrigg, J., Lorenzini, M., Lumley, M. and Elliott, P., 2019. Diagnostic performance of imaging investigations in detecting and differentiating cardiac amyloidosis: a systematic review and meta‐analysis. ESC heart failure, 6(5), pp.1041-1051.
- Yang, J.C., Fox, J., Chen, C. and Yu, A.F., 2018. Cardiac ATTR amyloid nuclear imaging—not all bone scintigraphy radionuclide tracers are created equal. Journal of Nuclear Cardiology, 25(5), pp.1879-1884.
- Cioffi, C.L., Raja, A., Muthuraman, P., Jayaraman, A., Jayakumar, S., Varadi, A., Racz, B. and Petrukhin, K., 2021. Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Their Common Age-Related Comorbidities. Journal of Medicinal Chemistry, 64(13), pp.9010-9041.
- Gertz, M.A., Mauermann, M.L., Grogan, M. and Coelho, T., 2019. Advances in the treatment of hereditary transthyretin amyloidosis: a review. Brain and behavior, 9(9), p.e01371.
- Yamamoto, H. and Yokochi, T., 2019. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC heart failure, 6(6), pp.1128-1139.