Diagnostic Considerations

Given the rarity of TTR-related amyloidosis (ATTR) and the challenge posed by its pattern of producing seemingly unrelated symptoms, ATTR has been widely underdiagnosed and misdiagnosed, thereby prolonging the time to appropriate treatment. Common misdiagnoses made in patients with peripheral nervous complaints include the following^[22]:

Idiopathic axonal polyneuropathy
Chronic inflammatory demyelinating polyneuropathy
Lumbar spinal stenosis
Charcot-Marie-Tooth disease

With the high prevalence of alcoholism/alcohol abuse and diabetes in the United States population, neurologic findings may well be discounted as progressive sequalae of those known conditions, if present in an individual patient's history, and ATTR may be missed without further diagnostic workup.

The American Journal of Cardiology emphasizes the need for high degree of suspicion for ATTR in patients found to have heart failure with preserved ejection fraction along with symptoms related to the peripheral or autonomic nervous systems—information which patients may not offer unless the clinician specifically asks, in the course of a thorough interview focusing on signs, symptoms, and a complete family history.^[25]Similarly, given the strong co-occurrence of cardiac and neurologic manifestations of ATTR, all patients with amyloid peripheral or autonomic neuropathy need screening for cardiac involvement.

Differential Diagnoses

Workup

Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005 Jul. 62(7):1057-62. [QxMD MEDLINE Link].
Ando Y, Suhr OB. Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid. 1998 Dec. 5(4):288-300. [QxMD MEDLINE Link].
Plante-Bordeneuve V, Lalu T, Misrahi M, et al. Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology. 1998 Sep. 51(3):708-14. [QxMD MEDLINE Link].
Hagiwara K, Ochi H, Suzuki S, et al. Highly selective leptomeningeal amyloidosis with transthyretin variant Ala25Thr. Neurology. April 2009. 72:1358-60. [QxMD MEDLINE Link].
U.S. FDA Approves VYNDAQEL® and VYNDAMAX™ for use in Patients with Transthyretin Amyloid Cardiomyopathy, a Rare and Fatal Disease. Pfizer Press Release. 06 May 2019. Available at https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vyndaqel_and_vyndamax_for_use_in_patients_with_transthyretin_amyloid_cardiomyopathy_a_rare_and_fatal_disease.
Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep. 10(3):160-84. [QxMD MEDLINE Link].
Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008. 40 (3):232-9. [QxMD MEDLINE Link].
Zhen DB, Swiecicki PL, Zeldenrust SR, Dispenzieri A, Mauermann ML, Gertz MA. Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. Clin Genet. 2015 Oct. 88 (4):396-400. [QxMD MEDLINE Link].
Bulawa C, Connelly S, DeVit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. PNAS. June 12, 2012. 109:9629-9634. [QxMD MEDLINE Link].
Suhr OB, Svendsen IH, Andersson R, Danielsson A, Holmgren G, Ranløv PJ. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Intern Med. 2003 Sep. 254(3):225-35. [QxMD MEDLINE Link].
Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997 Feb 13. 336(7):466-73. [QxMD MEDLINE Link].
Saraiva MJ, Birken S, Costa PP. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest. 1984 Jul. 74(1):104-19. [QxMD MEDLINE Link].
Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Adv Hum Genet. 1991. 20:69-123, 309-11. [QxMD MEDLINE Link].
Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. December 2003. Volume 17, Issue 6:909–927. [QxMD MEDLINE Link]. [Full Text].
Rapezzi C, Riva L, Quarta CC, Perugini E, Salvi F, Longhi S. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid. 2008 Mar. 15(1):40-8. [QxMD MEDLINE Link].
Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain. 2000 Jul. 123 (Pt 7):1495-504. [QxMD MEDLINE Link].
Ruberg FL, Berk JL. Transthyretin (TTR) Cardiac Amyloidosis. Circulation. 04 Sept 2012. 126:1286-1300. [QxMD MEDLINE Link]. [Full Text].
Wange N, Anan I, Ericzon BG, Pennlert J, Pilebro B, Suhr OB, et al. Atrial Fibrillation and Central Nervous Complications in Liver Transplanted Hereditary Transthyretin Amyloidosis Patients. Transplantation. 2018 Feb. 102(2):e59-e66. [QxMD MEDLINE Link]. [Full Text].
Phull P, Sanchorawala V, Connors LH, Doros G, Ruberg FL, Berk JL, et al. Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR). Amyloid. 2018 Mar. 25(1):62-67. [QxMD MEDLINE Link]. [Full Text].
Rapezzi C, Perugini E, Salvi F, Grigioni F, Riva L, Cooke RM, et al. Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: towards tailoring of therapeutic strategies?. Amyloid. 2006 Sep. 13(3):143-53. [QxMD MEDLINE Link].
Parman Y, Adams D, Obici L, et al. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol. 2016. 29 (suppl 1):S000–S000. [QxMD MEDLINE Link].
Adams D, Suhr OB, Hund E, Obici L, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016. 29 (suppl1):S000-S000. [QxMD MEDLINE Link].
Vergaro G, Solal AC, Emdin M. Wild Type Transthyretin Amyloidosis: Don't Miss Diagnosis!. Int J Cardiol. 01 Aug 2020. 312:96-97. [QxMD MEDLINE Link]. [Full Text].
Simmons Z, Specht, C. The Neuromuscular Manifestations of Amyloidosis. Journal of Clin Neuromuscular Dis. March 2010. 11:145-157. [QxMD MEDLINE Link].
Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015. 66:2451-66. [QxMD MEDLINE Link].
Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2020 Jan 6. [QxMD MEDLINE Link].
[Guideline] Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet Journal of Rare Diseases. 2013. v.8, 31:[QxMD MEDLINE Link]. [Full Text].
Wiklund R, Kadkhodaee A, Andersson K, et al. Normal scores of deep breathing tests: beware of dysrhythmia in transthyretin amyloidosis. Amyloid: The Journal of Protein Folding Disorders. 25 Jan 2018. 54-61. [Full Text].
Klaassen SHC, Tromp J, Nienhuis HLA, van der Meer P, van den Berg MP, Blokzijl H, et al. Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide. Am J Cardiol. 2018 Jan 1. 121(1):107-112. [QxMD MEDLINE Link]. [Full Text].
Gertz MA, Dispenzieri A, Sher T. Pathophysiology and treatment of cardiac amyloidosis. Nat Rev Cardiol. 2015 Feb. 12 (2):91-102. [QxMD MEDLINE Link].
Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. June 14, 2016. Volume 133, Issue 24:2404-2412. [QxMD MEDLINE Link]. [Full Text].
Wisniowski B, Wechalekar A. Confirming the Diagnosis of Amyloidosis. Acta Haematol. 16 Jan 2020. 1-10. [QxMD MEDLINE Link]. [Full Text].
Treglia G, Glaudemans AWJM, Bertagna F, Hazenberg BPC, Erba PA, Giubbini R, et al. Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis. Eur J Nucl Med Mol Imaging. 2018 Oct. 45(11):1945-1955. [QxMD MEDLINE Link]. [Full Text].
