Amyloid Diseases at the Molecular Level: General Overview and Focus on AL Amyloidosis

  • Mario Nuvolone
  • Giovanni Palladini
  • Giampaolo MerliniEmail author
Part of the Current Clinical Pathology book series (CCPATH)


The amyloidoses encompass a heterogeneous group of diseases, wherein a misfolded protein accumulates extracellularly in the form of amyloid deposits, resulting in tissue damage and organ dysfunction.

Intrinsic instability, increased concentration, proteolytic cleavage and/or mutations of a precursor protein favour its conversion into an aggregation-prone misfolded state, which ultimately results in the formation of amyloid fibrils through poorly identified prefibrillar oligomeric species. The latter are believed to be the main culprit for the toxicity.

Numerous unrelated proteins can undergo this process, resulting in different types of the disease. Among these, systemic immunoglobulin light chain (AL) amyloidosis is caused by a usually small and nonproliferating plasma cell clone, which resides in the bone marrow and secretes an amyloidogenic light chain into the circulation. Almost any organ can be the site of amyloid deposition, rendering AL a truly protean condition.

The identification of a monoclonal component in a patient with histological evidence of amyloid disease is strongly suggestive, but not pathognomonic, of AL amyloidosis. Correct typing requires a scrupulous and multidisciplinary approach and forms the basis for an etiological therapy. Standard therapies aim at eradicating the amyloidogenic precursor, but novel complementary therapeutic approaches are under intense scrutiny.


Amyloidosis Amyloid Protein misfolding Protein toxicity Oligomers Plasma cell dyscrasia 


  1. 1.
    Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349:583–96.PubMedGoogle Scholar
  2. 2.
    Carrell RW, Lomas DA. Conformational disease. Lancet. 1997;350:134–8.PubMedGoogle Scholar
  3. 3.
    Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014;15:384–96.PubMedGoogle Scholar
  4. 4.
    Fandrich M, Fletcher MA, Dobson CM. Amyloid fibrils from muscle myoglobin. Nature. 2001;410:165–6.PubMedGoogle Scholar
  5. 5.
    Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006;75:333–66.PubMedGoogle Scholar
  6. 6.
    Ryno LM, Wiseman RL, Kelly JW. Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. Curr Opin Chem Biol. 2013;17:346–52.PubMedGoogle Scholar
  7. 7.
    Westermark GT, Westermark P. Serum amyloid A and protein AA: molecular mechanisms of a transmissible amyloidosis. FEBS Lett. 2009;583:2685–90.PubMedGoogle Scholar
  8. 8.
    Corlin DB, Heegaard NH. Beta(2)-microglobulin amyloidosis. Subcell Biochem. 2012;65:517–40.PubMedGoogle Scholar
  9. 9.
    Abrahamson M, Grubb A. Increased body temperature accelerates aggregation of the Leu-68→Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. Proc Natl Acad Sci USA. 1994;91:1416–20.PubMedCentralPubMedGoogle Scholar
  10. 10.
    McCutchen SL, Lai Z, Miroy GJ, Kelly JW, Colon W. Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease. Biochemistry. 1995;34:13527–36.PubMedGoogle Scholar
  11. 11.
    Booth DR, et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature. 1997;385:787–93.PubMedGoogle Scholar
  12. 12.
    Isaacson RL, Weeds AG, Fersht AR. Equilibria and kinetics of folding of gelsolin domain 2 and mutants involved in familial amyloidosis-Finnish type. Proc Natl Acad Sci USA. 1999;96:11247–52.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Raimondi S, et al. Effects of the known pathogenic mutations on the aggregation pathway of the amyloidogenic peptide of apolipoprotein a-I. J Mol Biol. 2011;407:465–76.PubMedGoogle Scholar
  14. 14.
    Valleix S, et al. Hereditary systemic amyloidosis due to Asp76Asn variant beta2-microglobulin. N Engl J Med. 2012;366:2276–83.PubMedGoogle Scholar
  15. 15.
    Rowczenio DM, et al. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat. 2014;35:E2403–12.PubMedGoogle Scholar
  16. 16.
    Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17:909–27.PubMedGoogle Scholar
  17. 17.
    Kim SH, et al. Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nat Neurosci. 1999;2:984–8.PubMedGoogle Scholar
  18. 18.
    Chen CD, et al. Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization. EMBO J. 2001;20:6277–87.PubMedCentralPubMedGoogle Scholar
  19. 19.
    De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 2010;6:99–107.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Goate A, Hardy J. Twenty years of Alzheimer’s disease-causing mutations. J Neurochem. 2012;120 Suppl 1:3–8.PubMedGoogle Scholar
  21. 21.
    Saraiva MJ. Transthyretin amyloidosis: a tale of weak interactions. FEBS Lett. 2001;498:201–3.PubMedGoogle Scholar
  22. 22.
    Westermark P, Mucchiano G, Marthin T, Johnson KH, Sletten K. Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques. Am J Pathol. 1995;147:1186–92.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Solomon A, et al. Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I. Arthritis Rheum. 2006;54:3545–50.PubMedGoogle Scholar
  24. 24.
    Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119:223–8.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003;10:160–84.PubMedGoogle Scholar
  26. 26.
    Obici L, et al. Structure, function and amyloidogenic propensity of apolipoprotein A-I. Amyloid. 2006;13:191–205.PubMedGoogle Scholar
  27. 27.
    Yazaki M, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res Commun. 2000;274:702–6.PubMedGoogle Scholar
  28. 28.
    Tsuchiya A, Yazaki M, Kametani F, Takei Y, Ikeda S. Marked regression of abdominal fat amyloid in patients with familial amyloid polyneuropathy during long-term follow-up after liver transplantation. Liver Transpl. 2008;14:563–70.PubMedGoogle Scholar
  29. 29.
    Liepnieks JJ, Zhang LQ, Benson MD. Progression of transthyretin amyloid neuropathy after liver transplantation. Neurology. 2010;75:324–7.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Ihse E, Suhr OB, Hellman U, Westermark P. Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis. J Mol Med. 2011;89:171–80.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Obici L, Perfetti V, Palladini G, Moratti R, Merlini G. Clinical aspects of systemic amyloid diseases. Biochim Biophys Acta. 2005;1753:11–22.PubMedGoogle Scholar
  32. 32.
    Obici L, Raimondi S, Lavatelli F, Bellotti V, Merlini G. Susceptibility to AA amyloidosis in rheumatic diseases: a critical overview. Arthritis Rheum. 2009;61:1435–40.PubMedGoogle Scholar
  33. 33.
    Saraiva MJ. Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies. Expert Rev Mol Med. 2002;4:1–11.PubMedGoogle Scholar
  34. 34.
    Sipe JD, et al. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid. 2012;19:167–70.PubMedGoogle Scholar
  35. 35.
    Kisilevsky R, Fraser P. Proteoglycans and amyloid fibrillogenesis. Ciba Found Symp. 1996;199:58–67. discussion 68–72, 90–103.PubMedGoogle Scholar
  36. 36.
    Nelson SR, Lyon M, Gallagher JT, Johnson EA, Pepys MB. Isolation and characterization of the integral glycosaminoglycan constituents of human amyloid A and monoclonal light-chain amyloid fibrils. Biochem J. 1991;275(Pt 1):67–73.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Pepys MB, et al. Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure. Proc Natl Acad Sci USA. 1994;91:5602–6.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Pepys MB. Amyloidosis. Annu Rev Med. 2006;57:223–41.PubMedGoogle Scholar
  39. 39.
    Hawkins PN, Myers MJ, Lavender JP, Pepys MB. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component. Lancet. 1988;1:1413–8.PubMedGoogle Scholar
  40. 40.
    Hazenberg BP, et al. Diagnostic performance of 123I-labeled serum amyloid P component scintigraphy in patients with amyloidosis. Am J Med. 2006;119(355):e15–24.PubMedGoogle Scholar
  41. 41.
    Tennent GA, Lovat LB, Pepys MB. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. Proc Natl Acad Sci USA. 1995;92:4299–303.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Botto M, et al. Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nat Med. 1997;3:855–9.PubMedGoogle Scholar
  43. 43.
    Pepys MB, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature. 2002;417:254–9.PubMedGoogle Scholar
  44. 44.
    Bodin K, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468:93–7.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Cohen AS, Calkins E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature. 1959;183:1202–3.PubMedGoogle Scholar
  46. 46.
    Eanes ED, Glenner GG. X-ray diffraction studies on amyloid filaments. J Histochem Cytochem. 1968;16:673–7.PubMedGoogle Scholar
  47. 47.
    Termine JD, Eanes ED, Ein D, Glenner GG. Infrared spectroscopy of human amyloid fibrils and immunoglobulin proteins. Biopolymers. 1972;11:1103–13.PubMedGoogle Scholar
  48. 48.
    Petkova AT, et al. A structural model for Alzheimer’s beta-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA. 2002;99:16742–7.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Jaroniec CP, MacPhee CE, Astrof NS, Dobson CM, Griffin RG. Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril. Proc Natl Acad Sci USA. 2002;99:16748–53.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Ritter C, et al. Correlation of structural elements and infectivity of the HET-s prion. Nature. 2005;435:844–8.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Makin OS, Atkins E, Sikorski P, Johansson J, Serpell LC. Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci USA. 2005;102:315–20.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Nelson R, et al. Structure of the cross-beta spine of amyloid-like fibrils. Nature. 2005;435:773–8.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation. Structure. 2010;18:1244–60.PubMedGoogle Scholar
  54. 54.
    Sawaya MR, et al. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature. 2007;447:453–7.PubMedGoogle Scholar
  55. 55.
    Fitzpatrick AW, et al. Atomic structure and hierarchical assembly of a cross-beta amyloid fibril. Proc Natl Acad Sci USA. 2013;110:5468–73.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Dobson CM, Karplus M. The fundamentals of protein folding: bringing together theory and experiment. Curr Opin Struct Biol. 1999;9:92–101.PubMedGoogle Scholar
  57. 57.
