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Electroretinogram abnormalities in FKRP-related limb–girdle muscular dystrophy (LGMDR9)

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Abstract

Background

Dystroglycanopathies are a heterogeneous group of membrane-related muscular dystrophies. The dystroglycanopathy phenotype includes a spectrum of severity ranging from severe congenital muscular dystrophy to adult-onset limb–girdle muscular dystrophy (LGMD). LGMDR9 is a dystroglycanopathy caused by mutations in the FKRP gene. Previous studies have characterized electroretinogram findings of dystroglycanopathy mouse models but have not been reported in humans.

Purpose

This study set out to characterize the electroretinogram in eight participants with LGMDR9.

Methods

Eight participants were recruited from an ongoing dystroglycanopathy natural history study at the University of Iowa (NCT00313677). Inclusion criteria for the current study were children and adults > 6 years old with confirmed LGMDR9. Age similar controls were identified from our electrophysiology service normative control database. Full-field electroretinograms were recorded using ISCEV standards. Six of the eight participants underwent light-adapted ON/OFF testing.

Results

The electronegative electroretinogram was not seen in any participants with LGMDR9. An unusual sawtooth pattern in the 30 Hz flicker with faster rise than descent was noted in all 8 participants. Our cases showed a decreased b-wave amplitude in light-adapted ON responses (p = 0.011) and decreased d-wave amplitude in light-adapted OFF responses (p = 0.015). Decreased b-wave amplitude in light-adapted 3.0 testing (p = 0.015) and decreased flicker ERG amplitudes were also detected (p = 0.0018). Additionally, compared to controls, participants with LGMDR9 had decreased a-wave amplitudes on dark-adapted 10 testing (p = 0.026).

Conclusions

Abnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram may be specific for LGMDR9. If confirmed in a larger population and if related to disease stage, these tests are potential biomarkers which could be useful as endpoints in clinical treatment trials.

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Acknowledgements

Amanda Pfeifer provided technical assistance with creation of figures.

Funding

Ronald Keech Professorship (Drack), University of Iowa ERG fund (Drack, Pfeifer), Research to Prevent Blindness (All Authors). Natural history study (Mathews) supported by the NIH through the Iowa Wellstone Muscular Dystrophy Cooperative Research Center (U54 NS053672) and ICTS Clinical Research Unit by citing grant UL1TR002537.

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Authors and Affiliations

  1. University of Iowa Carver College of Medicine, Iowa City, USA

    Joshua L. Hagedorn & Arlene V. Drack

  2. Stead Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Carrie Stephan & Katherine D. Mathews

  3. Department of Neurology, University of Iowa, Iowa City, IA, USA

    Katherine D. Mathews

  4. Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA

    Joshua L. Hagedorn, Taylor M. Dunn, Sajag Bhattarai, Wanda Pfeifer & Arlene V. Drack

  5. Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA

    Taylor M. Dunn

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  1. Joshua L. Hagedorn
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Correspondence to Wanda Pfeifer or Arlene V. Drack.

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Not applicable.

Ethics approval

This prospective study was approved by the Institutional Review Board of the University of Iowa (IRB ID #201805774) and conformed to the requirements of the United States Health Insurance Portability and Privacy Act.

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All subjects freely consented to participate in this study, and an informed consent was obtained from all participants included in the study.

Statement of human rights

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the University of Iowa Institutional Review Board (Approval Date: 6/18/18; IRB Approval Number: 201805774) and in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Hagedorn, J.L., Dunn, T.M., Bhattarai, S. et al. Electroretinogram abnormalities in FKRP-related limb–girdle muscular dystrophy (LGMDR9). Doc Ophthalmol 146, 7–16 (2023). https://doi.org/10.1007/s10633-022-09909-4

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  • DOI: https://doi.org/10.1007/s10633-022-09909-4

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