Rapezzi C, Merlini G, Quarta, C, et al. Systemic Cardiac Amyloidosis: Disease Profiles and Clnical Courses of the 3 Main Types. Circulation. Sep 2009. 120:1203-1212. [QxMD MEDLINE Link].
Montagna P, Marchello L, Plasmati R, et al. Electromyographic findings in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP). Electroencephalogr Clin Neurophysiol. 1996 Oct. 101(5):423-30. [QxMD MEDLINE Link].
Planté-Bordeneuve V, Ferreira A, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy. Neurology. Aug 2007. 69:693-698. [QxMD MEDLINE Link].
Inês M, Coelho T, Conceição I, Ferreira L, de Carvalho M, Costa J. Health-related quality of life in hereditary transthyretin amyloidosis polyneuropathy: a prospective, observational study. Orphanet J Rare Dis. 2020 Mar 6. 15 (1):67. [QxMD MEDLINE Link]. [Full Text].
Ueda M, Sekijima Y, Koike H, Yamashita T, Yoshinaga T, Ishii T, et al. Monitoring of asymptomatic family members at risk of hereditary transthyretin amyloidosis for early intervention with disease-modifying therapies. J Neurol Sci. 2020 Apr 2. 414:116813. [QxMD MEDLINE Link].
Hawkins, P. N., Ando, Y., Dispenzeri, A., et al. Evolving landscape in the management of transthyretin amyloidosis. Annals of Medicine. 2015 Nov 17. 47(8):625–638. [QxMD MEDLINE Link]. [Full Text].
Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5. 379 (1):11-21. [QxMD MEDLINE Link].
Merlini G, Coelho T, Waddington Cruz M, Li H, Stewart M, Ebede B. Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years. Neurol Ther. 2020 Feb 27. [QxMD MEDLINE Link].
Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK1, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;. 379(1):22-31. [QxMD MEDLINE Link]. [Full Text].
Brannagan TH 3rd, et al; NEURO-TTR Open-Label Extension Investigators. Early Data on Long-Term Efficacy and Safety of Inotersen in Patients With Hereditary Transthyretin Amyloidosis: A 2-Year Update From the Open-Label Extension of the NEURO-TTR Trial. Eur J Neurol. 2020 Apr 28. [QxMD MEDLINE Link].
FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis. U.S. Food & Drug Administration. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated#:~:text=On%20May%203%2C%20the%20U.S.,approved%20treatments%20for%20ATTR%2DCM.. May 6, 2019; Accessed: July 23, 2020.
Cruz MW, Benson MD. A Review of Tafamidis for the Treatment of Transthyretin-Related Amyloidosis. Neurol Ther. 2015. 4:61-79. [QxMD MEDLINE Link].
Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long- term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 05 Aug 2016. Vol. 23 , Iss. 3:178-183. [QxMD MEDLINE Link]. [Full Text].
Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 13 Sept 2018. 379:1007-1016. [Full Text].
Suhr OB, Larsson M, Ericzon B-G, Wilczek HE. Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. Transplantation. 2015. 00:1-9. [QxMD MEDLINE Link].
Adams D, Tournev IL, Taylor MS, Coelho T, Pante-bordeneuve V, Berk JL, et al. HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (1234). Presented at the April 19, 2021 at the American Academy of Neurology 2021 Annual Meeting. Neurology. 2021 Apr 13. 96(15 suppl):[Full Text].
Amvuttra (vutrisiran) [package insert]. Cambridge, MA: Alnylam Pharmaceuticals. 2022 Jun. Available at [Full Text].