    Dobson CM. Getting out of shape. Nature. 2002;418:729–30.PubMedGoogle Scholar
  58. 58.
    Chiti F, Dobson CM. Amyloid formation by globular proteins under native conditions. Nat Chem Biol. 2009;5:15–22.PubMedGoogle Scholar
  59. 59.
    Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8:101–12.PubMedGoogle Scholar
  60. 60.
    Glabe CG. Structural classification of toxic amyloid oligomers. J Biol Chem. 2008;283:29639–43.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Stefani M. Structural polymorphism of amyloid oligomers and fibrils underlies different fibrillization pathways: immunogenicity and cytotoxicity. Curr Protein Pept Sci. 2010;11:343–54.PubMedGoogle Scholar
  62. 62.
    Serio TR, et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science. 2000;289:1317–21.PubMedGoogle Scholar
  63. 63.
    Knowles TP, et al. An analytical solution to the kinetics of breakable filament assembly. Science. 2009;326:1533–7.PubMedGoogle Scholar
  64. 64.
    Hawkins PN, Pepys MB. A primed state exists in vivo following histological regression of amyloidosis. Clin Exp Immunol. 1990;81:325–8.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Simons JP, et al. Pathogenetic mechanisms of amyloid A amyloidosis. Proc Natl Acad Sci USA. 2013;110:16115–20.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Harris DL, King E, Ramsland PA, Edmundson AB. Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes. J Mol Recognit. 2000;13:198–212.PubMedGoogle Scholar
  67. 67.
    Stevens FJ, Kisilevsky R. Immunoglobulin light chains, glycosaminoglycans, and amyloid. Cell Mol Life Sci. 2000;57:441–9.PubMedGoogle Scholar
  68. 68.
    Yan SD, et al. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med. 2000;6:643–51.PubMedGoogle Scholar
  69. 69.
    Sousa MM, Cardoso I, Fernandes R, Guimaraes A, Saraiva MJ. Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am J Pathol. 2001;159:1993–2000.PubMedGoogle Scholar
  70. 70.
    Andersson K, Olofsson A, Nielsen EH, Svehag SE, Lundgren E. Only amyloidogenic intermediates of transthyretin induce apoptosis. Biochem Biophys Res Commun. 2002;294:309–14.PubMedGoogle Scholar
  71. 71.
    Lambert MP, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998;95:6448–53.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Hartley DM, et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999;19:8876–84.PubMedGoogle Scholar
  73. 73.
    Walsh DM, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9.PubMedGoogle Scholar
  74. 74.
    Liao R, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. 2001;104:1594–7.PubMedGoogle Scholar
  75. 75.
    Brenner DA, et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res. 2004;94:1008–10.PubMedGoogle Scholar
  76. 76.
    Shi J, et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci USA. 2010;107:4188–93.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Silveira JR, et al. The most infectious prion protein particles. Nature. 2005;437:257–61.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Campioni S, et al. A causative link between the structure of aberrant protein oligomers and their toxicity. Nat Chem Biol. 2010;6:140–7.PubMedGoogle Scholar
  79. 79.
    Kyle RA, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79:1817–22.PubMedGoogle Scholar
  80. 80.
    Pinney JH, et al. Systemic amyloidosis in England: an epidemiological study. Br J Haematol. 2013;161:525–32.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520–30.PubMedGoogle Scholar
  82. 82.
    Gertz MA, Kyle RA, Greipp PR. The plasma cell labeling index: a valuable tool in primary systemic amyloidosis. Blood. 1989;74:1108–11.PubMedGoogle Scholar
  83. 83.
    Rajkumar SV, Gertz MA, Kyle RA. Primary systemic amyloidosis with delayed progression to multiple myeloma. Cancer. 1998;82:1501–5.PubMedGoogle Scholar
  84. 84.
    Gertz MA, Kyle RA, Noel P. Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenstrom’s macroglobulinemia. J Clin Oncol. 1993;11:914–20.PubMedGoogle Scholar
  85. 85.
    Hofmann-Guilaine C, et al. Association light chain deposition disease (LCDD) and amyloidosis. One case. Pathol Res Pract. 1985;180:214–9.PubMedGoogle Scholar
  86. 86.
    Adami F, et al. Coexistence of primary AL amyloidosis and POEMS syndrome: efficacy of melphalan-dexamethasone and role of biochemical markers in monitoring the diseases course. Am J Hematol. 2010;85:131–2.PubMedGoogle Scholar
  87. 87.
    Adams D, et al. New elements in the diagnosis and the treatment of primary AL amyloid polyneuropathy and neuropathy due to POEMS syndrome. Rev Neurol (Paris). 2011;167:57–63.Google Scholar
  88. 88.
    Cohen AD, et al. Systemic AL amyloidosis due to non-Hodgkin’s lymphoma: an unusual clinicopathologic association. Br J Haematol. 2004;124:309–14.PubMedGoogle Scholar
  89. 89.
    Telio D, et al. Two distinct syndromes of lymphoma-associated AL amyloidosis: a case series and review of the literature. Am J Hematol. 2010;85:805–8.PubMedGoogle Scholar
  90. 90.
