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.
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.
Natural courseedit
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]
Diagnosisedit
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]
Treatmentedit
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) amyloidosisedit
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]
^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. PMC3647259. 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. PMC3487372. PMID 23130126.
^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.
^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. PMC4642128.
External linksedit
The Amyloidosis Center at Boston University
Mayo Clinic Definition
A Patient Guide to Amyloidosis
December 02, 2023
wild, type, transthyretin, amyloid, wtta, also, known, senile, systemic, amyloidosis, disease, that, typically, affects, heart, tendons, elderly, people, caused, accumulation, wild, type, that, normal, protein, called, transthyretin, this, contrast, related, c. 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 1 Signs and symptoms 2 Natural course 3 Diagnosis 4 Treatment 4 1 Orphan drug status for transthyretin TTR amyloidosis 5 See also 6 References 7 External linksSigns and symptoms editWild 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 Natural course editThe 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 editThe 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 editNo 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 edit 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 See also editTransthyretin related hereditary amyloidosis AmyloidosisReferences edit 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 Salvado M Gamez 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 External links editThe Amyloidosis Center at Boston University Mayo Clinic Definition A Patient Guide to Amyloidosis Retrieved from https en wikipedia org w index php title Wild type transthyretin amyloid amp oldid 1187401457, wikipedia, wiki, book, books, library,
