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Unique retinal signaling defect in GNB5-related disease

  • Zhuo Shao
  • Anupreet Tumber
  • Jason Maynes
  • Erika Tavares
  • Peter Kannu
  • Elise Heon
  • Ajoy VincentEmail author
Clinical Case Report

Abstract

Objective

To report a unique retinal signaling defect in GNB5-related disease.

Methods

A 3-year-old female child underwent detailed systemic and ophthalmological evaluation. The eye examination included fundus photography, spectral domain optical coherence tomography and an extended protocol full-field electroretinography (ERG) including the ISCEV recommended standard steps. The dark-adapted (DA) ERGs were performed to a series of white flashes (range 0.006–30.0 cd s m−2) and two red flashes. The DA ERGs to higher stimulus intensities (3.0, 10.0 and 30.0 cd s m−2) were tested using a range of inter-stimulus intervals (ISI) of up to 60 s. In addition to standard light-adapted (LA) ERGs, a short-duration (0.5 s) LA 3.0 30-Hz flicker ERG and a long-duration LA ON–OFF ERG were also performed. Genetic testing included microarray, mitochondrial genome testing and whole exome sequencing.

Results

The child was diagnosed to have status epilepticus and bradycardia at 6 months of age. Subsequently, she was diagnosed to have global developmental delay and hypotonia. On ophthalmological evaluation, the child fixes and follows light. Fundus evaluation showed mild optic disk pallor; macular SD-OCT was normal. The dim flash DA ERGs (DA 0.006 and DA 0.01 cd s m−2) were non-detectable. DA red flash ERGs showed the presence of an x-wave (cone component) and no rod component. The DA 3.0, 10.0 and 30.0 ERGs showed electronegative configuration regardless of the ISI; the averaged a-wave amplitude (4 flashes) was smaller at shorter ISI but became normal at a prolonged ISI (60 s). The LA 30-Hz flicker ERG was severely reduced but detectable for the initial 0.5 s; this became non-detectable after 5 s of averaging. The LA 3.0 2-Hz ERG showed markedly reduced a- and b-wave amplitudes and a reduced b:a ratio; the LA ON–OFF ERGs were non-detectable. WES identified a homozygous null mutation in G protein subunit beta 5 (GNB5; c.1032C>A/p.Tyr344*).

Conclusion

This report identifies for the first time a unique retinopathy associated with biallelic mutations in GNB5. The observed phenotype is consistent with a dual retinal signaling defect reminiscent of features of bradyopsia and rod ON-bipolar dysfunction.

Keywords

GTP-binding protein beta subunits Electroretinography Light signal transduction Bradyopsia Retinal ON-bipolar cell signaling RGS proteins 

Notes

Funding

This work was supported by the Foundation Fighting Blindness, USA (Grant No: CD-CL-0617-0727-HSC). The funding organization had no role in the design or conduct of this research.

Compliance with ethical standards

Statement of human rights

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments.

Statement on the welfare of animals

This article does not contain any studies with animals performed by any of the authors.

Conflict of interest

No conflicting relationships exist for any author.

Informed consent

The patient’s guardian has consented to the submission of the case report to the journal.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Clinical and Metabolic GeneticsThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of Ophthalmology and Vision Sciences, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  3. 3.Division of Molecular Medicine, The Hospital for Sick Children Faculty of MedicineUniversity of TorontoTorontoCanada
  4. 4.Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada

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