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Transthyretin Amyloidosis (TTR) Information, Diagnosis, and Treatment
Early Diagnosis and Treatment Are Critical, but Elusive
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. However, patients with the condition typically die 10 years after the onset of symptoms, so early identification, diagnosis, and treatment are critical.
Disease Education Information
What Is Transthyretin (TTR ) Amyloidosis?
TTR amyloidosis is caused by misfolding of the transthyretin (TTR) protein, a secondary transporter of thyroxine and retinol-binding protein, which causes protein deposits called amyloid, to form within the body’s tissues and organs. In TTR familial amyloid polyneuropathy (TTR-FAP), these amyloids cause damage to the nerves that control senses, movement, and involuntary bodily functions.
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.
What is TTR-FAP 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. TTR-CM tends to affect older males, ie., men who are 65 or older.
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. 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.
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. 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.
Not everyone who inherits the mutant TTR gene will develop TTR-FAP. However, once symptoms of the disease are seen, it is critical that individuals discuss them closely with doctors and family members. 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.
TTR-CM results when amyloid build up in the myocardium, or heart muscles, and results in heart failure. It comes in two forms: familial amyloid cardiomyopathy (TTR-FAC) and age-related, or senile, amyloidosis. Patients usually exhibit symptoms of congestive heart failure, including:
- Shortness of breath
- Labored breathing during exercise
- Peripheral swelling (edema caused by a buildup of fluid in the lower limbs)
- Fainting (syncope)
- Generalized fatigue
The mutation that causes familial amyloid cardiomyopathy is found almost exclusively in African Americans, while age-related amyloidosis primarily affects Caucasian men over the age of 65.
How is TTR amyloidosis diagnosed?
TTR-FAP can be difficult to recognize and manage. Misdiagnosis is common and definitive diagnosis can be delayed for years, postponing adequate treatment and genetic counseling, and leading to possible irreversible damage.
Red flag symptoms suggesting a TTR-FAP diagnosis would include progressive nerve cell damage and one or more of the following
- Signs usually associated with early autonomic dysfunction (eg incontinence, dry mouth)
- Heart failure symptoms
- Severe chronic diarrhea, constipation, or alternating bouts of constipation and diarrhea
- Weight loss that cannot be explained
- Carpal tunnel syndrome
- Impaired kidney function
- Floaters or vitreous opacity.
The disease is commonly mistaken for other forms of neuropathy, including chronic inflammatory demyelinating polyneuropathy, progressive diabetic neuropathy, and paraneoplastic syndrome, caused by the presence of a tumor.
Family history should be investigated, and a thorough neurological examination should be performed, including small-fiber assessment, nerve conduction studies, electro- and echocardiograms, and laboratory evaluations.
TTR genotyping and tissue biopsy, using Congo red staining, should be performed to confirm amyloid deposition.
Individuals who are suspected of carrying the gene, but who do not yet show any symptoms of the disease, should be monitored closely. Physicians should perform the following tests regularly:
- Neurological screening (which should, ideally, be done annually)
- Clinical evaluation of weight, autonomic and renal function
- Regular eye exams
- Testing for carpal tunnel syndrome and cardiac function
Patients suspected of having TTR-CM should be evaluated by echocardiography, which will help confirm suspicions. The disease is often marked by thickening of the heart’s left ventricle wall and septum. Congo red staining will offer definitive diagnosis.
Endomyocardial biopsy (EMB) has been the gold standard for diagnosis; however, amyloidosis may be diagnosed without EMB via imaging and tissue biopsy
Can TTR amyloidosis Be Treated?
Liver, or liver and heart transplantation may be suitable for some patients with early-onset disease.
In some countries outside the US, medication for TTR stabilization is also available as an option for the treatment of TTR FAP.
Gene therapy is also being investigated as a possible treatment.