    Ikee R, Kobayashi S, Hemmi N, Suzuki S, Miura S. Amyloidosis associated with chronic lymphocytic leukemia. Amyloid. 2005;12:131–4.PubMedGoogle Scholar
  91. 91.
    Perfetti V, et al. AL amyloidosis. Characterization of amyloidogenic cells by anti-idiotypic monoclonal antibodies. Lab Invest. 1994;71:853–61.PubMedGoogle Scholar
  92. 92.
    McElroy Jr EA, Witzig TE, Gertz MA, Greipp PR, Kyle RA. Detection of monoclonal plasma cells in the peripheral blood of patients with primary amyloidosis. Br J Haematol. 1998;100:326–7.PubMedGoogle Scholar
  93. 93.
    Perfetti V, et al. Cells with clonal light chains are present in peripheral blood at diagnosis and in apheretic stem cell harvests of primary amyloidosis. Bone Marrow Transplant. 1999;23:323–7.PubMedGoogle Scholar
  94. 94.
    Manske MK, et al. Quantitative analysis of clonal bone marrow CD19+ B cells: use of B cell lineage trees to delineate their role in the pathogenesis of light chain amyloidosis. Clin Immunol. 2006;120:106–20.PubMedGoogle Scholar
  95. 95.
    Solomon A, Macy SD, Wooliver C, Weiss DT, Westermark P. Splenic plasma cells can serve as a source of amyloidogenic light chains. Blood. 2009;113:1501–3.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Perfetti V, et al. Membrane CD22 defines circulating myeloma-related cells as mature or later B cells. Lab Invest. 1997;77:333–44.PubMedGoogle Scholar
  97. 97.
    Perfetti V, Vignarelli MC, Casarini S, Ascari E, Merlini G. Biological features of the clone involved in primary amyloidosis (AL). Leukemia. 2001;15:195–202.PubMedGoogle Scholar
  98. 98.
    Perfetti V, et al. The degrees of plasma cell clonality and marrow infiltration adversely influence the prognosis of AL amyloidosis patients. Haematologica. 1999;84:218–21.PubMedGoogle Scholar
  99. 99.
    Paiva B, et al. The clinical utility and prognostic value of multiparameter flow cytometry immunophenotyping in light-chain amyloidosis. Blood. 2011;117:3613–6.PubMedGoogle Scholar
  100. 100.
    Kourelis TV, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol. 2013;31:4319–24.PubMedGoogle Scholar
  101. 101.
    Pardanani A, et al. Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis. Blood. 2003;101:827–30.PubMedGoogle Scholar
  102. 102.
    Dispenzieri A, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2006;107:3378–83.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Wechalekar AD, et al. A new staging system for AL amyloidosis incorporating serum free light chains, cardiac troponin-T and NT-proBNP. Blood. 2009;114. abstr. 2796.Google Scholar
  104. 104.
    Kumar S, et al. A novel prognostic staging system for light chain amyloidosis (AL) incorporating markers of plasma cell burden and organ involvement. Blood. 2009;114. abstr. 2797.Google Scholar
  105. 105.
    Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011;29:1924–33.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Comenzo RL, et al. Mobilized CD34+ cells selected as autografts in patients with primary light-chain amyloidosis: rationale and application. Transfusion. 1998;38:60–9.PubMedGoogle Scholar
  107. 107.
    Fonseca R, et al. Chromosomal abnormalities in systemic amyloidosis. Br J Haematol. 1998;103:704–10.PubMedGoogle Scholar
  108. 108.
    Hayman SR, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood. 2001;98:2266–8.PubMedGoogle Scholar
  109. 109.
    Perfetti V, et al. Translocation T(4;14)(p16.3;q32) is a recurrent genetic lesion in primary amyloidosis. Am J Pathol. 2001;158:1599–603.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Bochtler T, et al. Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14). Blood. 2011;117:3809–15.PubMedGoogle Scholar
  111. 111.
    Bochtler T, et al. Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone. Amyloid. 2014;21:9–17.PubMedGoogle Scholar
  112. 112.
    Weinhold N, et al. Inherited genetic susceptibility to monoclonal gammopathy of unknown significance. Blood. 2014;123:2513–7. quiz 2593.PubMedGoogle Scholar
  113. 113.
    Weinhold N, et al. The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat Genet. 2013;45:522–5.PubMedGoogle Scholar
  114. 114.
    Chubb D, et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet. 2013;45:1221–5.PubMedGoogle Scholar
  115. 115.
    Weinhold N, et al. Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma. Leukemia. 2014;28:2254–6.Google Scholar
  116. 116.
    Abraham RS, et al. Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis. Blood. 2005;105:794–803.PubMedGoogle Scholar
  117. 117.
    Zhou P, et al. Clonal plasma cell pathophysiology and clinical features of disease are linked to clonal plasma cell expression of cyclin D1 in systemic light-chain amyloidosis. Clin Lymphoma Myeloma Leuk. 2012;12:49–58.PubMedGoogle Scholar
  118. 118.
