Wild-type transthyretin amyloid

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Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA), [1] is a disease that typically affects the heart and tendons of elderly people. It is caused by the accumulation of a wild-type (that is to say a normal) protein called transthyretin. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated transthyretin protein tends to deposit much earlier 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.

Contents

Signs and symptoms

Wild-type transthyretin amyloid accumulates mainly in the heart, where it causes stiffness and often thickening of its walls, leading consequently to shortness of breath and intolerance to exercise, called diastolic dysfunction. Excessively slow heart rate can also occur, such as in sick sinus syndrome, with ensuing fatigue and dizziness. Wild-type transthyretin deposition is also a common cause of carpal tunnel syndrome 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. [2] There appears to be an increased risk of developing hematuria or blood in the urine due to urological lesions.[ citation needed ]

Natural course

The disorder typically affects the heart and its prevalence increases in older age groups. Men are affected much more frequently than women, [3] and up to 25% of men over the age of 80 may have evidence of WTTA. [4]

Patients often present with increased thickness of the wall of the main heart chamber, the left ventricle. 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 the left bundle branch block. Low ECG signals such as QRS complexes are widely considered a marker of cardiac amyloidosis. [5]

A much better survival has been reported for patients with WTTA as opposed to cardiac AL amyloidosis. [6]

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. [7] The diagnosis is confirmed on the basis of a biopsy, which can be treated with a special stain called Congo Red 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. [8]

Treatment

No drug has been shown to be able to arrest or slow down the process of this condition. [9] There is promise that two drugs, tafamidis and diflunisal, [10] 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. [11]

A 2021 investigational first-in-human study demonstrated that NTLA-2001, a therapeutic agent based on the CRISPR-Cas9 system, induces targeted knockout of the transthyretin protein. [12]

Orphan drug status for transthyretin (TTR) amyloidosis

Because of preliminary data suggesting the drug may have activity, the U.S. FDA in 2013 granted tolcapone "orphan drug status" in studies aiming at the treatment of transthyretin familial amyloidosis (ATTR). [13] However, as of 2015 tolcapone was not FDA approved for the treatment of this disease. [14]

See also

Related Research Articles

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<span class="mw-page-title-main">Microangiopathy</span> Medical condition

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<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

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 loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">Transthyretin</span> Serum protein related to amyloid diseases

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. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.

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<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR, or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.

<span class="mw-page-title-main">Cardiac amyloidosis</span> Medical condition

Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with a corrected analysis only during autopsy. Advancements of technologies have increased earlier accuracy of diagnosis. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.

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<span class="mw-page-title-main">Tafamidis</span> Medication for transthyretin amyloidosis

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 cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.

<span class="mw-page-title-main">Amyloid cardiomyopathy</span> Medical condition

Amyloid cardiomyopathy is a condition resulting in the death of part of the myocardium. It is associated with the systemic production and release of many amyloidogenic proteins, especially immunoglobulin light chain or transthyretin (TTR). It can be characterized by the extracellular deposition of amyloids, foldable proteins that stick together to build fibrils in the heart.

Familial amyloid cardiomyopathy (FAC), or transthyretin amyloid cardiomyopathy (ATTR-CM) results from the aggregation and deposition of mutant and wild-type transthyretin (TTR) protein in the heart. TTR is usually circulated as a homo-tetramer—a protein made up of four identical subunits—however, in FAC populations, TTR dissociates from this typical form and misassembles into amyloid fibrils which are insoluble and resistant to degradation. Due to this resistance to degradation, when amyloid fibrils accumulate in the heart's walls, specifically the left ventricle, rigidity prevents the heart from properly relaxing and refilling with blood: this is called diastolic dysfunction which can ultimately lead to heart failure.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

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 left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

Vutrisiran, sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.

<span class="mw-page-title-main">Acoramidis</span> Chemical compound

Acoramidis, sold under the brand name Attruby, is a medication used for the treatment of cardiomyopathy. It is a near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation, to treat transthyretin amyloid cardiomyopathy. It is taken by mouth.

Lawreen Marie Heller Connors was an American biochemist, medical researcher, and college professor. She was a professor of pathology and laboratory medicine at Boston University School of Medicine from 1998 until she retired in 2022. Her research focused on the protein amyloid, and the related disease, amyloidosis. She was director of the Amyloidosis Center at Boston University, and co-director of the Amyloid Pathology Diagnostic Testing Laboratory.

