Cardiomyopathy of wild type or hereditary transthyretin mediated amyloidosis is a rare form of cardiomyopathy caused by mutations in the transthyretin (TTR) gene. This gene is responsible for the production of a protein called transthyretin, which is involved in transporting thyroid hormone and retinol-binding protein. Mutations in this gene can lead to the overproduction of a protein called amyloid, which can accumulate in the heart and other organs, leading to cardiomyopathy. Symptoms of this condition include fatigue, shortness of breath, and an irregular heartbeat. Treatment options include medications, lifestyle changes, and surgery. In some cases, a liver transplant may be recommended to replace the mutated gene with a healthy one.

Wild-type transthyretin amyloid

Illness

Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA), is a disease that typically affects the heart and tendons of the elderly. It is caused by the accumulation of wild type (I mean a normal) protein called transthyretin. This is in contrast to a related condition called hereditary transthyretin-related amyloidosis where a genetic mutation transthyretin the protein tends to be deposited at a much earlier age than in WTTA due to abnormal conformation and bioprocessing. It belongs to a group of diseases called amyloidosischronic progressive conditions linked to the abnormal deposition of normal or abnormal proteins, because these proteins are misshapen and cannot be properly degraded and eliminated by cellular metabolism.

Signs and symptoms

Wild-type amyloid transthyretin accumulates primarily in the heartwhere it causes stiffness and often thickening of its walls, consequently leading to shortness of breath and exercise intolerance, called diastolic dysfunction. Excessively slow heart rate may also occur, as in sick sinus syndrome, with consequent fatigue and dizziness. Wild-type transthyretin deposition is also a common cause of carpal tunnel syndrome in elderly men, and can cause pain, tingling and loss of sensation in the hands. Some patients may develop carpal tunnel syndrome as an initial symptom of wild-type amyloid transthyretin. There appears to be an increased risk of developing hematuria or blood in the urine due to urologic injuries.

natural course

The disorder usually affects the heart and its prevalence increases in older age groups. Men are affected much more often than women, and up to 25% of men over age 80 may have evidence of WTTA.

Patients often have increased wall thickness in the main cardiac chamber, Left ventricle. People affected by WTT amyloidosis are likely to have needed a pacemaker before diagnosis and have a high incidence of partial electrical blockage of the heart known as left bundle branch block. Low ECG signals such as QRS complexes are widely considered a marker of cardiac amyloidosis.

Much better survival has been reported for patients with WTTA as opposed to cardiac AL amyloidosis.

Diagnosis

The condition is suspected in an elderly person, especially a male, who has symptoms of heart failure, such as shortness of breath or swollen legs, and or disease of the heart’s electrical system with consequent slow heart rate, dizziness or fainting. The diagnosis is confirmed based on a biopsy, which can be treated with a special stain called Congo red which will be positive in this condition, and immunohistochemistry. However, this disease can now be diagnosed non-invasively with the help of Tc-99m pyrophosphate scintigraphy.

Treatment

No drug has been shown to be able to interrupt or slow down the process of this condition. There is promise that two drugs, tafamidis and diflunisalmay improve the outlook, as they have been shown in randomized clinical trials to benefit the patient affected by the FAP-1 related condition, also known as hereditary transthyretin-related amyloidosis. Permanent pacing may be used in cases of symptomatic slow heart rate (bradycardia). Heart failure medications can be used to treat symptoms of breathing difficulty and congestion.

A first experimental study in humans demonstrated that NTLA-2001, a therapeutic agent based on CRISPR-Cas9 system, induces targeted knockout of transthyretin protein.

Orphan drug status for transthyretin amyloidosis (TTR)

Due to preliminary data suggesting that the drug may have activity, the US FDA has granted tolcapone[circular reference] “orphan drug status” in studies targeting the treatment of transthyretin familial amyloidosis (ATR). However, tolcapone is not approved by the FDA for the treatment of this disease.

See too

References

External Links


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1. Wild-type transthyretin amyloid
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3. Amyloidogenic transthyretin
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5. Transthyretin variants
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7. Amyloidogenesis
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