    Zhou P, et al. CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy. Blood. 2008;111:3403–6.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Deshmukh M, Elderfield K, Rahemtulla A, Naresh KN. Immunophenotype of neoplastic plasma cells in AL amyloidosis. J Clin Pathol. 2009;62:724–30.PubMedGoogle Scholar
  120. 120.
    Kumar S, Kimlinger TK, Lust JA, Donovan K, Witzig TE. Expression of CD52 on plasma cells in plasma cell proliferative disorders. Blood. 2003;102:1075–7.PubMedGoogle Scholar
  121. 121.
    Kyle RA, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–9.PubMedGoogle Scholar
  122. 122.
    Madan S, et al. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc. 2010;85:232–8.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Perfetti V, et al. Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood. 2002;100:948–53.PubMedGoogle Scholar
  124. 124.
    Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera GA. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood. 2001;98:714–20.PubMedGoogle Scholar
  125. 125.
    Abraham RS, et al. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood. 2003;101:3801–8.PubMedGoogle Scholar
  126. 126.
    Bellavia D, et al. Utility of Doppler myocardial imaging, cardiac biomarkers, and clonal immunoglobulin genes to assess left ventricular performance and stratify risk following peripheral blood stem cell transplantation in patients with systemic light chain amyloidosis (Al). J Am Soc Echocardiogr. 2011;24:444–54.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Perfetti V, et al. Evidence that amyloidogenic light chains undergo antigen-driven selection. Blood. 1998;91:2948–54.PubMedGoogle Scholar
  128. 128.
    Abraham RS, et al. Analysis of somatic hypermutation and antigenic selection in the clonal B cell in immunoglobulin light chain amyloidosis (AL). J Clin Immunol. 2004;24:340–53.PubMedGoogle Scholar
  129. 129.
    Abraham RS, et al. Novel analysis of clonal diversification in blood B cell and bone marrow plasma cell clones in immunoglobulin light chain amyloidosis. J Clin Immunol. 2007;27:69–87.PubMedGoogle Scholar
  130. 130.
    Hurle MR, Helms LR, Li L, Chan W, Wetzel R. A role for destabilizing amino acid replacements in light-chain amyloidosis. Proc Natl Acad Sci USA. 1994;91:5446–50.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Helms LR, Wetzel R. Specificity of abnormal assembly in immunoglobulin light chain deposition disease and amyloidosis. J Mol Biol. 1996;257:77–86.PubMedGoogle Scholar
  132. 132.
    Bellotti V, Merlini G. Toward understanding the molecular pathogenesis of monoclonal immunoglobulin light-chain deposition. Nephrol Dial Transplant. 1996;11:1708–11.PubMedGoogle Scholar
  133. 133.
    Raffen R, et al. Physicochemical consequences of amino acid variations that contribute to fibril formation by immunoglobulin light chains. Protein Sci. 1999;8:509–17.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Myatt EA, et al. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci USA. 1994;91:3034–8.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Wall J, Murphy CL, Solomon A. In vitro immunoglobulin light chain fibrillogenesis. Methods Enzymol. 1999;309:204–17.PubMedGoogle Scholar
  136. 136.
    Ramirez-Alvarado M, Merkel JS, Regan L. A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro. Proc Natl Acad Sci USA. 2000;97:8979–84.PubMedCentralPubMedGoogle Scholar
  137. 137.
    Wall JS, et al. Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vlambda6 proteins. J Mol Recognit. 2004;17:323–31.PubMedGoogle Scholar
  138. 138.
    Baden EM, Randles EG, Aboagye AK, Thompson JR, Ramirez-Alvarado M. Structural insights into the role of mutations in amyloidogenesis. J Biol Chem. 2008;283:30950–6.PubMedCentralPubMedGoogle Scholar
  139. 139.
    Schormann N, Murrell JR, Liepnieks JJ, Benson MD. Tertiary structure of an amyloid immunoglobulin light chain protein: a proposed model for amyloid fibril formation. Proc Natl Acad Sci USA. 1995;92:9490–4.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Pokkuluri PR, Solomon A, Weiss DT, Stevens FJ, Schiffer M. Tertiary structure of human lambda 6 light chains. Amyloid. 1999;6:165–71.PubMedGoogle Scholar
  141. 141.
    Randles EG, Thompson JR, Martin DJ, Ramirez-Alvarado M. Structural alterations within native amyloidogenic immunoglobulin light chains. J Mol Biol. 2009;389:199–210.PubMedCentralPubMedGoogle Scholar
  142. 142.
    Poshusta TL, et al. Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis. PLoS One. 2009;4:e5169.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Bellotti V, Mangione P, Merlini G. Review: immunoglobulin light chain amyloidosis–the archetype of structural and pathogenic variability. J Struct Biol. 2000;130:280–9.PubMedGoogle Scholar
  144. 144.
    Sletten K, Natvig JB, Husby G, Juul J. The complete amino acid sequence of a prototype immunoglobulin-lambda light-chain-type amyloid-fibril protein AR. Biochem J. 1981;195:561–72.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Omtvedt LA, et al. Glycosylation of immunoglobulin light chains associated with amyloidosis. Amyloid. 2000;7:227–44.PubMedGoogle Scholar
  146. 146.
