Inherited retinal disease

Less severe hereditary retinopathies can result from subtle genotypic variants


Posted: Monday, March 1, 2021

Bart P Leroy Ghent MD, PhD

Not all hereditary retinopathies show their typical, severe phenotype and maculopathy in some cases might present at the mild end of the disease’s spectrum, according to Bart P Leroy Ghent MD, PhD, University Hospital and Ghent University Ghent, Belgium.

“Mild end-of-the-spectrum retinal disease can result from pathogenic genetic variants with milder effects than the usual phenotype. The genotypic spectra of these conditions are also wider than we initially thought,” Dr Leroy told the Retina 2020 meeting, funded by the Irish patient-led charity, Fighting for Sight.

The diagnostic process in cases of suspected hereditary retinal dystrophies begins with asking patients the right questions in language they can understand about the nature of their visual complaints and the time of onset, he noted. Also important is drawing a pedigree and looking for potential causes for the disorder with specialised imaging. In addition, patients should undergo functional testing with psychophysics and electrophysiology. The clinical diagnosis should be confirmed with genotyping.

Ocular genetics has identified 307 genes for inherited retinal and optic neuropathy diseases, Dr Leroy said. He added that ocular genetics has come a long way in recent years. In particular, high-throughput molecular sequencing technology, such as whole exome sequencing, is rapidly replacing the older, Sanger sequencing.

In cases where the diagnosis is uncertain, the technology can be used to find the subtle variants of a suspect gene as well as pathogenic variants of unsuspected genes.

The variants can include deep intronic variants in regulatory sequences, deep intronic mutations or subtle copy number variations. The molecular findings should be interpreted in the context of the clinical presentation, Dr Leroy said.

“Whole exome sequencing can be very powerful tool, but you have to be aware of how you communicate to patients that not all the variants identified are pathogenic and sometimes the laboratory is unable to say what is the real cause of the disease. What you then have to try and do is correlate what you see clinically with what you have genetically,” he added.

Dr Leroy presented a few case studies to illustrate his approach to the diagnosis of hereditary retinopathies. In the first case, a 23-year-old woman was referred with a possibly inherited maculopathy, indicated by the presence of bilateral, relative, central scotoma. She had a best-corrected visual acuity of 10/10 vision in both eyes with no change over the past two years.

Her medical check-up was normal. Goldmann visual field showed some relative scotomata. Conventional fundoscopy showed no abnormalities. However, deep phenotyping with near-infrared autofluorescence imaging showed flecks in the central fovea area and the surrounding macula. Optical coherence tomography (OCT) also showed abnormalities in the central foveal region in both eyes.

Colour vison testing showed no abnormalities and full-field flash ERG was also normal. However, molecular testing showed the patient had two heterozygous and likely pathogenic variants of the ABCA4 gene, leading to diagnosis of mild Stargardt disease.

In another case, a five-year-old child was referred with central visual loss occurring over the previous six months with a diagnosis of Stargardt disease. Fundoscopy revealed an abnormality in the central area macula that grew over the course of two years’ follow-up. OCT showed outer retinal layer loss and flash electroretinography (ERG) was abnormal for both rods and cones.

Molecular genetic screening showed one variant of unknown significance on one allele of the gene ABCA4. However, not convinced of the Stargardt disease diagnosis, Dr Leroy and his associates performed whole exome sequencing. It revealed biallelic mutations in the MFSD8 gene, variants of which cause neuronal ceroid lipofuscinosis 7 (NCL7).

“Isolated maculopathy can be an early sign of a rapidly evolving retinal dystrophy suggestive of neuronal ceroid lipofuscinosis, before systemic signs develop,” he said.

Dr Leroy also described the case of an 18-year-old female patient who had diagnosis of retinal dystrophy at four years of age and now complained of a slowly progressive decrease in visual acuity in both eyes. She was referred by a uveitis specialist who wanted to determine if her condition was a dystrophy or was inflammatory.

Her best corrected vision was 5/10 in her right eye and 1/10 in her left eye. Fundoscopy showed a very abnormal lesion with yellowish discoloration. Blue-light autofluorescence showed satellite lesions the appearance did not change over time. Full-field flash ERG was fairly normal as was electro-oculography (EOG), indicating normal function of the pigment epithelium together with the photoreceptors.

In both eyes OCT showed a thinning and atrophic area with a conserved foveal depression. Whole exomal sequencing showed that the patient was compound heterozygous for two variants, one in exon four and one on exon six of RDH12, the Leber congenital amaurosis gene.

“I’m sure with the advent of such screening tools more surprises are ahead for us ophthalmic genetic specialists,” Dr Leroy predicted.

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