Abstract
Purpose :
Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Genetic variants in IMPDH1 are responsible for RP10 autosomal dominant retinitis pigmentosa (adRP) or Leber congenital amaurosis 10. IMPDH1 is ubiquitous in cellular location but variants are associated with Retinitis Pigmentosa (RP). This study reports the ophthalmic natural history a family with a novel IMPDH1variant. The phenotype and natural history are compared to the reported literature.
Methods :
Multimodal imaging and functional studies documented the patient’s phenotype. These included: Best-corrected visual acuity (BCVA), fundus photograph, fundus autofluorescence (FAF), full field electroretinogram (ffERG), pattern ERG (pERG), optical coherence tomography (OCT) and visual field (VF) data. A literature search was performed. IMPDH1genetic variants were mapped and ophthalmic phenotypes were compared.
Results :
We report 3 cases from a 2 generational family with a novel heterozygous pathogenic variant p.Lys314Gln (exon 10). The ophthalmic phenotype showed best eye BCVA of 0.4, 0.56, and 0.9 logMAR in last follow up of the 3 patients at ages 13.2, 14.2, and 41.6 years (yrs) respectively
Diffuse outer retinal atrophy with mild pigmentary changes was found in all patients. FAF showed early macular involvement with diffuse macular hyperautofluorescence surrounded by hypoAF. Foveal ellipsoid zone island was intact in the youngest patient (8.3 yrs) but was discontinuous in the older sibling (10.6 yrs) and the mother (37 yrs). Constricted visual fields to <20deg (legal Blindness) were identified in all three with the youngest reaching this level by 12.2 yrs. The ffERG showed an almost extinguished dark adapted (DA) and light adapted response with DA responses affected earlier and the pERG showed significant macular dysfunction at diagnosis in each case.
Literature review identified a further 57 heterozygous variants. Exon 10 is a hotspot with 18 variants, including our family. A consistent feature was the mild pigmentary retinopathy and early macular involvement.
Conclusions :
We report a novel IMPDH1 genetic variant in a two-generation family. Early central visual loss is a prominent feature consistent with the early macular involvement reflecting the different pathophysiology compared to other RP groups as both the rod and cone degeneration occur in a comparable time course.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.