    Connors LH, et al. Heterogeneity in primary structure, post-translational modifications, and germline gene usage of nine full-length amyloidogenic kappa1 immunoglobulin light chains. Biochemistry. 2007;46:14259–71.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Lim A, Wally J, Walsh MT, Skinner M, Costello CE. Identification and location of a cysteinyl posttranslational modification in an amyloidogenic kappa1 light chain protein by electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry. Anal Biochem. 2001;295:45–56.PubMedGoogle Scholar
  148. 148.
    Lavatelli F, et al. A novel approach for the purification and proteomic analysis of pathogenic immunoglobulin free light chains from serum. Biochim Biophys Acta. 2011;1814:409–19.PubMedGoogle Scholar
  149. 149.
    Lavatelli F, et al. Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Mol Cell Proteomics. 2008;7:1570–83.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Solomon A, et al. Light chain-associated amyloid deposits comprised of a novel kappa constant domain. Proc Natl Acad Sci USA. 1998;95:9547–51.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Klimtchuk ES, et al. The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain. Biochemistry. 2010;49:9848–57.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Brambilla F, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood. 2012;119:1844–7.PubMedGoogle Scholar
  153. 153.
    Vrana JA, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957–9.PubMedGoogle Scholar
  154. 154.
    Vrana JA, et al. Clinical diagnosis and typing of systemic amyloidosis in subcutaneous fat aspirates by mass spectrometry-based proteomics. Haematologica. 2014;99:1239–47.PubMedCentralPubMedGoogle Scholar
  155. 155.
    Grogg KL, Aubry MC, Vrana JA, Theis JD, Dogan A. Nodular pulmonary amyloidosis is characterized by localized immunoglobulin deposition and is frequently associated with an indolent B-cell lymphoproliferative disorder. Am J Surg Pathol. 2013;37:406–12.PubMedGoogle Scholar
  156. 156.
    Nasr SH, et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int. 2013;83:463–70.PubMedGoogle Scholar
  157. 157.
    Picken MM. Non-light-chain immunoglobulin amyloidosis: time to expand or refine the spectrum to include light + heavy chain amyloidosis? Kidney Int. 2013;83:353–6.PubMedGoogle Scholar
  158. 158.
    Reixach N, Deechongkit S, Jiang X, Kelly JW, Buxbaum JN. Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci USA. 2004;101:2817–22.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Diomede L, et al. A caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis. Blood. 2014;123:3543–52.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Mishra S, et al. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol. 2013;305:H95–103.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Comenzo RL, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood. 1996;88:2801–6.PubMedGoogle Scholar
  162. 162.
    Dember LM, et al. Effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on al amyloidosis-associated renal disease. Ann Intern Med. 2001;134:746–53.PubMedGoogle Scholar
  163. 163.
    Palladini G, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood. 2006;107:3854–8.PubMedGoogle Scholar
  164. 164.
    Trinkaus-Randall V, et al. Cellular response of cardiac fibroblasts to amyloidogenic light chains. Am J Pathol. 2005;166:197–208.PubMedCentralPubMedGoogle Scholar
  165. 165.
    Monis GF, et al. Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts. Am J Pathol. 2006;169:1939–52.PubMedGoogle Scholar
  166. 166.
    Teng J, et al. Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Lab Invest. 2004;84:440–51.PubMedGoogle Scholar
  167. 167.
    Keeling J, Teng J, Herrera GA. AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells. Lab Invest. 2004;84:1322–38.PubMedGoogle Scholar
  168. 168.
    Prokaeva T, et al. Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival. Arthritis Rheum. 2007;56:3858–68.PubMedGoogle Scholar
  169. 169.
    Perfetti V, et al. The repertoire of lambda light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44. Blood. 2012;119:144–50.PubMedGoogle Scholar
  170. 170.
    Prokaeva T, Spencer B, et al. Contribution of light chain variable region genes to organ tropism and survival in AL amyloidosis. Amyloid. 2010;17:62. Abstract OP-046.Google Scholar
  171. 171.
    Enqvist S, Sletten K, Stevens FJ, Hellman U, Westermark P. Germ line origin and somatic mutations determine the target tissues in systemic AL-amyloidosis. PLoS One. 2007;2:e981.PubMedCentralPubMedGoogle Scholar
  172. 172.
    Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909.PubMedGoogle Scholar
  173. 173.
    Cowan AJ, et al. Macroglossia—not always AL amyloidosis. Amyloid. 2011;18:83–6.PubMedGoogle Scholar
  174. 174.
    Merlini G, Palladini G. Differential diagnosis of monoclonal gammopathy of undetermined significance. Hematol Am Soc Hematol Educ Program. 2012;2012:595–603.Google Scholar
  175. 175.
    Gertz MA, Lacy MQ, Dispenzieri A. Immunoglobulin light chain amyloidosis and the kidney. Kidney Int. 2002;61:1–9.PubMedGoogle Scholar
  176. 176.
    Gertz MA, et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol Dial Transplant. 2009;24:3132–7.PubMedGoogle Scholar
  177. 177.
