Autosomal dominant gyrate atrophy-like choroidal dystrophy revisited: 45 years follow-up and association with a novel C1QTNF5 missense variant

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level

Mevalonate kinase deficiency associated with ataxia and retinitis pigmentosa in two brothers with MVK gene mutations

Purpose: To report the clinical and molecular genetic findings in two brothers with retinitis pigmentosa (RP) and mevalonate kinase deficiency (MKD). Methods: The brothers were examined clinically and with fundus autofluorescence, near-infrared auto fluorescence, and Spectral domain optical coherence tomography. Targeted resequencing was done with a custom designed gene panel containing 78 genes associated with RP. Mutations were confirmed by direct Sanger sequencing. Results: Both brothers, aged 46 and 47 years, were found to carry compound heterozygous mutations in the MVK gene (c.59A>C, c.1000G>A) encoding mevalonate kinase. They presented with severe ataxia, pseudophakia due to early onset cataract, and progressed retinitis pigmentosa. In one brother with cystoid macular edema, treatment with dorzolamide was beneficial. Serum IgD levels were markedly increased in both brothers and mevalonic acid blood and urine levels were markedly increased in, the one brother who could be examined. The disease severity differed between the brothers one had more severe ataxia and less severe visual deficiency compared to the other. Conclusion: MKD can be associated with RP and early onset cataract. Most MKD patients developing RP carry the (p.Ala334Thr) mutation. Macular edema can be treated using local dorzolamide

Wide-field optical coherence tomography in ABCA4-associated inherited retinal dystrophies

Aim: With a need to expand the monitoring options in therapeutic clinical trials, we evaluated the additional information provided by wide-field optical coherence tomography (W-OCT) compared to conventional macular volume scan OCT (M-OCT) in ABCA4 gene-associated inherited retinal dystrophies (ABCA4-IRD).Methods: A consecutive series of 52 ABCA4-IRD patients (mean age at last examination: 35.9 years, range 8.8-68.7 years) was examined between 2015 and 2021. Ophthalmologic examination included clinical examination, M-OCT [20 × 20 degree field (6.2 mm × 6.2 mm)], W-OCT [55 × 25 degree field (16.1 mm × 7.3 mm)], multicolor reflectance photography, fundus (FAF), and near-infrared autofluorescence (NIA) in macular and wide-field mode. Molecular genetic testing to confirm the clinical phenotype was performed in all patients.Results: In 37/52 (71.2%) of patients W-OCT revealed alterations of the outer retinal layers beyond the area covered by M-OCT at their last examination. In 15 patients, lesions were located within the area covered by M-OCT. Lesions beyond M-OCT consisted of subretinal material (31/37), as well as patches (18/37) or large continuous areas (3/37) of photoreceptor and retinal pigment epithelial dystrophy. In one patient, W-OCT identified peripheral lesions that were not detectable in wide-field FAF and NIA. In 48/52 patients, two causative mutations in the ABCA4 gene were identified, while the remaining four patients carried one pathogenic ABCA4 variant.Conclusion: W-OCT as well as wide-field FAF and NIA document lesions in the retinal mid- and far periphery in the majority of ABCA4-IRD patients and provide means for detailed analysis of progression and future treatment planning and monitoring