Transthyretin Amyloidosis (TTR): Diagnosis and Treatment


Early Diagnosis and Treatment Are Critical, but Elusive

Transthyretin Amyloidosis (TTR)

TTR amyloidosis is a progressive and, ultimately, fatal rare disease that destroys nerve cells governing various bodily functions. Because its symptoms are often similar to those of other diseases, the condition can be difficult to recognize and diagnose properly.[1,2] However, patients with the condition typically die 10 years after the onset of symptoms, so early identification, diagnosis, and treatment are critical.[2]

On this page, you will find information on the condition, its diagnosis and treatment.

 

What Is Transthyretin (TTR ) Amyloidosis?

TTR amyloidosis is caused by misfolding of the transthyretin (TTR) protein, a primary transporter of thyroxine and vitamin A, which causes protein deposits called amyloid, to form within the body’s tissues and organs.[1,2,3]

In TTR familial amyloid polyneuropathy (TTR-FAP), these amyloids cause damage to the nerves that control senses, movement, and involuntary bodily functions.[1,2]

In TTR cardiomyopathy (TTR-CM), they cause cardiomyopathy, or damage to the heart’s muscles, impeding the heart’s ability to pump blood throughout the body.[2]

 

What is TTR-FAP/TTR-CM and who gets it?

Approximately 10,000, or 1.1 per 100,000 people in the world, are estimated to be living with TTR-FAP, which often shows up when patients are in their thirties or forties.[1,4,5] TTR-CM tends to affect older males, i.e. men who are 45 or older.[6]

However, many cases of both forms of the disease are never diagnosed, or are mistaken for other diseases, so it is likely that more people have this disease.[2,5] As awareness of the condition increases, and patient diagnosis improves, the medical community will have a better idea of how many people suffer from both forms of this rare disease.[5]

Both forms of the disease are caused by a genetic mutation. TTR-FAP results from over 100 different mutations in the TTR gene that cause protein misfolding.[1,6] Only one mutant gene is needed to transmit the disease, and an affected parent has a 50% chance of passing the mutation on to his or her children.[4,5]

Not everyone who inherits the mutant TTR gene will develop TTR-FAP or TTR-CM.[2] However, once symptoms of the disease are seen, it is critical that individuals discuss them closely with doctors and family members.[2] Physicians treating a patient with symptoms of the condition must examine the patient’s family history closely, not only to determine whether there might be a genetic basis for the symptoms, but also to identify other people in the family who may carry the mutant gene, yet not exhibit symptoms of the disease. These individuals could benefit from genetic counseling and early monitoring of symptoms.[2]
 

TTR-CM

TTR-CM may result in heart failure.[6,7] It comes in two forms: hereditary amyloid cardiomyopathy and age-related, or wild-type, amyloidosis.[6,7] Patients usually exhibit symptoms of congestive heart failure, including:[8,9]     
•    Shortness of breath[8,9]
•    Labored breathing during exercise[8,9]
•    Peripheral swelling (edema caused by a buildup of fluid in the lower limbs)[8,9]
•    Fainting (syncope)[10]
•    Generalized fatigue[10]


Can TTR amyloidosis Be Treated?

Liver, or liver and heart transplantation may be suitable for some patients with early-onset disease.[6]
In Singapore, medication for TTR stabilization is now available as an option for the treatment of TTR-CM.[11]
Gene therapy is also being investigated as a possible treatment.[7]

 


References

1. Stewart M, Shaffer S, Murphy B, et al. Characterizing the high disease burden of transthyretin amyloidosis for patients and caregivers. Neurol Ther. 2018;7(2):349-364.
2. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
3. Peroutka SJ. Genetic Disorders of the Autonomic Nervous System. In: Waxman SG, ed. Molecular Neurology, Academic Press; 2007: 321-332.
4. Plante-Bordeneuve V. Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol. 2014;261(6):1227-1233.
5. Schmidt H, Waddington Cruz M, Botteman MF, et al. Global epidemiology of transthyretin familial amyloid polyneuropathy: a systematic review. Poster presented at: The International Society of Amyloidosis—XV International Symposium on Amyloidosis (ISA), July 3–7, 2016; Uppsala, Sweden
6. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300
7. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28(1):10-21.
8. Sekijima Y. Hereditary Transthyretin Amyloidosis. 2001 Nov 5 [updated 2018 Dec 20]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
9. Rapezzi C, Lorenzini M, Longhi S, et al. Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015;20(2):117-124.
10. Nativi-Nicolau J, Maurer MS. Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. Curr Opin Cardiol. 2018;33(5):571-579.
11. Health Sciences Authority (HSA). New drug approvals - Feb 2020. https://www.hsa.gov.sg/announcements/new-drug-approval/new-drug-approvals---feb-2020. Accessed August 23, 2020.

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