Retinopathies resulting from mutations in the gene for the enzyme retinal dehydrogenase (RDH12) mainly include severe, early-onset rod-cone dystrophies. Because this disease progresses gradually and small areas of the retina are retained late into the disease, there is a broad window of opportunity for gene therapy, according to Bart Leroy MD, PhD, Ghent University Hospital, Ghent, Belgium.
“Because of those normal areas, there is a window of opportunity to treat these patients,” Dr Leroy told the 18th EURETINA Congress in Vienna, Austria.
Bart Leroy MD, PhD
In the process of phototransduction, a photon is converted into an electrical signal when it hits an opsin chromophore. The signal is generated by the isomerisation of 11-cis retinal into all-trans retinal, which changes the opsin protein’s configuration in a way that hyperpolarises the cell membrane. Following its release of all-trans retinal from the opsin, all-trans retinal is converted by the RDH12 enzyme into all-trans retinol, to be recycled in the retinal pigment epithelium.
Dysfunction of the RDH12 enzyme leads to the accumulation of toxic by-products in the photoreceptor, leading ultimately to its death. The mutations in the RDH12 enzyme gene that give rise to retinal pathologies in humans are primarily autosomal recessive in their expression. There are also rare reports of autosomal dominant mutations.
THE GHENT STUDY
To better characterise the RDH12 retinal dystrophy phenotypes, Dr Leroy and his associates have been conducting a prospective natural history study, called the Ghent Study, involving an expanding series of patients.
Their analysis of 23 patients from 14 families with RDH12-related retinal dystrophy showed that the condition generally has an early onset and results in a severe, progressive rod-cone dystrophy. In addition, some specific characteristics of RDH12-related retinopathies include an early macular atrophy with yellowish colouration and patchy preservation of the peripheral and peripapillary retina.
The findings of a British study, which described the phenotype of RDH12-related retinal dystrophies in 29 families, appeared to support those of the Ghent researchers. The disease characteristics the study identified included an early, severe rod-cone dystrophy with an extensive, generalised atrophy of the retina and the retinal pigment epithelium, progressing to a dense and widespread intraretinal pigment migration.
The British researchers also noted a severe atrophy of the macula, with pigmentation and yellowing with a corresponding loss of fundus autofluorescence and marked retinal thinning and excavation at the macula on OCT by adulthood.
The Ghent team have since expanded their study to now include more than 30 patients from Europe, Africa and Asia, Dr Leroy said. He presented the latest findings in 29 patients from 20 families. All have proven RDH12 mutations, with a total of 23 pathogenic sequence variants.
The mean age of onset of the retinopathy was 3.9 years and all patients had decreased best-corrected visual acuity from early childhood; 25 have night blindness; 10 have moderate photophobia; and 12
have nystagmus.
PATCHY PRESERVATION
All eyes had patchy preservation of the peripheral retina, Dr Leroy said. When viewed by high-resolution optical coherence tomography (OCT) the areas of better-preserved structure corresponded with the more normal areas seen on near-infrared reflectance imaging.
Another common characteristic of the phenotype was peripapillary preservation of the retina, which was present in 18 patients. Again, the fundoscopically normal areas of the peripapillary retina corresponded with structurally normal areas observed with OCT. They also corresponded with areas of visual function as measured with Goldmann visual fields.
A third common characteristic of RDH12-related retinal dystrophies is yellowish discolouration of the macula. The discolouration may result from a highlighting of the yellow pigment in the macula, caused by atrophy of the retinal pigment epithelium. This causes less absorption of incident light, reflection of it on the inner side of the posterior sclera and highlighting of the yellow pigment due to a second pass of the light rays, Dr Leroy hypothesised.
Dr Leroy noted that among their study’s population was a woman who was diagnosed with macular dystrophy when she was three years of age, yet now, 20 years later although there is atrophy of the fundus in the posterior pole, the remaining retina is seems completely normal. Similar cases were reported in a Chinese study.
Bart Leroy: Bart.Leroy@UGent.be
