Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA), is a disease that typically affects the heart and tendons of elderly people. It is caused by accumulation of a

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

(that is to say a normal) protein called

transthyretin Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol' ...

. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated

protein tends to deposit at a much earlier age than in WTTA, due to abnormal conformation and bioprocessing. It belongs to a group of diseases called amyloidosis, chronic progressive conditions linked to abnormal deposition of normal or abnormal proteins, because these proteins are misshapen and cannot be properly degraded and eliminated by the cell metabolism.

Signs and symptoms

Wild-type transthyretin amyloid accumulates mainly in the

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, where it causes stiffness and often thickening of its walls, leading consequently to shortness of breath and intolerance to exercise, called

diastolic dysfunction Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the l ...

. Excessively slow heart rate can also occur, such as in

sick sinus syndrome Sinus node dysfunction (SND), also known as sick sinus syndrome (SSS), is a group of abnormal heart rhythms ( arrhythmias) usually caused by a malfunction of the sinus node, the heart's primary pacemaker. Tachycardia-bradycardia syndrome is a varia ...

, with ensuing fatigue and dizziness. Wild-type transthyretin deposition is also a common cause of

carpal tunnel syndrome Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparen ...

in elderly men, which may cause pain, tingling and loss of sensation in the hands. Some patients may develop carpal tunnel syndrome as an initial symptom of wild-type transthyretin amyloid. There appears to be an increase in the risk for developing

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...

or blood in the urine due to urological lesions.

Natural course

The disorder typically affects the heart and its prevalence increases in older age groups. Men are affected much more frequently than women, and up to 25% of men over the age of 80 may have evidence of WTTA. Patients often present with increased thickness of the wall of the main heart chamber, the

left ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...

. People affected by WTT amyloidosis are likely to have required a pacemaker before diagnosis and have a high incidence of a partial electrical blockage of the heart, known as

left bundle branch block Left bundle branch block (LBBB) is a conduction abnormality in the heart that can be seen on an electrocardiogram (ECG). In this condition, activation of the left ventricle of the heart is delayed, which causes the left ventricle to contract late ...

. Low

ECG Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...

signals such as QRS complexes are widely considered a marker of cardiac amyloidosis. A much better survival has been reported for patients with WTTA as opposed to cardiac

AL amyloidosis Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis in the US. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein ...

Diagnosis

The condition is suspected in an elderly person, especially male, presenting with symptoms of heart failure such as shortness of breath or swollen legs, and or disease of the electrical system of the heart with ensuing slow heart rate, dizziness or fainting spells. The diagnosis is confirmed on the basis of a biopsy, which can be treated with a special stain called

Congo Red Congo red is an organic compound, the sodium salt of 3,3′-( ,1′-biphenyl4,4′-diyl)bis(4-aminonaphthalene-1-sulfonic acid). It is an azo dye. Congo red is water-soluble, yielding a red colloidal solution; its solubility is greater in organic ...

that will be positive in this condition, and immunohistochemistry. However, this disease can now non-invasively be diagnosed with the help of Tc-99m pyrophosphate scintigraphy.

Treatment

No drug has been shown to be able to arrest or slow down the process of this condition. There is promise that two drugs,

tafamidis Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyo ...

and

diflunisal Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It wa ...

, may improve the outlook, since they were demonstrated in randomized clinical trials to benefit patient affected by the related condition FAP-1 otherwise known as transthyretin-related hereditary amyloidosis. Permanent pacing can be employed in cases of symptomatic slow heart rate ( bradycardia). Heart failure medications can be used to treat symptoms of difficulty breathing and congestion. An investigational first-in-human study has demonstrated that NTLA-2001, a therapeutic agent based on the

CRISPR-Cas9 Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic ...

system, induces targeted knockout of the transthyretin protein.

Orphan drug status for transthyretin (TTR) amyloidosis

Because of preliminary data suggesting the drug may have activity, the U.S. FDA has granted tolcapone "orphan drug status" in studies aiming at the treatment of transthyretin

familial amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...

(ATTR). However, tolcapone is not FDA approved for the treatment of this disease.

References

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External links

The Amyloidosis Center at Boston University

Mayo Clinic Definition

A Patient Guide to Amyloidosis
Amyloidosis Histopathology Structural proteins