Unique retinal signaling defect in GNB5-related disease

• Published in: Documenta ophthalmologica 2020-06, Vol.140 (3), p.273-277
• Main Authors: Shao, Zhuo, Tumber, Anupreet, Maynes, Jason, Tavares, Erika, Kannu, Peter, Heon, Elise, Vincent, Ajoy
• Format: Article
• Language: English
• Subjects: Bradycardia; Clinical Case Report; Defects; Electroretinograms; Epilepsy; Eye examinations; Genetic screening; Genomes; Medicine; Medicine & Public Health; Mitochondria; Mutation; Ophthalmology; Phenotypes; Photography; Retina; Retinopathy
• ISSN: 0012-4486; 1573-2622
• DOI: 10.1007/s10633-019-09735-1

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.