Multi-system neurological disorder associated with a CRYAB variant

Menachem Sadeh*, Dolev Rahat, Vardiella Meiner, Yakov Fellig, Michael Arad, Ora Schueler-Furman, Ying Hu, Yan Li, Carsten G. Bönnemann, Alexander Lossos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


We report a multiplex family with extended multisystem neurological phenotype associated with a CRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its ability to suppress protein aggregation. In accordance with the molecular findings, muscle biopsies revealed subsarcolemmal deposits that appeared dark with H&E and trichrome staining were negative for the other routine histochemical staining and for amyloid with the Congo-red stain. Electron microscopy demonstrated that the deposits were composed of numerous parallel fibrils. Laser microdissection and mass spectrometry-based proteomic analysis revealed that the inclusions are almost exclusively composed of crystallized chaperones/heat shock proteins. Moreover, a structural model suggests that Ser153 could be involved in monomer stabilization, dimer association, and possible binding of partner proteins. We propose that our report potentially expands the complex phenotypic spectrum of alpha B-crystallinopathies with possible effect of a CRYAB variant on the central nervous system.

Original languageAmerican English
Pages (from-to)117-125
Number of pages9
Issue number2
StatePublished - May 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.


  • CNS involvement
  • Crystallinopathy
  • Whole exome sequencing


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