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

Koike, Haruki; Mouri, Naohiro; Fukami, Yasuyuki; Iijima, Masahiro; Matsuo, Koji; Yagi, Nobuyasu; Saito, Asami; Nakamura, Hajime; Takahashi, Keita; Nakae, Yoshiharu; Okada, Yohei; Tanaka, Fumiaki; Sobue, Gen; Katsuno, Masahisa

doi:10.1016/j.jns.2020.117305

Cited by 8 publications

(12 citation statements)

References 31 publications

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“…Electron microscopy examination of nerve biopsy specimens from ATTRv amyloidosis patients demonstrated atrophy of Schwann cells opposed to amyloid fibril aggregates and loss of axons associated with these Schwann cells ( Figure 1 and Figure 2 ) [ 26 , 27 , 28 , 29 ]. The atrophy of Schwann cells near amyloid fibril masses has also been reported in specimens from AL amyloidosis patients ( Figure 3 ) [ 21 , 30 , 31 ]. Similar findings have also been reported in the hearts of these patients [ 4 ].…”

Section: Ultrastructure Of Tissue Damagementioning

confidence: 52%

“…According to studies of autopsy specimens obtained from patients with ATTRv amyloidosis, the extent of the degeneration of neurons in the sensory and autonomic ganglia is positively correlated with the amount of amyloid, suggesting that neurodegeneration occurs as a result of amyloid deposition [ 4 , 25 ]. Electron microscopy examination of nerve biopsy specimens from ATTRv amyloidosis and AL amyloidosis patients demonstrated atrophy of the Schwann cells and loss of associated axons near amyloid fibril aggregates [ 21 , 26 , 27 , 28 , 29 , 30 , 31 ]. Similar findings also were reported in cardiac autopsy specimens from ATTR amyloidosis patients [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Well-known textbook features of polyneuropathies resulting from ATTR and AL amyloidoses are progressive symmetrical sensory impairments collectively known as dissociated sensory loss, which is characterized by a loss of nociception and thermal sensation, as well as autonomic dysfunction such as diarrhea/constipation, orthostatic intolerance, dysuria, and erectile dysfunction, due to the loss of small-diameter nerve fibers [ 4 , 20 , 21 ]. These characteristics are particularly conspicuous during the early phase of neuropathy, and motor dysfunction is considered a later manifestation [ 11 ].…”

Section: What Are Attr Amyloidosis and Al Amyloidosis?mentioning

confidence: 99%

“…Another important finding regarding tissue damage resulting from amyloid deposition is the obscuration of the basement and cytoplasmic membranes near amyloid fibrils. Electron microscope studies of nerve biopsy specimens have demonstrated that the membranes of Schwann cells become obscure when they are near amyloid fibrils in both ATTR amyloidosis and AL amyloidosis patients ( Figure 2 and Figure 3 ) [ 21 , 28 , 29 , 30 , 31 ]. The contours of Schwann cells may completely disappear when Schwan cells are surrounded by amyloid fibrils, suggesting that the destruction of these membranes occurs as a result of amyloid fibril formation [ 29 ].…”

Section: Ultrastructure Of Tissue Damagementioning

confidence: 99%

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The Ultrastructure of Tissue Damage by Amyloid Fibrils

Koike

Katsuno

2021

Molecules

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Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: 1) reducing or preventing the production of causative proteins; 2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or 3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

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Section: Ultrastructure Of Tissue Damagementioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: What Are Attr Amyloidosis and Al Amyloidosis?mentioning

confidence: 99%

Section: Ultrastructure Of Tissue Damagementioning

confidence: 99%

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The Ultrastructure of Tissue Damage by Amyloid Fibrils

Koike

Katsuno

2021

Molecules

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“…Immunohistochemistry of amyloid deposits is important to distinguish TTR from other proteins that may cause amyloidosis, particularly immunoglobulin light chain associated with light chain (AL) amyloidosis [55]. Mass spectrometry is also useful to determine the specific amyloid-forming protein in tissue samples [56][57][58].…”

Section: Biopsymentioning

confidence: 99%

Multidisciplinary Approaches for Transthyretin Amyloidosis

et al. 2021

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Amyloid Neuropathy: From Pathophysiology to Treatment in Light‐Chain Amyloidosis and Hereditary Transthyretin Amyloidosis

Chompoopong,

Mauermann,

Siddiqi

et al. 2024

Annals of Neurology

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Amyloid neuropathy is caused by deposition of insoluble β‐pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light‐chain amyloidosis, a clonal non‐proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood–nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length‐dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early‐onset Val30Met ATTRv, whereas other ATTRv and light‐chain amyloidosis often present with large‐ and small‐fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone‐avid radiotracer cardiac imaging. Treatment of light‐chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5‐year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024

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

Cited by 8 publications

References 31 publications

The Ultrastructure of Tissue Damage by Amyloid Fibrils

The Ultrastructure of Tissue Damage by Amyloid Fibrils

Multidisciplinary Approaches for Transthyretin Amyloidosis

Amyloid Neuropathy: From Pathophysiology to Treatment in Light‐Chain Amyloidosis and Hereditary Transthyretin Amyloidosis

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