Sant’Anna, R., Gallego, P., Robinson, L. Z., et al. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Nature Communications. 2016 Feb 23. 7:[QxMD MEDLINE Link]. [Full Text].
Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013 Dec 25. 310(24):2658-67. [QxMD MEDLINE Link].
Anderson P. NSAID halts progression in familial amyloid polyneuropathy. December 30, 2013. Medscape Medical News. Available at http://www.medscape.com/viewarticle/818483. Accessed: January 10, 2017.
The Familial Amyloidotic Polyneuropathy World Transplant Registry. Available at http://www.fapwtr.org. April 24, 2018; Accessed: May 1, 2020.
Ericzon B-G, Wilczek HE, Larsson M, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative?. Transplantation. 2015. 99:1847-1854. [QxMD MEDLINE Link].
Beirao JM, Maleiro J, Lemos C, Beirao I, Costa P, Torres P. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. Amyloid. 2015. 22:117-122. [QxMD MEDLINE Link].
aus dem Siepen F, Bauer R, Aurich M, Buss SJ, Steen H, Altland K, et al. Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an observational study. Drug Design, Development and Therapy. 2015 Dec 4. v9:6319–6325. [QxMD MEDLINE Link]. [Full Text].
Desai HV, Aronow WS, Peterson SJ, et al. Cardiac Amyloidosis: Approaches to Diagnosis and Management. Cardiology in Review. Jan 2010. 18:1-11. [QxMD MEDLINE Link].
Berk JL, Barroso FA, Coelho A. Oligonucleotide Drugs for Transthyretin Amyloidosis. N Engl J Med. 2018 Nov 22. 379:2085-2086. [QxMD MEDLINE Link]. [Full Text].
Ericzon BG, Larsson M, Herlenius G, Wilczek HE. Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR). Amyloid. 2003 Aug. 10 Suppl 1:67-76. [QxMD MEDLINE Link].
Damas AM, Saraiva MJ. Review: TTR amyloidosis-structural features leading to protein aggregation and their implications on therapeutic strategies. J Struct Biol. 2000 Jun. 130(2-3):290-9. [QxMD MEDLINE Link].
Monteiro E, Freire A, Barroso E. Familial amyloid polyneuropathy and liver transplantation. J Hepatol. 2004 Aug. 41(2):188-94. [QxMD MEDLINE Link].
Lauro A, Diago Usò T, Masetti M, Di Benedetto F, Cautero N, De Ruvo N, et al. Liver transplantation for familial amyloid polyneuropathy non-VAL30MET variants: are cardiac complications influenced by prophylactic pacing and immunosuppressive weaning?. Transplant Proc. 2005 Jun. 37(5):2214-20. [QxMD MEDLINE Link].
Klabunde T, Petrassi HM, Oza VB, et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol. 2000 Apr. 7(4):312-21. [QxMD MEDLINE Link].
Tojo K, Sekijima Y, Kelly JW, et al. Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci Res. 2006. 56:441-449. [QxMD MEDLINE Link].
Palha JA, Ballinari D, Amboldi N, Cardoso I, Fernandes R, Bellotti V, et al. 4'-Iodo-4'-deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid. Am J Pathol. 2000 Jun. 156(6):1919-25. [QxMD MEDLINE Link].
Peterson SA, Klabunde T, Lashuel HA, et al. Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci U S A. 1998 Oct 27. 95(22):12956-60. [QxMD MEDLINE Link].
Saraiva MJ. Transthyretin amyloidosis: a tale of weak interactions. FEBS Lett. 2001 Jun 8. 498(2-3):201-3. [QxMD MEDLINE Link].
Suhr OB, Herlenius G, Friman S. Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl. 2000 May. 6(3):263-76. [QxMD MEDLINE Link].

