What is gelsolin amyloidosis?

Updated: May 09, 2019
  • Author: Robert O Holmes, Jr, DO; Chief Editor: Herbert S Diamond, MD  more...
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This disorders was first reported in 1969 and found to be heritable in a Finnish family in an autosomal dominant fashion. A flurry of research uncovered the molecular dysfunction of the disease but a treatment approach has yet to be devised. Gelsolin amyloidosis has now been described in countries all over the world and is often undiagnosed or misdiagnosed. [66]

Amyloid fibrils include a gelsolin fragment that contains a point mutation. Two amyloidogenic gelsolin mutations are described. "A G654A or G654T DNA mutation in the gelsolin coding area (q32–34) of chromosome 9, which changes an aspartate at position 187 in the gelsolin protein to an asparagine or tyrosine (D187N/Y) residue respectively. These mutations lead to gelsolin fragment formation and amyloidogenesis." [66] .

The precursor protein in gelsolin amyloidosis (AGel) is the ubiquitous actin-modulating protein gelsolin, but the mutated form lacks a crucial calcium binding site, allowing it to unfold and expose the amino acid chain to proteolysis while processed in the Golgi and again after exocytosis, forming an 8- and 5-kd amyloidogenic fragment. [67, 68] When the gelsolin gene is transcribed, some is spliced to form cytoplasm and some is secreted from the cell, but only the secreted forms deposit as amyloid secondary to faulty post-translational modification of gelsolin. [69] Mass spectrometric-based proteomic analysis and immunohistochemical staining can reliably differentiate amyloid as gelsolin type. [70, 71, 72]

Most early symptoms are ocular; thus, the ophthalmologist is crucial in early diagnosis. Clinical characteristics include slowly progressive cranial neuropathies, distal peripheral neuropathy, and lattice corneal dystrophy. Gelsolin gene sequencing is the only confirmatory test, but tissue samples can also be stained with tagged, commercially available gelsolin antibodies to provide a solid pathology diagnosis. [73] An extremely detailed review of this condition, along with the recent scientific developments, was published by Solomon et al in 2012. [66]

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