    Bergesio F, et al. Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome. Nephrol Dial Transplant. 2008;23:941–51.PubMedGoogle Scholar
  178. 178.
    Palladini G, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124:2325–32.Google Scholar
  179. 179.
    Leung N, et al. Severity of baseline proteinuria predicts renal response in immunoglobulin light chain-associated amyloidosis after autologous stem cell transplantation. Clin J Am Soc Nephrol. 2007;2:440–4.PubMedGoogle Scholar
  180. 180.
    Leung N, et al. Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis. Am J Kidney Dis. 2005;46:270–7.PubMedGoogle Scholar
  181. 181.
    Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047–60.PubMedGoogle Scholar
  182. 182.
    Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97:75–84.PubMedGoogle Scholar
  183. 183.
    Maceira AM, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111:186–93.PubMedGoogle Scholar
  184. 184.
    Bellavia D, et al. Independent predictors of survival in primary systemic (Al) amyloidosis, including cardiac biomarkers and left ventricular strain imaging: an observational cohort study. J Am Soc Echocardiogr. 2010;23:643–52.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain amyloidosis. JACC Cardiovasc Imaging. 2010;3:333–42.PubMedGoogle Scholar
  186. 186.
    Buss SJ, et al. Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers. J Am Coll Cardiol. 2012;60:1067–76.PubMedGoogle Scholar
  187. 187.
    Quarta CC, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129:1840–9.PubMedGoogle Scholar
  188. 188.
    Merlini G, Narula J, Arbustini E. Molecular imaging of misfolded protein pathology for early clues to involvement of the heart. Eur J Nucl Med Mol Imaging. 2014;41:1649–51.PubMedGoogle Scholar
  189. 189.
    Merlini G, Palladini G. Amyloidosis: is a cure possible? Ann Oncol. 2008;19 Suppl 4:iv63–6.PubMedGoogle Scholar
  190. 190.
    Palladini G, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107:2440–5.PubMedGoogle Scholar
  191. 191.
    Dispenzieri A, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet. 2003;361:1787–9.PubMedGoogle Scholar
  192. 192.
    Palladini G, et al. The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood. 2010;116:3426–30.Google Scholar
  193. 193.
    Dispenzieri A, et al. High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis. Heart. 2014;100:383–8.PubMedGoogle Scholar
  194. 194.
    Dispenzieri A, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22:3751–7.PubMedGoogle Scholar
  195. 195.
    Palladini G, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;30:4541–9.PubMedGoogle Scholar
  196. 196.
    Kumar S, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30:989–95.PubMedCentralPubMedGoogle Scholar
  197. 197.
    Palladini G, et al. Holter monitoring in AL amyloidosis: prognostic implications. Pacing Clin Electrophysiol. 2001;24:1228–33.PubMedGoogle Scholar
  198. 198.
    Perlini S, et al. Prognostic value of fragmented QRS in cardiac AL amyloidosis. Int J Cardiol. 2013;167:2156–61.PubMedGoogle Scholar
  199. 199.
    Boldrini M, et al. Prevalence and prognostic value of conduction disturbances at the time of diagnosis of cardiac AL amyloidosis. Ann Noninvasive Electrocardiol. 2013;18:327–35.PubMedGoogle Scholar
  200. 200.
    Wechalekar AD, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121:3420–7.PubMedGoogle Scholar
  201. 201.
    Russo P, et al. Liver involvement as the hallmark of aggressive disease in light chain amyloidosis: distinctive clinical features and role of light chain type in 225 patients. Amyloid. 2011;18 Suppl 1:92–3.PubMedGoogle Scholar
  202. 202.
    Park MA, et al. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore). 2003;82:291–8.Google Scholar
  203. 203.
    Peters RA, et al. Primary amyloidosis and severe intrahepatic cholestatic jaundice. Gut. 1994;35:1322–5.PubMedCentralPubMedGoogle Scholar
  204. 204.
    Rubinow A, Koff RS, Cohen AS. Severe intrahepatic cholestasis in primary amyloidosis: a report of four cases and a review of the literature. Am J Med. 1978;64:937–46.PubMedGoogle Scholar
  205. 205.
    Ooi LL, Lynch SV, Graham DA, Strong RW. Spontaneous liver rupture in amyloidosis. Surgery. 1996;120:117–9.PubMedGoogle Scholar
  206. 206.
    Kacem C, Helali K, Puisieux F. Recurrent spontaneous hepatic rupture in primary hepatic amyloidosis. Ann Intern Med. 1998;129:339.PubMedGoogle Scholar
  207. 207.
    Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378:86–97.Google Scholar
  208. 208.
    Renzulli P, Schoepfer A, Mueller E, Candinas D. Atraumatic splenic rupture in amyloidosis. Amyloid. 2009;16:47–53.PubMedGoogle Scholar
  209. 209.
    Matsuda M, et al. Peripheral nerve involvement in primary systemic AL amyloidosis: a clinical and electrophysiological study. Eur J Neurol. 2011;18:604–10.PubMedGoogle Scholar
  210. 210.