Media Gallery

Transthyretin-related amyloidosis. Congo Red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light.

of 1

Known TTR Variants (adapted from Benson^[14] and Connors et al^[6])
Table. Diagnostic tests for transythyretin (TTR) amyloidosis

Known TTR Variants (adapted from Benson ^[14]and Connors et al ^[6])

Variant	Geographic Focus (Ethnic Origin)	Organs Involved
Gly6Ser	Caucasian	None
Cys10Arg	United States (Hungarian)	H, PN, AN, E
Leu12Pro	United Kingdom	CNS, AN, L, LM
Asp18Gly	United States (Hungarian)	CNS, LM
Met13Ile	Germany	None
Asp18Asn	United States	H
Asp18Glu	South America	AN, PN
Asp18Gly	Hungary	LM
Val20Ile	United States, Germany	H, CL
Ser23Asn	United States (Portuguese)	H, E, PN
Pro24Ser	United States	PN, H, CL
Ala25Ser	United States	PN, H, CL
Ala25Thr	Japan	CNS, PN
Val28Met	Portugal	AN, PN
Val30Met	Argentina, Brazil, China, Finland, France, Germany, Greece, Italy, Japan, Portugal, Sweden, Turkey, United States	PN, AN, E, LM
Val30Ala	United States (German)	AN, H
Val30Leu	Japan, United States	PN, AN, H, K
Val30Gly	United States	E, CNS, LM
Phe33Cys	United States	CL, E, K, H
Phe33Ile	Israel (Polish, Ashkenazi Jewish)	PN, E
Phe33Leu	United States (Polish, Lithuanian)	PN, AN, H
Phe33Val	United Kingdom, Japan, China	PN
Arg34Thr	Italy	PN, H
Lys35Asn	France	PN, H, AN
Ala36Pro	Greece, Italy, United States (Jewish)	PN, E, CNS, CL
Asp38Ala	Japan	H, PN, AN
Trp41Leu	United States (Russian)	E, PN
Glu42Gly	Japan, Russia, United States	PN, AN, H
Glu42Asp	France	H
Phe44Ser	United States, Japan	PN, H, AN, E
Ala45Thr	Italy, Ireland, United States	H
Ala45Asp	United States , Ireland, Italy	PN, H
Ala45Ser	Sweden	H
Gly47Ala	Italy, Germany, France	PN, H, AN
Gly47Arg	Japan	PN, AN
Gly47Val	Sri Lanka	H, AN, PN, CL
Gly47Glu	Germany, Italy, Turkey, United States	H, K, PN, AN
Thr49Ala	France, Italy (Sicily)	PN, CL, H
Thr49Ile	Japan	PN, H
Thr49Pro	United States	H
Ser50Arg	Japan, France, Italy	PN, H, AN
Ser50Ile	Japan	PN, H, AN
Glu51Gly	United States	H
Ser52Pro	United Kingdom	PN, AN, H, K
Gly53Glu	Basque	CNS, LM, PN, H
Glu54Gly	United Kingdom	PN, E, AN
Glu54Lys	Japan	PN, AN, H
Leu55Pro	United States (Dutch, German), Taiwan	PN, E, H, AN
Leu55Arg	Germany	PN, LM
Leu55Gln	United States (Spanish)	AN, E, PN
Leu58His	United States, Germany	H, CL
His56Arg	United States	H
Leu58Arg	Japan	AN, E, CL, H
Thr59Lys	Italy, United States (Chinese)	H, PN, AN
Thr60Ala	Ireland, United States (Appalachian), Australia, Germany, United Kingdom, Japan	H, PN, GI, CL
Glu61Lys	Japan	PN
Phe64Leu	Italy, United States	PN, H, CL
Phe64Ser	Canada (Italian), United Kingdom	CNS, PN, E, LM
Ile68Leu	Germany, United States	H
Tyr69His	United States, Scotland, Canada	E, LM
Tyr69Ile	Japan	CL, H, AN
Lys70Asn	United States, Germany	CL, E, PN
Val71Ala	France, Spain	PN, E , CL
Ile73Val	Bangladesh	PN, AN
Asp74His	Germany	None
Ser77Tyr	Germany, France, United Kingdom	PN, H, K
Ser77Phe	France	PN, AN, H
Tyr78Phe	France (Italian)	PN, CL, S
Ala81Thr	United States	H
Ile84Ser	United States (Swiss), Hungary	H, CL, E, LM
Ile84Asn	Italy, United States	E, H, CL
Ile84Thr	Germany, United Kingdom	PN, AN, H
Glu89Gln	Italy/Sicily	PN, H, CL
Glu89Lys	United States	PN, H, AN
His90Asn	Portugal, Germany	None
Ala91Ser	France	PN, H, CL, AN
Gln92Lys	Japan	H
Ala97Gly	Japan	H, PN
Ala97Ser	China, France, Taiwan	PN, H
Gly101Ser	Japan	None
Arg103Ser	United States	H
Pro102Arg	Germany	None
Arg104Cys	United States	None
Arg104His	Japan, United States (Chinese)	None
Ile107Met	Germany	H, PN
Ile107Val	United States(German), Japan	PN, H, CL
Ala109Val	United States	None
Ala108Ala	Portugal	None
Ala109Thr	Portugal	None
Ala109Ser	Japan	PN, AN
Leu111Met	Denmark	H, CL
Ser112Ile	Italy	PN, H
Tyr114Cys	Holland, Japan	PN, E, H, LM, AN, CNS
Tyr114His	Japan	CL, S
Tyr116Ser	France	PN, CL, AN
Thr119Met	United States, Portugal	None
Ala120Ser	Afro-Caribbean	PN, H, AN
Val122Ile	Africa, United States, Portugal	H
Val122Ala	United States (Alaska), United Kingdom	PN, H, E
Deletion of 122Val	Ecuador, United States, Spain	PN, CNS, GI, CL, H
Pro125Ser	Italy	None

