Diagnosis of Inherited Retinal Diseases. / Diagnose erblicher Netzhauterkrankungen.

Inherited retinal diseases are a frequent cause of severe visual impairment or blindness in children and adults of working age. Across this group of diseases, there is great variability in the degree of visual impairment, the impact on everyday life, disease progression, and the suitability to therapeutic intervention. Therefore, an early and precise diagnosis is crucial for patients and their families. Characterizing inherited retinal diseases involves a detailed medical history, clinical examination with testing of visual function, multimodal retinal imaging as well as molecular genetic testing. This may facilitate a distinction between different inherited retinal diseases, as well as a differentiation from monogenic systemic diseases with retinal involvement, and from mimicking diseases.

Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials.

Within the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leber's congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.

[Leber's Hereditary Optic Neuropathy]. / Leberʼsche hereditäre Optikusneuropathie.

Leber's hereditary optic neuropathy (LHON) typically affects young adults with a higher prevalence in men, but can ultimately occur at any age and also in women. LHON is caused by point mutations in the mitochondrial DNA, which lead to a defect in complex I of the mitochondrial respiratory chain. This in turn causes dysfunction and later degeneration of retinal ganglion cells, followed by ascending optic atrophy. Classically, LHON presents as a subacute unilateral loss of visual acuity, dyschromatopsia in the red-green axis and a central or centrocecal scotoma. The partner eye usually develops similar symptoms within 3 - 6 months of onset of the disease. In 25% of cases, however, the disease begins bilaterally. In the natural course of the disease, the majority of patients remain with a visual acuity less than 0.1, even though a small proportion may experience a spontaneous improvement in visual acuity. In 2015, the ubiquinone analogue Idebenone was approved by the European Medicines Agency for the treatment of LHON. The decisive factors for therapeutic success are an early start and an appropriate treatment duration. It should also be noted that a proportion of patients may experience a delayed response to therapy. However, a complete recovery of visual acuity is rare even under therapy. Since patients affected by LHON are mostly young adults of working age, who go largely blind more or less acutely, immediate support with magnifying vision aids and advice on social and vocational rehabilitation is essential. Alternative therapeutic approaches such as gene therapy, neuroprotection or stem cell-based aspects are currently the subject of clinical studies and offer hope for further perspectives for those affected. Although with Idebenone a causal therapy has already been approved for LHON, many questions regarding the pathogenesis of the disease have not yet been completely clarified. This particularly concerns gender prevalence and possible additional triggers or protective factors. In this overview, the clinical course of LHON, diagnostics and current therapy recommendations as well as the special features and current explanatory approaches to incomplete penetrance and symptoms of LHON are explained.

[Corneal disease in childhood-Hereditary, degenerative or infectious?] / Hornhauterkrankungen im Kindesalter ­ Hereditär, degenerativ oder infektiös?

BACKGROUND: Adequate visual acuity significantly contributes to the age-appropriate development of children's neurobehavior. Infantile corneal opacities are rare but implicate a high potential for amblyopia. OBJECTIVE: This review aims to provide an overview of the most common causes of infantile corneal opacities and highlights ophthalmopathological correlations. METHODS: The following review is based on an extensive literature search. RESULTS: If metabolic diseases, traumatic or infectious events can be excluded as a cause for an infantile corneal opacity, it is important to focus on the 3Ds, corneal dysgenesis, corneal dystrophy or corneal degeneration. DISCUSSION: If corneal opacities occur in childhood, early recognition, diagnosis, and initiation of treatment, including prophylaxis of amblyopia, are of utmost importance. In unexplained corneal opacities the histopathological work-up of the explanted cornea can contribute to the final diagnosis.

Characterization of a novel non-canonical splice site variant (c.886-5T>A) in NBAS and description of the associated phenotype.

BACKGROUND: Biallelic pathogenic variants in the neuroblastoma-amplified sequence (NBAS) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger-Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1-bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non-canonical splice site variant of unclear significance (c.886-5T>A; p.?). RESULTS: Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger-Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886-5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the ß-propeller region of the protein. CONCLUSION: We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS-related disorders, could be explained by residual protein function mediated by the non-canonical splice site variant c.886-5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS-related disorders.

Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center. METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine. RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05). CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.

Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response.

Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.

Convergence of evolutionary algorithms on the n-dimensional continuous space.

Evolutionary algorithms (EAs) are random optimization methods inspired by genetics and natural selection, resembling simulated annealing. We develop a method that can be used to find a meaningful tradeoff between the difficulty of the analysis and the algorithms' efficiency. Since the case of a discrete search space has been studied extensively, we develop a new stochastic model for the continuous n-dimensional case. Our model uses renewal processes to find global convergence conditions. A second goal of the paper is the analytical estimation of the computation time of EA with uniform mutation inside the (hyper)-sphere of volume 1, minimizing a quadratic function.