To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 (CEP290-LCA) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition.
This is a retrospective review of records of five patients with CEP290-LCA. Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths.
All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals.
We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.

To report the concurrent presentation and management of IQCB1-associated Leber Congenital Amaurosis and NDP-associated Familial Exudative Vitreoretinopathy (FEVR).
A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described.
Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518_1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans. In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone.
The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1-associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.

Leber congenital amaurosis (LCA), although rare, is one of the most severe forms of early-onset inherited retinal dystrophy (IRD). Here, we review the molecular genetics and phenotypic characteristics of patients with NMNAT1-associated IRD. The longitudinal clinical and molecular findings of a Japanese girl diagnosed with LCA associated with pathogenic variants in NMNAT1 c.648delG, (p.Trp216Ter*) and c.709C>T (p.Arg237Cys) have been described to highlight the salient clinical features of NMNAT1-associated IRD.

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Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969 ) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors.

OBJECTIVE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome.
METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing.
RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia.
CONCLUSIONS: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.

BACKGROUND: Leber\'s congenital amaurosis (LCA) is a known inherited retinal disease (IRD) associated with severe visual loss, nystagmus, amaurotic pupils, oculo-digital sign and markedly reduced or absent electroretinograms (ERG). Retinal astrocytic hamartomas (RAH) is a benign vascularized glial tumor of the retina. There is no known association of these two entities, more so in siblings.
METHODS: A pair of siblings diagnosed as LCA who presented with RAH with no extraocular symptoms or signs of phakomatosis were imaged. Multimodal imaging was performed and are elaborately described in this article.
CONCLUSIONS: LCA in siblings with multiple RAHs is an extremely rare association. Recent advances in retinal imaging tools have aided in diagnosing even subtle and early RAH with high sensitivity using Infrared imaging (IRI) and Optical coherence tomography (OCT).

BACKGROUND: Leber congenital amaurosis (LCA) is the earliest onset and the most severe form of all inherited retinal degenerative disorders, characterized by blindness, or severe visual impairment from birth, and typically exhibits clinical and genetic heterogeneity. Recently, 14 causative genes of LCA were reported. We performed whole-exome sequencing (WES) for Japanese siblings, and identified a novel homozygous nonsense mutation in the RPGR-interacting protein 1 (RPGRIP1) gene. We also report their follow-up data over 27 years.
METHODS: Patient 1 is a 37-year-old male. In 1992, his eye position indicated orthophoria, however, horizontal nystagmus was evident, and he complained of photophobia. His best corrected decimal visual acuity (BCVA) was 0.2 (S + 6.5/C-3.5/170°) OD and 0.1 (S + 6.0/C-2.5/10°) OS. Fundus examination revealed bisymmetrical inferior focal retinal pigment epithelium (RPE) mottling. Bright-flash electroretinogram (ERG) revealed a subnormal pattern, while 30 Hz flicker ERG was non-recordable in both eyes. At his final visit in 2019, his BCVA was 0.09 (S + 3.5/C-3.5/180°) OD and 0.09 (S + 3.0/C-4.0/10°) OS. Patient 2, a 34-year-old female, is the sibling of patient 1. In 1992, her BCVA was 0.05 (S + 6.0) OD and 0.06 (S + 5.0) OS. She was in a chin-up position during visual acuity testing. Horizontal nystagmus was evident, and she also complained of photophobia. Bright-flash ERG was severely attenuated, and 30 Hz flicker ERG was non-recordable in both eyes. At her final visit in 2019, her BCVA was 0.02 (uncorrectable) OD and 0.03 (uncorrectable) OS. There were no other patients with LCA in their family and their parents were non-consanguineous. WES revealed a homozygous, consecutive, two-nucleotide variation in the RPGRIP1 gene (NM_020366: exon15:c.G2294A and c.C2295A, p.C765X), resulting in a premature stop codon. We interpreted this variation as a novel pathogenic mutation of RPGRIP1 that contributes to LCA6 development.
CONCLUSIONS: Herein, we report a novel nonsense mutation of RPGRIP1 in two patients with LCA6 and present their long-term follow-up data. These clinical data linked to genotypes provide important information for the development of new treatments, such as gene therapy, as well as for genetic counseling.

Background: Leber congenital amaurosis (LCA) is a subgroup of early onset retinal dystrophy, manifesting with early or congenital visual loss, wandering nystagmus, amaurotic pupils, oculodigital sign, reduced retinal thickness on optical coherence tomography and abnormal electroretinogram. Today, mutations of about 25 genes account for 80% of individuals with LCA. The AIPL1 mutations causing LCA type 4 account for about 5-10% of this group. Case Report: Three affected siblings with vision loss, nystagmus, cataracts, stage 4 keratoconus, retinal abnormalities (black spots), lack of glaucoma, and dysmorphic features from a consanguineous marriage had LCA type 4 with a novel homozygous missense mutations of AIPL1(c.862 C > T). Conclusion: Cortical cataracts, stage 4 keratoconus, retinal black spots, and lack of glaucoma along with mutations of AIPL1 (c.862 C > T) can be present in LCA type 4.

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