Author: Ángela González Alonso (Spain)
Co-authors: Gerardo Pedro García García, Angi Lizbeth Mendoza Moreira, Lucía Moreno Castro, María Belén Figuerola García, Juan José Pérez Santonja
Nyctalopia is the common manifestation of a genetically heterogeneous group of stationary or progressive disorders. Clinical findings are often very subtle or practically non-existent in patients that complain of night blindness, confronting us with a problem that we are quick to underestimate. Pathogenic mutations in more than 10 different genes are linked with similar phenotypes, and broad targeted Next-Generation Sequencing (NGS) panels, of even full exome analysis are required to clearly identify the subjacent disease. We report the case of a Spanish patient who presents with late-onset night blindness, harbouring a complex genotype and uncertain clinical and genetic diagnosis.
Department of Ophthalmology, University General Hospital of Alicante, Alicante, Spain. Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.
Clinical examination of the patient, including - Best-corrected visual acuity (BCVA). - Slit lamp biomicroscopy of the anterior segment. - Intraocular pressure measurement by handheld rebound tonometer (Icare Finland Oy, Vantaa, Finland). - Specular microscopy (Topcon, Tokyo, Japan). - Pachimetry (Pachmate 2, DGH Technology, Inc., Exton, Pennsylvania). - Indirect biomicroscopic examination of the ocular fundus with a 90-diopter lens and a Goldmann fundus contact lens (Volk Optical, Mentor, USA). - Retinography and fundus autofluorescence (FAF) image with a field of view of 45 degrees of the retina (DRI OCT Triton, Topcon, Tokyo, Japan). - Optical coherence tomography (OCT) of the macula and optic nerve head (DRI OCT Triton, Topcon, Tokyo, Japan). - Automated perimetry using the Humphrey field analyzer 30-2 program (Carl Zeiss, Jena, Germany). - Massive parallel DNA next-generation-sequencing (NGS) technique using a gene panel of 330 genes associated with IRD.
A 51-year-old male was referred with late-onset nyctalopia. The patient reported recent visual difficulty in relatively low light, without other symptoms, and a family history of low vision in several members of his family. Best corrected visual acuity (BCVA) was 10/10 in both eyes. Slit lamp examination revealed cornea guttata and bilateral clear crystalline lens. Fundus examination showed a mild phenotype characterised by a subtle macular distortion with non-specific central pigment changes. There were neither clinical changes nor degenerations of the peripheral retina. Spectral domain optical coherence tomography (SD-OCT) scan showed several well-delimited non-drusenoid RPE detachments and minimal non-specific inner segment/outer segment junction changes. The patient had normal vitamin A levels. The genetic testing revealed heterozygous mutations in five different genes related to IRDs: Variant c.4611G>A; p. (Thr1537=) in the ABCA4 gene, variant c.60G>T; p. (Leu20Phe) in the USH2A gene, variant c.1169G>T; p.(Arg390Leu) in the CYP4V2 gene, variant c.1645C>T; p. (Arg549*) in the CEP290 gene and variant c.49G>A; p. (Ala17Thr) in the GRK1 gene.
The patient showed a complex genotype combining heterozygous mutations in several genes related with five different IRDs that share nyctalopia as a common symptom. Variant c.4611G>A; p.Thr1537= in the ABCA4 gene is a synonymous single nucleotide variant reported as benign in databases, and related to cone-rod dystrophy, severe early-childhood-onset retinal dystrophy and fundus flavimaculatus. We also consider this mutation to be benign or non-causative of the patient’s phenotype. Variant c.60G>T; p.Leu20Phe in the USH2A gene is a variant of unknown significance (VUS) associated with retinitis pigmentosa. Variant c.1645C>T; p. Arg549* in the CEP290 gene has been described as pathogenic in Leber congenital amaurosis and Bardet-Biedl syndrome. Both VUS, p.(Arg390Leu) in CYP4V2 and p. (Ala17Thr) in GRK1, are respectively linked to Bietti corneorretinal crystalline dystrophy and Oguchi disease type 2. Interestingly, these diseases are more common in Asian than in European patients. The finding of this complex genotype represents a challenge to determine its role in the disease and complicates genetic diagnosis. Further segregation of the different variants in the proband’s family should provide additional information to evaluate both the pathogenicity of this complex genotype and its diagnosis value, as well as to improve genetic counselling.
The authors declare that there has not a financial interest in the subject matter or receives money from any mentioned company.