    Caccialanza R, et al. Nutritional status of outpatients with systemic immunoglobulin light-chain amyloidosis 1. Am J Clin Nutr. 2006;83:350–4.PubMedGoogle Scholar
  211. 211.
    Caccialanza R, et al. Malnutrition at diagnosis predicts mortality in patients with systemic immunoglobulin light-chain amyloidosis independently of cardiac stage and response to treatment. JPEN J Parenter Enteral Nutr. 2014;38:891–4.PubMedGoogle Scholar
  212. 212.
    Sattianayagam PT, et al. A prospective study of nutritional status in immunoglobulin light chain amyloidosis. Haematologica. 2013;98:136–40.PubMedCentralPubMedGoogle Scholar
  213. 213.
    Gertz MA, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79:319–28.PubMedGoogle Scholar
  214. 214.
    Gertz MA, Merlini G. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion. Amyloid. 2010;17:48–9.Google Scholar
  215. 215.
    Merlini G, et al. The Pavia approach to clinical protein analysis. Clin Chem Lab Med. 2001;39:1025–8.PubMedGoogle Scholar
  216. 216.
    Palladini G, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem. 2009;55:499–504.PubMedGoogle Scholar
  217. 217.
    Anesi E, et al. Therapeutic advances demand accurate typing of amyloid deposits. Am J Med. 2001;111:243–4.PubMedGoogle Scholar
  218. 218.
    Lachmann HJ, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346:1786–91.PubMedGoogle Scholar
  219. 219.
    Palladini G, Obici L, Merlini G. Hereditary amyloidosis. N Engl J Med. 2002;347:1206–7. author reply 1206–7.PubMedGoogle Scholar
  220. 220.
    Kyle RA, Rajkumar SV. Epidemiology of the plasma-cell disorders. Best Pract Res Clin Haematol. 2007;20:637–64.PubMedGoogle Scholar
  221. 221.
    Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J. Seeking confidence in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. Blood. 2006;107:3489–91.PubMedGoogle Scholar
  222. 222.
    Wechalekar AD, Offer M, Gillmore JD, Hawkins PN, Lachmann HJ. Cardiac amyloidosis, a monoclonal gammopathy and a potentially misleading mutation. Nat Clin Pract Cardiovasc Med. 2009;6:128–33.PubMedGoogle Scholar
  223. 223.
    Kyle RA, et al. Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood. 1999;93:1062–6.PubMedGoogle Scholar
  224. 224.
    Palladini G, et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007;110:787–8.PubMedGoogle Scholar
  225. 225.
    Merlini G, et al. Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci USA. 1995;92:2959–63.PubMedCentralPubMedGoogle Scholar
  226. 226.
    Gianni L, Bellotti V, Gianni AM, Merlini G. New drug therapy of amyloidoses: resorption of AL-type deposits with 4′-iodo-4′-deoxydoxorubicin. Blood. 1995;86:855–61.PubMedGoogle Scholar
  227. 227.
    Gertz MA, et al. A multicenter phase II trial of 4′-iodo-4′deoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid. 2002;9:24–30.PubMedGoogle Scholar
  228. 228.
    Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating physicians. Blood. 2013;121:5124–30.PubMedGoogle Scholar
  229. 229.
    Ohno S, et al. The antisense approach in amyloid light chain amyloidosis: identification of monoclonal Ig and inhibition of its production by antisense oligonucleotides in in vitro and in vivo models. J Immunol. 2002;169:4039–45.PubMedGoogle Scholar
  230. 230.
    Phipps JE, et al. Inhibition of pathologic immunoglobulin-free light chain production by small interfering RNA molecules. Exp Hematol. 2010;38:1006–13.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Hovey BM, et al. Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Ther. 2011;18:1150–6.Google Scholar
  232. 232.
    Zhou P, Ma X, Iyer L, Chaulagain C, Comenzo RL. One siRNA pool targeting the lambda constant region stops lambda light-chain production and causes terminal endoplasmic reticulum stress. Blood. 2014;123:3440–51.PubMedGoogle Scholar
  233. 233.
    Cooley CB, et al. Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proc Natl Acad Sci USA. 2014;111:13046–51.Google Scholar
  234. 234.
    Hrncic R, et al. Antibody-mediated resolution of light chain-associated amyloid deposits. Am J Pathol. 2000;157:1239–46.PubMedCentralPubMedGoogle Scholar
  235. 235.
    Solomon A, Weiss DT, Wall JS. Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies. Cancer Biother Radiopharm. 2003;18:853–60.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Mario Nuvolone
    • 1
    • 2
  • Giovanni Palladini
    • 3
  • Giampaolo Merlini
    • 3
    Email author
  1. 1.Institute of NeuropathologyUniversity Hospital of ZurichZurichSwitzerland
  2. 2.Amyloidosis Research and Treatment Center, Foundation Scientific Institute Policlinico San Matteo, Department of Molecular MedicineUniversity of PaviaPaviaItaly
  3. 3.Department of Molecular Medicine and Amyloidosis Research and Treatment CenterFoundation IRCCS Policlinico San Matteo and University of PaviaPaviaItaly

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