References

  1. ↑ Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ (April 2013). "Senile systemic amyloidosis: clinical features at presentation and outcome". Journal of the American Heart Association. 2 (2): e000098. doi:10.1161/JAHA.113.000098. PMC   3647259 . PMID   23608605.
  2. ↑ Sekijima Y, Uchiyama S, Tojo K, Sano K, Shimizu Y, Imaeda T, Hoshii Y, Kato H, Ikeda S (November 2011). "High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly". Human Pathology (Submitted manuscript). 42 (11): 1785–91. doi:10.1016/j.humpath.2011.03.004. hdl: 10091/16883 . PMID   21733562.
  3. ↑ Ng B, Connors LH, Davidoff R, Skinner M, Falk RH (June 2005). "Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis". Archives of Internal Medicine. 165 (12): 1425–9. doi: 10.1001/archinte.165.12.1425 . PMID   15983293.
  4. ↑ Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L (2008-01-01). "Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study". Annals of Medicine. 40 (3): 232–9. doi:10.1080/07853890701842988. PMID   18382889. S2CID   23446885.
  5. ↑ Falk RH (September 2005). "Diagnosis and management of the cardiac amyloidoses". Circulation. 112 (13): 2047–60. doi: 10.1161/CIRCULATIONAHA.104.489187 . PMID   16186440.
  6. ↑ Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, Salvi F, Ciliberti P, Pastorelli F, Biagini E, Coccolo F, Cooke RM, Bacchi-Reggiani L, Sangiorgi D, Ferlini A, Cavo M, Zamagni E, Fonte ML, Palladini G, Salinaro F, Musca F, Obici L, Branzi A, Perlini S (September 2009). "Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types". Circulation. 120 (13): 1203–12. doi: 10.1161/CIRCULATIONAHA.108.843334 . PMID   19752327.
  7. ↑ Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD (April 2012). "Updates in cardiac amyloidosis: a review". Journal of the American Heart Association. 1 (2): e000364. doi:10.1161/JAHA.111.000364. PMC   3487372 . PMID   23130126.
  8. ↑ Masri, Ahmad; Bukhari, Syed; Ahmad, Shahzad; Nieves, Ricardo; Eisele, Yvonne S.; Follansbee, William; Brownell, Amy; Wong, Timothy C.; Schelbert, Erik; Soman, Prem (2020). "Efficient 1-Hour Technetium-99 m Pyrophosphate Imaging Protocol for the Diagnosis of Transthyretin Cardiac Amyloidosis". Circulation: Cardiovascular Imaging. 13 (2): e010249. doi: 10.1161/circimaging.119.010249 . ISSN   1941-9651. PMC   7032611 . PMID   32063053.
  9. ↑ Dubrey S, Ackermann E, Gillmore J (August 2015). "The transthyretin amyloidoses: advances in therapy". Postgraduate Medical Journal. 91 (1078): 439–48. doi:10.1136/postgradmedj-2014-133224. PMID   26048914. S2CID   8077907.
  10. ↑ Sekijima Y (June 2014). "Recent progress in the understanding and treatment of transthyretin amyloidosis". Journal of Clinical Pharmacy and Therapeutics. 39 (3): 225–33. doi: 10.1111/jcpt.12145 . PMID   24749898. S2CID   20492854.
  11. ↑ Quarta CC, Kruger JL, Falk RH (September 2012). "Cardiac amyloidosis". Circulation. 126 (12): e178–82. doi: 10.1161/CIRCULATIONAHA.111.069195 . PMID   22988049.
  12. ↑ Gillmore, Julian D.; Gane, Ed; Taubel, Jorg; Kao, Justin; Fontana, Marianna; Maitland, Michael L.; Seitzer, Jessica; O'Connell, Daniel; Walsh, Kathryn R.; Wood, Kristy; Phillips, Jonathan (2021-08-05). "CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis". New England Journal of Medicine. 385 (6): 493–502. doi: 10.1056/NEJMoa2107454 . ISSN   0028-4793. PMID   34215024. S2CID   235722446.
  13. ↑ "Tolcapone". FDA: Search Orphan Drug Designations and Approvals. 1 January 2013.
  14. ↑ Reig, N.; Ventura, S.; Salvadó, M.; Gámez, J.; Insa, R. (2015). "SOM0226, a repositioned compound for the treatment of TTR amyloidosis". Orphanet J Rare Dis. 10 (Suppl 1): P9. doi: 10.1186/1750-1172-10-s1-p9 . PMC   4642128 .
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