Two distinct mechanisms of neuropathy in immunoglobulin light chain (AL) amyloidosis

2021 ◽  
pp. 117305
Author(s):  
Haruki Koike ◽  
Naohiro Mouri ◽  
Yuki Fukami ◽  
Masahiro Iijima ◽  
Koji Matsuo ◽  
...  
Keyword(s):  
Light Chain ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain

scholarly journals Hereditary systemic immunoglobulin light-chain amyloidosis

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3281-3286 ◽  
Author(s):  
Merrill D. Benson ◽  
Juris J. Liepnieks ◽  
Barbara Kluve-Beckerman
Keyword(s):  
Light Chain ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Immunoglobulin Light Chain ◽  
Region Gene ◽  
Dna Analyses ◽  
Key Points ◽  
Constant Region Gene ◽  
Immunoglobulin Light Chain Amyloidosis

Key Points Protein and DNA analyses reveal that mutation in the immunoglobulin κ light-chain constant region gene may cause hereditary amyloidosis. Sequencing of immunoglobulin light-chain constant region genes is indicated for patients with AL amyloidosis and no evidence of a plasma cell dyscrasia.

Autologous Stem Cell Transplantation In Immunoglobulin Light Chain Amyloidosis With Factor X Deficien

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2151-2151
Author(s):  
Stefan F Cordes ◽  
Morie A Gertz ◽  
Francis K Buadi ◽  
Yi Lin ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Stem Cell ◽  
Light Chain ◽  
Research Funding ◽  
Splenic Rupture ◽  
Al Amyloidosis ◽  
Factor X ◽  
Immunoglobulin Light Chain ◽  
Hemorrhagic Complications ◽  
Transient Improvement

Abstract Background Acquired factor X (FX) deficiency is associated with immunoglobulin light chain (AL) amyloidosis and may be accompanied by hemorrhage. There are limited data on the effects of autologous stem cell transplant (ASCT) on FX deficiency. We reviewed hemorrhagic complications and the effect of high dose melphalan (HDM) and ASCT on FX levels in AL amyloidosis patients with FX deficiency. Methods We conducted a retrospective chart review of patients with AL amyloid with FX levels below 60%, not on chronic anti-coagulation who underwent HDM/ASCT at the Mayo Clinic, Rochester, MN between 1995 and 2011. Results Forty-one of 358 patients (11%) met our study criteria. Median pre-ASCT FX was 45% (range: 2%, 59%). The most common bleeding complication was central line associated n=15 (37%) followed by gastrointestinal n=10 (24%) and genitourinary n=9 (22%). The most frequent and severe bleeding complications occurred in patients with FX levels less than 10%. Four patients required emergent splenectomy owing to splenic rupture; one of these patients died from hemorrhagic shock. Periprocedural prophylaxis included activated recombinant Factor VII (rFVIIa) infusions, fresh frozen plasma (FFP) infusions and platelet transfusions. rFVIIa was efficacious in controlling bleeding during splenectomy (n=5) and, in conjunction with arterial embolization, for retroperitoneal bleed (n=1). Elective splenectomy for FX deficiency (n=1) resulted in only transient improvement in FX level. No relationship between the degree of pre-ASCT FX deficiency and other laboratory values (alkaline phosphatase, AST, total bilirubin, serum albumin, total serum protein, serum creatinine, total urine protein, beta2 microglobulin, troponin T) was found. Post-ASCT FX levels were determined in seventeen patients. In four of these patients, post-ASCT FX levels were determined in the acute/subacute phase of ASCT before steady state FX levels could be achieved; the median change in FX for these patients was -6.5% (range: -19%, 3%). In the remaining thirteen patients, who were between 99 and 1920 days from ASCT, FX improved by median 26% (range: -15%, 92%). Overall post-ASCT FX increased in twelve of thirteen (92%) patients. The improvement in FX correlated with improvement in the degree of proteinuria (p = 0.04) and showed a trend towards significant correlation with improvement in serum alkaline phosphatase (p = 0.06). Conclusions Hemorrhagic complications are most frequent and severe for FX levels below 10%. rFVIIa infusions, FFP and platelets were effective prophylactic agents. In the single patient who underwent elective splenectomy, a transient improvement in FX level was seen. Splenectomy was otherwise reserved for patients with splenic rupture/hematoma. Post-ASCT FX levels increased in twelve (92.3%) of the remaining thirteen patients; five of the patients (38.5%) were no longer FX deficient after ASCT. The degree of improvement in FX levels was correlated with improvement in markers of renal or hepatic involvement by amyloid. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Immunoglobulin light chain, Blimp‐1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis

2011 ◽  
Vol 90 (5) ◽  
pp. 528-539 ◽  
Author(s):  
Amanda Flies ◽  
Tahamtan Ahmadi ◽  
Ashley J Parks ◽  
Tatiana Prokaeva ◽  
Liangping Weng ◽  
...  
Keyword(s):  
Light Chain ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Cytochrome P4501b1

Immunoglobulin Light Chain Amyloidosis Presenting as Inferior Vena Cava Thrombosis

2021 ◽  
pp. 000313482110508
Author(s):  
Anna Axentiev ◽  
Marina Rozik ◽  
Eliza Slama ◽  
Viney Setya
Keyword(s):  
Inferior Vena Cava ◽  
Rare Disease ◽  
Light Chain ◽  
Inferior Vena ◽  
Vena Cava ◽  
Abdominal Fat ◽  
Al Amyloidosis ◽  
Fat Pad ◽  
Renal Veins ◽  
Immunoglobulin Light Chain

Immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by the deposition of misfolded extracellular proteins within various body tissues resulting in dysfunction of the cardiac, renal, gastrointestinal, hematologic, and nervous systems, among others. Systemic AL amyloidosis often presents with a constellation of vague symptoms such as fatigue, dyspnea, and abdominal pain. Untreated AL amyloidosis with cardiac involvement is rapidly fatal with a median survival of 6 months. In this report, we will highlight the case of a 43-year-old female who presented with generalized abdominal symptoms and fatigue. She was found to have extensive inferior vena cava (IVC) thrombosis extending into the renal veins bilaterally in the setting of nephrotic range proteinuria, new onset arrhythmia, diastolic heart failure, gastrointestinal, and autonomic dysfunction. She received systemic thrombolytic therapy for the IVC and renal vein thrombosis. The multiorgan involvement led us to consider the possibility of amyloidosis. Abdominal fat pad biopsy was performed as part of the diagnostic effort. The abdominal fat pad biopsy did not reveal AL amyloidosis. Ultimately, the diagnosis of systemic AL amyloidosis was made on the basis of pathology from luminal biopsies obtained during outpatient esophagogastroduodenoscopy that was performed days prior to her admission. Unique to our case is the patient presentation with extensive thrombotic disease of the IVC and renal veins. It is important to understand the disease process, presenting signs and symptoms as well as diagnostic essentials based on current literature in order to minimize the morbidity and mortality of this rare disease.

Immunoglobulin Light Chain Gene Constant Region Is An Invariable Part of Amyloid Deposits in AL Amyloidosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3128-3128
Author(s):  
Jason D. Theis ◽  
Julie A. Vrana ◽  
Jeffrey D. Gamez ◽  
Angela Dispenzieri ◽  
Stephen R. Zeldenrust ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Proteomic Analysis ◽  
Laser Microdissection ◽  
Variable Region ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Immunoglobulin Light Chain ◽  
Amyloid Deposits ◽  
Region I

Abstract Background: Amyloidosis caused by immunoglobulin light chain (IGLC) deposition, so-called AL-type or primary amyloidosis, is the most common type of amyloidosis. It has been long believed that IGLC variable regions form the core of the AL-type amyloid deposits and peptides derived from IGLC constant region peptides are only occasionally integrated into this core. For this reason, the scientific effort to identify thge risk factors for development of AL amyloidosis and the biochemical characteristics amyloid deposits has focused on IGLC variable region derived proteins. To understand the peptide constituents of AL amyloidosis better, we undertook a comprehensive study of AL amyloidosis using a novel mass spectrometry based proteomic analysis approach. Methods: Paraffin embedded tissue from 100 cases of AL amyloidosis was studied. In each case amyloid type was previously established by clinical and pathological examination. Congo red stained paraffin sections were prepared and amyloid deposits were microdissected by laser microdissection microscopy. The microdissected tissue fragments were processed and trypsin digested into peptides. The peptides were analyzed by nano-flow liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS). The resulting LC-MS/MS data were correlated to theoretical fragmentation patterns of tryptic peptide sequences from the Swissprot database using Scaffold (Mascot, Sequest, and X!Tandem search algorithms). Peptide identifications were accepted if they could be established at greater than 90.0% probability and protein identifications were accepted if they could be established at greater than 90.0% probability and contain at least 2 identified spectra. The identified proteins were subsequently examined for the presence or absence of amyloid related peptides. Results and Discussion: LC-MS/MS gave peptide profiles consistent with AL amyloidosis in each case. The analysis showed IGLC-lambda deposition in 66 cases and IGLC-kappa deposition in 34 of cases. In each case, LC MS/MS confirmed the previous clinicopathological diagnosis. Interestingly peptides representing IGLC constant region were present in each case. Using this LC-MS/MS methodology, theoretically it is possible to cover 78% of the IGLC-lambda and 87% IGLC-kappa constant regions. In our samples, the average coverage of the IGLC-lambda and IGLC-kappa constant regions were 40% (range 14–78%)and 55% (range 16–87%) respectively. Additionally, the distribution of the peptides suggested that in the majority of the cases whole of the IGLC constant region was deposited. LC MS/MS also identified IGLC-lambda variable region peptides in 37 of 66 cases and IGLC-kappa variable region peptides in 29 of 34 cases studied. The variable region coverage was more restricted and the peptides identified were frequently within the framework segments. It is likely that the peptides derived from CDR segments were present but not detected by the methodology as somatic hypermutation randomly alters the amino acid sequence in the CDR segments and such new sequences are not available in public databases used by algorithms for peptide identification. In the cases with the IGLC variable region hits, it was also possible to assign variable region family usage. IGLC-lambda cases frequently used IGLC-lambda variable region I, II and III families whereas, in IGLC-kappa cases, IGLC-kappa variable region I and III families dominated. Conclusions: AL amyloidosis can be accurately diagnosed using laser microdissection and LC-MS/MS based proteomic analysis in routine clinical specimens. AL amyloidosis invariably contains IGLC constant region peptides and, frequently, the whole of the constant region is deposited. This finding suggests that studies on molecular pathogenesis of amyloidosis should not only consider the IGLC-variable region but also the constant region. It is possible to identify IGLC variable region family usage in AL amyloidosis using LC MS/MS based proteomic analysis. In the clinical setting, this information may be helpful in predicting organ distribution and clinical outcome.

Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5601-5601
Author(s):  
Andrew J. Cowan ◽  
David G. Coffey ◽  
Teresa S. Hyun ◽  
Pamela S. Becker ◽  
Damian J. Green ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasma Cell ◽  
Light Chain ◽  
Congo Red ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Immunoglobulin Light Chain ◽  
Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

scholarly journals Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Paolo Swuec ◽  
Francesca Lavatelli ◽  
Masayoshi Tasaki ◽  
Cristina Paissoni ◽  
Paola Rognoni ◽  
...  
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Cardiac Amyloid
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