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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.

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^[update] tolcapone was not FDA approved for the treatment of this disease.^[14]

References

^ 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.
^ 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.
^ 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.
^ 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.
^ Falk RH (September 2005). "Diagnosis and management of the cardiac amyloidoses". Circulation. 112 (13): 2047–60. doi:10.1161/CIRCULATIONAHA.104.489187. PMID 16186440.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Quarta CC, Kruger JL, Falk RH (September 2012). "Cardiac amyloidosis". Circulation. 126 (12): e178–82. doi:10.1161/CIRCULATIONAHA.111.069195. PMID 22988049.
^ 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.
^ "Tolcapone". FDA: Search Orphan Drug Designations and Approvals. 1 January 2013.
^ 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.