We present here the case histories of two siblings, a boy and a girl, with Leber\'s congenital amaurosis (LCA). The diagnosis was based on non-recordable full-field electroretinogram (ffERG). The long-term ophthalmologic follow-up included kinetic perimetry (Goldmann), visual evoked potentials with flash stimulation, optical coherence tomography (OCT: B-scan images at the area of fovea), and multifocal ERG. The boy (sibling 1, born in 1986) was sent for electrophysiological examination at the age of four because he had nystagmus from birth. The diagnosis would be LCA based on non-recordable ffERG. Four years later, his visual acuity decreased rapidly due to vitreous opacification, caused by the autoimmune reaction of the retinal pigment epithelial cells. This was treated successfully with steroid injections, administered parabulbarly. Retinal autoimmune panel was not performed. Genetic testing became available only in 2019, and it revealed a RPE65 gene mutation: (NM_000329.2) c.{442G>A};{442G>A} (p.{Glu148Lys}; {Glu148Lys}). His sister (sibling 2, born in 1993) showed similar symptoms, caused by the same genetic mutation. Even though their parents were free of symptoms, it appeared that they were heterozygous carriers of the same mutation. Research of the family tree revealed a consanguineous marriage four generations before. Both siblings received successful gene therapy relatively late in their age: sibling 1 was 35 and sibling 2 was 28 years old, meaning that they were at an advanced stage of the disease. Nevertheless, follow-up examinations showed measurable improvements in their retinal function. The study shows that electrophysiological examinations, including flash-evoked responses, are useful in the objective evaluation of the progression in the central photoreceptor loss during the follow-up of LCA. The results also show that gene therapy can have beneficial effects even at an advanced stage of the disease.

Mutations in CEP290, which encodes a centrosomal protein, cause Joubert syndrome, retinal dystrophy, and several other manifestations. Retinal dystrophy related to CEP290 mutation (Leber\'s congenital amaurosis type 10) presents with a severe visual impairment from birth, wandering eye movements, and oculodigital reflex. Fundus examination may initially be normal, but varying degrees of retinal pigmentation can be detected over time. This report presents 4 children who were referred to the ophthalmology clinic with a lack of eye contact and the suspicion of low vision. The ophthalmological examination revealed very poor visual function, the vision slightly improved over time, and enophthalmos became evident. There was neuromotor retardation in their history and mutations in the CEP290 gene were revealed in the whole-exome analysis. Both pediatricians and ophthalmologists should be aware of the coincidence between severe vision loss and neuromotor retardation and should refer patients for genetic testing if they suspect it. Genetic diagnosis will enable patients to be followed both neurologically and ophthalmologically and to benefit from rehabilitation opportunities that will contribute to visual and neurological development. It will also allow the family to receive genetic counseling on disease progression and heredity, and to follow ongoing gene therapy studies for mutations in the relevant gene.

