LECT-2 Amyloidosis: What do we Know?

Abstract

Amyloidosis is a rare group of diseases characterized by abnormal folding of proteins and extracellular deposition of insoluble fibrils. It can be localized to one organ system or can have systemic involvement. The kidney is the most common organ to be involved in systemic amyloidosis often leading to renal failure and the nephrotic syndrome. The two most common types of renal amyloidosis are immunoglobulin light chain-derived amyloidosis (AL) and reactive amyloidosis (AA). A novel form of amyloidosis (ALECT2) derived from leukocyte chemotactic factor 2 (LECT-2) and primarily involving the kidneys was first described by Benson et al in 2008. The liver was subsequently identified as the second most common organ involved in ALECT2 amyloidosis. LECT-2 is a unique protein that can form amyloid deposits even in its unmutated form. Patients with ALECT2 present with minimal proteinuria in contrast to other forms of amyloidosis especially AL and AA. They may present with slightly elevated serum creatinine. Nephrotic syndrome and hematuria are rare. ALECT2 can be found in association with other types of amyloidosis as well as malignancies or autoimmune diseases. ALECT2 may be confused with amyloidosis associated with light and heavy chain monoclonal gammopathy if the immunofluorescence is positive with anti-light chain and anti-AA sera. The other organs involved are the duodenum, adrenal gland, spleen, prostate, gall bladder, pancreas, small bowel, parathyroid gland, heart, and pulmonary alveolar septa, but consistently uninvolved organs included brain and fibroadipose tissue. A renal biopsy along with characteristic features found on immunohistochemistry and mass spectrometry is diagnostic of ALECT2. ALECT2 should be suspected when all markers for AL and AA are negative. Proper diagnosis of ALECT2 can determine need for supportive care versus more aggressive interventions.

Spatial resolution of renal amyloid deposits through MALDI-MSI: a combined digital and molecular approach to monoclonal gammopathies

“…Furthermore, the study lacks additional confirmation of the abundance of proteins characterising renal amyloid plaques, which could be obtained using complementary tandem MS approaches. Future research should be directed towards characterising biopsies diagnosed with other common subtypes of amyloidosis and should therefore include leukocyte chemotactic factor 2 amyloidosis (ALECT2), which is rapidly emerging as the second most common type of amyloidosis after light-chain amyloidosis25 and transthyretin amylodiosis (ATTR), the incidence of which affects nearly 25% of adults >85 years at autopsy 26. In addition, the potential application of machine learning algorithms to MALDI-MSI27 could further enhance the proposed automated approach and potentially integrate it into the routine workflow of the pathologist in a streamlined manner.…”

Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core

“…ALECT2 has been found in high prevalence among patients of Mexican descent in the southwest United States, those of Punjabi descent, First Nations peoples in British Columbia, Egyptians, Chinese of Han ethnicity, and Native Americans 11 . There remains a need for diagnostic tools to distinguish ALECT2 from other renal amyloid diseases in patients and avoid misdiagnosis and improper treatment 12 . In contrast to some other systemic amyloid diseases, there are no available treatments for ALECT2 and no molecules that effectively target the amyloid state of its namesake, LECT2.…”

Yet Another Amyloidosis

“…It has a characteristic pattern of tissue deposition, occurring primarily as diffuse involvement of the renal cortex rather than of the medullary interstitium or the glomerulus. Hepatic involvement also exhibits a characteristic pattern of deposition in the periportal parenchyma and around the periphery of the portal triad and central venules 6…”

“…The proteins most acknowledged as causes of amyloidosis are immunoglobulin light chains, 3 serum amyloid protein A, 4 and transthyretin. 5 In the current issue of the Journal of Investigative Medicine, Mann and colleagues 6 present a review article discussing the clinical features, pathogenesis, and current understanding of an under-recognized but relatively frequent amyloidosis disorder caused by the deposition of leukocyte chemotactic factor 2 (LECT-2).…”

“…Hepatic involvement also exhibits a characteristic pattern of deposition in the periportal parenchyma and around the periphery of the portal triad and central venules. 6 It is reasonable to expect that ALECT-2 will become more widely recognized in the future. LECT-2 is a neutrophil chemotactic factor produced in the liver and is part of the inflammatory response to hepatic fat deposition.…”