Mass spectrometry analysis for amyloidosis typing - is the future bright for its clinical implementation?

Hill, Michelle M.; Mollee, Peter

doi:10.1080/14789450.2017.1322905

Cited by 3 publications

(4 citation statements)

References 15 publications

(19 reference statements)

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“…MS can reveal new amyloid-forming proteins, for example, identification of leukocyte cell-derived chemotaxin-2 (LECT2) as a frequent cause of liver amyloidosis [ 24 ]. With significant technical advantages over immunohistochemistry, MS has been proposed as the new gold standard for amyloid typing based on promising reports of diagnostic precision [ 25 ]. In a study by Vrana et al [ 26 ], the MS-based proteomic analysis of subcutaneous fat aspiration samples provided unprecedented sensitivity and specificity for the diagnosis and typing of amyloidosis, including rare hereditary and iatrogenic variants.…”

Section: Discussionmentioning

confidence: 99%

“…Maria M. Picken has discussed in her article some limitations of MS: (a) low-abundance proteins/peptides might be difficult to detect because their signals might be overshadowed by data from more abundant proteins; (b) the protein fragments obtained after enzymatic digestion must be of a size suitable for MS [ 27 ]. As protein identification by MS relies on database matching, mutated peptides will not be detected using this strategy [ 25 ]. Sharing from our experience, inadequate samples might be another limitation.…”

Section: Discussionmentioning

confidence: 99%

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Do Not Ignore Those Raccoon Eyes; They May Indicate Lethal AL Amyloidosis

2022

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Light chain (AL) amyloidosis is a lethal form of systemic amyloidosis that arises from the clonal expansion of CD38+ plasma cells. Organ damage occurs when these plasma cells produce misfolded immunoglobulin light chains, which form amyloid fibrils and deposit in tissues. A minority of patients with AL amyloidosis show “raccoon eyes” caused by increased vascular fragility from accumulation of amyloid fibrils. Amyloidosis can be directly associated with bleeding diathesis due to factor X deficiency as factor X binds to amyloid fibrils primarily in the liver and spleen. A 65-year-old Caucasian male presented with random bruising in the upper chest and around the eyes for 1.5 years. Physical examination was unremarkable, except for neck bruising. Pertinent workup showed protein electrophoresis with a faint M spike, increased serum lambda light chains, a kappa to lambda ratio of 0.06, increased Bence-Jones proteins, reduced factor X activity, elevated NT-proBNP. The bone marrow biopsy was positive for Congo red stain for amyloid protein. Magnetic resonance imaging revealed diffuse enhancement of the right and left ventricle subendocardial late gadolinium, consistent with cardiac amyloidosis. The patient started systemic therapy with a regimen of daratumumab, cyclophosphamide, bortezomib, and dexamethasone. After one cycle of therapy, lambda light chains normalized with an improvement in bruising. Diagnostic delays for cardiac patients are concerning as the median survival rate among these patients, when not treated, is approximately 6 months after the onset of symptoms. Since timely treatment can prevent organ damage, clinicians should be aware of specific clinical signs such as raccoon eyes and the importance of systemic evaluation for a prompt diagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Do Not Ignore Those Raccoon Eyes; They May Indicate Lethal AL Amyloidosis

2022

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“…It is widely accepted that proteomics is becoming an invaluable tool for diagnosis of systemic amyloidosis [17] , [19] and represents a technique under rapid evolution in terms of pre-analytical treatment of samples, technological progress of spectrometers, and bioinformatics analysis of raw data. Our study mostly focuses on the possibility to get better results just intervening on the pre-analytical treatment of the tissue specimens.…”

Section: Discussionmentioning

confidence: 99%

Increasing the accuracy of proteomic typing by decellularisation of amyloid tissue biopsies

Mangione

Mazza

Gilbertson

et al. 2017

Journal of Proteomics

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Diagnosis and treatment of systemic amyloidosis depend on accurate identification of the specific amyloid fibril protein forming the tissue deposits. Confirmation of monoclonal immunoglobulin light chain amyloidosis (AL), requiring cytotoxic chemotherapy, and avoidance of such treatment in non-AL amyloidosis, are particularly important. Proteomic analysis characterises amyloid proteins directly. It complements immunohistochemical staining of amyloid to identify fibril proteins and gene sequencing to identify mutations in the fibril precursors. However, proteomics sometimes detects more than one potentially amyloidogenic protein, especially immunoglobulins and transthyretin which are abundant plasma proteins. Ambiguous results are most challenging in the elderly as both AL and transthyretin (ATTR) amyloidosis are usually present in this group. We have lately described a procedure for tissue decellularisation which retains the structure, integrity and composition of amyloid but removes proteins that are not integrated within the deposits. Here we show that use of this procedure before proteomic analysis eliminates ambiguity and improves diagnostic accuracy.SignificanceUnequivocal identification of the protein causing amyloidosis disease is crucial for correct diagnosis and treatment. As a proof of principle, we selected a number of cardiac and fat tissue biopsies from patients with various types of amyloidosis and show that a classical procedure of decellularisation enhances the specificity of the identification of the culprit protein reducing ambiguity and the risk of misdiagnosis.

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“…Interestingly, MS can even be used upfront as it detects subtle amyloid deposition in an earlier stage than Congo red staining 57. The MS diagnosis of amyloidosis is based on detection of serum amyloid P component, apolipoprotein E, vitronectin and perlecan since all of these proteins are linked to both AL and AA amyloidoses 56–59. Although mostly tissue extraction and liquid chromatography (LC)-based MS techniques have been used for analysis of amyloid,56 MALDI IMS might be very suitable as well.…”

Section: Matrix-assisted Laser Desorption/ionisation Imaging Mass Spementioning

confidence: 99%

Next-generation protein analysis in the pathology department

et al. 2019

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Traditionally, immunohistochemistry (IHC) is used by pathologists to localise specific proteins or peptides in tissue slides. In the era of personalised medicine, however, molecular tissue analysis becomes indispensable for correct diagnosis, prognosis and therapeutic decision, not only on the DNA or mRNA level but also on the protein level. Combining molecular information with imaging presents many advantages. Therefore, matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI IMS) is a promising technique to be added to the armamentarium of the pathologist. Here, we focus on the workflow, advantages and drawbacks of both MALDI IMS and IHC. We also briefly discuss a few other protein imaging modalities and give examples of applications.

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Mass spectrometry analysis for amyloidosis typing - is the future bright for its clinical implementation?

Cited by 3 publications

References 15 publications

Do Not Ignore Those Raccoon Eyes; They May Indicate Lethal AL Amyloidosis

Do Not Ignore Those Raccoon Eyes; They May Indicate Lethal AL Amyloidosis

Increasing the accuracy of proteomic typing by decellularisation of amyloid tissue biopsies

Next-generation protein analysis in the pathology department

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