BACKGROUND: Leber\'s congenital amaurosis is a genetically determined disease belonging to the group of hereditary retinal dystrophies that leads to significant visual impairment in childhood. The disease initially causes a concentric narrowing of the visual field and, with time, loss of central vision. The RPE65 gene mutation-related retinal dystrophy is the first ophthalmic disease for which gene therapy is available using voretigene neparvovec (Luxturna®, Novartis Pharmaceuticals AG, Basel, Switzerland).
OBJECTIVE: To present the treatment outcomes of Hungarian patients who were the first to receive voretigene neparvovec gene therapy for the RPE65 biallelic gene mutation.
METHODS: Two patients with RPE65 biallelic gene mutations confirmed by genetic testing received voretigene neparvovec gene therapy in one eye each. Before treatment and during the follow-up period, we assessed the best corrected visual acuity, the central retinal thickness, the degree of visual field defects and performed electrophysiological studies.
RESULTS: Both the best corrected visual acuity (+3 letters in the older sibling and +10 letters in the younger sibling) and the degree of visual field narrowing improved in both patients. The change in visual function resulted in a significant improvement in the quality of life of our patients.
CONCLUSIONS: Postoperative outcomes of our patients correlate with the results of clinical trials. Orv Hetil. 2022; 163(48): 1923-1931.
Bevezetés: A Leber-féle congenitalis amaurosis az örökletes ideghártya-dystrophiák csoportjába tartozó, genetikailag igazolható olyan kórkép, mely már fiatalkorban jelentős látásromláshoz vezet. A betegség először a látótér koncentrikus beszűkülését, idővel pedig a centrális látás elvesztését okozza. A voretigén neparvovec (Luxturna®, Novartis Pharmaceuticals AG, Bázel, Svájc) terápia révén az RPE65-gén mutációja következtében kialakuló ideghártya-dystrophia az első olyan szemészeti kórkép, mely esetén lehetőség van génterápia alkalmazására. Célkitűzés: Az RPE65 biallelikus génmutáció miatt voretigén neparvovec génterápiában elsőként részesült magyar betegek kezelési eredményeinek bemutatása. Módszer: Genetikai vizsgálattal igazoltan RPE65 biallelikus génmutációban szenvedő két betegünk egy-egy szemén voretigén neparvovec génterápiában részesült. A kezelést megelőzően, valamint az utánkövetés időszakában vizsgáltuk a legjobb korrigált látásélességet, a centrális retinavastagságot, a látótérszűkület mértékét, valamint elektrofiziológiai vizsgálatokat végeztünk. Eredmények: A kezelés hatására mind a legjobb korrigált látásélesség (a testvérpár idősebb tagjánál +3, a fiatalabb testvérnél +10 betű), mind a látótérszűkület mértéke javulást mutatott mindkét beteg esetében. A látásfunkciók változása jelentős életminőség-javulást eredményezett betegeink mindennapi életében. Következtetés: Betegeink posztoperatív eredményei korrelálnak a klinikai vizsgálatok eredményeivel. Orv Hetil. 2022; 163(48): 1923–1931.

BACKGROUND: Leber\'s congenital amaurosis (LCA) is a severe hereditary retinopathy disease that is characterized by early and severe reduction of vision, nystagmus, and sluggish or absent pupillary responses. To date, the pathogenesis of LCA remains unclear, and the majority of cases are caused by autosomal recessive inheritance. In this study, we explored the variant in the Crumbs homologue 1 (CRB1) gene in a Chinese family with LCA.
METHODS: We conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a Chinese family with LCA. A pathogenic variant was identified by capturing (the panel in NGS) and Sanger sequencing validation.
RESULTS: A nonsense variant (c.1499C>G) in the 6th exon of CRB1 gene in a Chinese family with LCA was identified, which predicted a change in the protein p. S500*, may lead to loss of gene function. We summarized the 76 variants reported thus far in CRB1 that caused LCA8.
CONCLUSIONS: This study reported a novel variant c.1499C>G (p. S500*) of the CRB1 gene occurred in a Chinese family with LCA, thus expanding the spectrum of CRB1 variants causing LCA.

Leber\'s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

Gene therapy has now evolved as the upcoming modality for management of many disorders, both inheritable and non-inheritable. Knowledge of genetics pertaining to a disease has therefore become paramount for physicians across most specialities. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber\'s congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Research in gene therapy has led to the development and approval of voretigene neparvovec (VN) for use in patients of LCA with a deficient biallelic RPE65 gene. The procedure involves delivery of a recombinant virus vector that carries the RPE65 gene in the subretinal space. This comprehensive review reports the evidence thus far in support of gene therapy for LCA. We explore and compare the various gene targets including but not limited to RPE65, and discuss the choice of vector and method for ocular delivery. The review details the evolution of gene therapy with VN in a phased manner, concluding with the challenges that lie ahead for its translation for use in communities that differ much both genetically and economically.

Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells. Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases. The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients. Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation. One of these targets is the increase of intracellular calcium ions, that has been detected in several murine models of inherited retinal degeneration. Recently, neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration. Here, we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches, such as the neuroprotective activity of the Pigment epithelium-derived factor. The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches. We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.

