Mass spectrometry analysis reveals non-mutated apolipoprotein A1 lumbosacral radiculoplexus amyloidoma

Abstract

Introduction: In rare instances, amyloidosis presents as a focal, macroscopic lesion involving peripheral neural tissues (amyloidoma). In all known reported cases, peripheral nerve amyloidomas have had immunoglobulin light-chain fibril composition and occurred in the context of paraproteinemia.

Methods: A 46-year-old man presented with progressive insidious-onset right lumbosacral radiculoplexus neuropathy without paraproteinemia. MRI-targeted fascicular nerve biopsy was performed on an enlarged sciatic nerve after earlier distal fibular nerve biopsy was nondiagnostic. Laser dissected mass spectroscopy of the discovered amyloid protein was performed after immunohistochemistry failed to identify the specific amyloid protein. Complete gene sequencing of apolipoprotein A1 (ApoA1) was performed.

Results: Only wild-type ApoA1 amyloid was found in the congophilic component in the nerve.

Conclusions: This case highlights the utility of MRI-guided fascicular nerve biopsy combined with laser-dissected mass spectrometric analysis. Importantly, the case expands the known causes of amyloidomas to include wild-type ApoA1.

Figure 1

3 Tesla MRI of the pelvis demonstrated marked enlargement and T2 hyperintensity of the right L4-S3 nerve roots (arrows), extending along the lumbosacral plexus to the level of the sciatic notch on axial (A) and coronal (B) images. Denervation edema and atrophy were seen in the right gluteus maximus (arrow head).

Figure 2

Osmificated teased fiber preparation (A) showed mostly empty fibers, often with adherent, amorphous, flocculent material. On methylene blue-stained epoxy-embedded semithin sections (B), a severely decreased density of myelinated fibers is seen, with only rare, intermediate sized fibers seen (arrow head), and frequent spherical aggregates of amorphous material (arrows). Congo red stained sections (C) revealed the endoneurium (asterisk) and perineurium (arrow) of some fascicles to be completely effaced by congophillic, amorphous material which was diffusely birefringent under polarized light (D), diagnostic of amyloidosis. A large, subperineurial collection of inflammatory cells was seen in one fascicle (arrow head – panel C) displacing surrounding amyloid.

Figure 3

The biopsied material showed frequent round intracellular inclusions scattered throughout the endoneurium which were congophilic (B) and displayed Maltese crosses with polarized light (A). Electron microscopy revealed starburst-shaped inclusions within mononuclear cells (C) demonstrated to be macrophages in conjunction with immunohistochemical preparations. At higher magnification (D) criss-crossing fibril formations typical of amyloid are seen.

Figure 4. ApoA1 Sequence and Identified Amino Acid Digests

Mass spectrophotometry identified sequences throughout the ApoA1 protein, representing 113 of 267 of the total amino acids (i.e. 42% of the total protein, identified and highlight yellow). One oxidated methionine residue was identified (highlighted green). The identified sequences were both within and outside the 93 amino acid amino terminal segment previously identified as amyloidogenic.