Table. Diagnostic tests for transythyretin (TTR) amyloidosis

Method	Material	Sensitivity	Specificity	Purpose
Pathologic
Congo Red	Tissue	Medium/High	High	Detecting amyloid deposits
BSB, FSB dyes	Tissue	High	Medium	Detecting amyloid deposits
Electron microscopy	Tissue	Medium	High	Confirming amyloid fibrils
Immunohistochemistry with anti-TTR antibodies	Tissue	High	Medium/High	Detecting TTR deposits
Genetic
PCR-RFLP	DNA	High	High	Detecting predicted mutations in the TTR gene
Real-time PCR (melting curve analysis)	DNA	High	High	Detecting predicted mutations in the TTR gene
PCR-SSCP	DNA	Medium	Medium	Screening for unknown mutations in the TTR gene
Sequencing	DNA	High	High	Detecting unknown mutations in the TTR gene
Mass Spectrometry (MS)
MALDI-TOF MS, ESI-MS	Serum protein	Medium/High	Medium	Detecting variant TTR
FT-ICR MS	Serum protein	Medium/High	Medium/High	Detecting variant TTR
SELDI-TOF MS	Serum protein	Medium/High	Medium	Detecting variant TTR
LC-MS/MS	Tissue	Medium	Medium	Identifying precursor proteins of amyloid fibrils, including variant TTR

Back to List

Author

Jefferson R Roberts, MD Chief of Rheumatology Service, Tripler Army Medical Center; Assistant Clinical Professor of Medicine, Uniformed Services University of the Health Sciences

Jefferson R Roberts, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Society for Simulation in Healthcare

Disclosure: Nothing to disclose.

Coauthor(s)

Mary L Lan, MD, MPH Resident Physician, Department of Medicine, Tripler Army Medical Center

Disclosure: Nothing to disclose.

Victoria M F Mank, MD Resident Physician, Department of Internal Medicine, Tripler Army Medical Center

Victoria M F Mank, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology

Disclosure: Stock ownership for: Johnson & Johnson.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University School of Medicine in Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Affairs Medical Center

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Aaron Pumerantz, DO Fellow Instructor, Department of Medicine, Uniformed Services University of the Health Sciences

Aaron Pumerantz, DO is a member of the following medical societies: American College of Physicians, American Medical Association, American Osteopathic Association

Disclosure: Nothing to disclose.

Christopher F Middleman, MD Staff Preceptor, Internal Medicine Clinic, Tripler Army Medical Center; Battalion Surgeon, US Army

Christopher F Middleman, MD is a member of the following medical societies: American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Gregory M Sprowl, MD Resident Physician, Department of Internal Medicine, Tripler Army Medical Center

Gregory M Sprowl, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Daniel R Jacobson, MD Professor of Medicine, Boston University School of Medicine; Chief of Oncology, Veterans Affairs Boston Healthcare System

Disclosure: Nothing to disclose.

Mariana J Kaplan, MD Assistant Professor, Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School

Disclosure: Nothing to disclose.

Seetha U Monrad, MD Clinical Instructor, Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School

Seetha U Monrad is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Robert John Oglesby, MD Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences

Robert John Oglesby, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and Arthritis Foundation

Disclosure: Nothing to disclose.