Introduction: Over a decade of research and development culminated in the 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN) for RPE65 mutation-associated inherited retinal disease (IRD), the first approved gene therapy for a hereditary genetic disease in the US, and the first and only pharmacologic treatment for an IRD.Areas covered: VN serves as a model for ocular gene therapy development, while RPE65 mutation-associated IRD serves as an example of a well-suited candidate disorder. This review also discusses development considerations for viral vector gene augmentation, and, studies that led to VN\'s FDA approval. Subretinal injection of VN resulted in improved performance on the novel multi-luminance mobility test (MLMT), light sensitivity, and visual fields in patients with RPE65 mutation-associated IRD, which predominantly impairs rod function. Additionally, the dosage, administration technique, pharmacokinetics, and safety data of VN are reviewed.Expert Opinion: As a model for development, special challenges associated with the introduction of this first ocular gene therapy include limited genetic testing in clinical practice, novel surgical complexity of ocular gene therapy administration, new functional vision endpoints, as well as unique development, launch, and reimbursement considerations associated with orphan therapies and one-time gene therapies.

Background: Inherited ocular conditions are a frequent cause of blindness. Gene therapy has encouraged the development of genetic testing, currently able to detect up to 80% of mutations in contrast to the 5% sensitivity achieved a few decades ago.Materials and methods: One hundred sixty-three patients with suspected genetic ocular disorders who were referred to a single clinician between August 2014 and August 2019 underwent a thorough ophthalmologic examination. Those diagnosed with congenital cataract, retinoblastoma, anterior segment dysgenesis, autoimmune retinal disease, posterior microphthalmia, or cobalamin C deficiency were excluded, along with patients who opted against genetic testing. Included probands were classified into a diagnostic clinical category and offered genetic testing. Blood samples were sent to foreign accredited diagnostic laboratories, followed by clinical interpretation of the results.Results: Of the 163 patients referred, 104 were enrolled in the study. Median age at disease onset was 2 years (range, 0 to 43 years). A molecular diagnosis was established at a median age of 10 years (range, 0.4 to 50 years). Disease-causing genotypes were identified in 82 of the probands, indicating a mutation detection rate of 78.8%. Mutations were identified in 38 genes, ABCA4 being the most commonly affected (23% of mutations), followed by CRB1 (13% of mutations). Whole-exome sequencing was performed in 6 patients, resulting in a definite diagnosis in 3 (50%).Conclusions: Molecular testing for inherited ocular conditions is feasible in developing countries by sending samples to certified foreign laboratories, with a mutation detection rate comparable to published values in developed countries. Further studies to identify more disease-causing genes may improve the overall sensitivity.

RPE65-associated LCA (RPE65-LCA) is an inherited retinal degeneration caused by the mutations of RPE65 gene and gene therapy has been developed to be a promising treatment. This study aims to evaluate the association between changes in visual function and application of gene therapy in patients with RPE65-LCA.
Several databases (PubMed, Cochrane Library, and Web of Science) were searched for results of studies describing efficacy of gene therapy in patients with RPE65-LCA. Six studies, which included one randomized and five prospective non-randomized clinical trials, 164 eyes met our search criteria and were assessed.
The BCVA significantly improved in treated eyes at 1 yr post treatment by - 0.10 logMAR (95% CI, - 0.17 - -0.04; p = 0·002), while there was no significant difference at 2-3 years post treatment (WMD: 0.01; 95% CI, - 0.00 - 0.02; p = 0·15). FST sensitivity to blue flashes also improved by 1.60 log (95% CI, 0.66-2.55; p = 0.0009), but no significant difference to red flashes (WMD: 0.86; 95% CI, - 0·29-2.01; p = 0.14) at 1 yr. There was no significant difference in central retinal thickness at 1 yr, but central retina in treated eyes appeared thinner at 2-3 years post treatment by 19.21 μm (95% CI, - 34.22 - -4.20; p = 0.01).
Human gene therapy is a pioneering treatment option for RPE65-LCA. Although its efficacy appears to be limited to less than 2 yrs after treatment, it carries the potential for further improvement and prolongation of efficacy.