Viktória Szabó

Pathogenesis and genetic basis for retinopathy of prematurity

Retinopathy of prematurity (ROP) is a vasoproliferative disorder affecting preterm infants with low gestational age and birth weight. In general more than 50% of preterm infants weighing less than 1250 g at birth show evidence of ROP and about 10% of the infants develop stage 3 ROP. However, retinal detachment occurs and leads to visual loss in only a few percent of infants with stage 3 or more severe ROP, and in most cases, spontaneously regresses. The most conspicuous question is why ROP in some premature infants progresses despite rigorous and timely intervention while in other cases with similar clinical characteristics it regresses. Genetic differences between the infants could be an explanation. Although many causative factors, like low birth weight, low gestational age and supplemental oxygen therapy are associated with ROP, several indirect lines of evidence suggest the role of a genetic component in the pathogenesis of ROP. The incidence of ROP is more frequent in white than in black infants and in males than in females. Genetic polymorphism may alter the function of the genes which normally control retinal vascularization, such as vascular endothelial growth factor (VEGF), which may also be involved in pathogenesis of ROP. Evaluation of candidate genetic polymorphism influencing the outcome of ROP may provide new information about the pathogenesis of the disease. Screening of genetic polymorphisms may also help to identify and treat the high risk infants in time.

Human brain of preterm infants after hypoxic-ischaemic injuries: no evidence of a substantial role for apoptosis by using a fine-tuned ultrasound-guided neuropathological analysis

Preterm birth may be associated with hypoxic-ischaemic encephalopathy (HIE) showing a well recognised number of patterns, including neuronal karyorrhexis/eosinophilia mostly at the diencephalon and brain stem and leukomalacia at the periventricular white matter. To investigate whether programmed cell death or apoptosis plays a role in HIE, we examined human brains of preterm infants. Brain tissue samples from 12 consecutive infants (24-34 weeks of gestation) were available at post-mortem examination (1998-2000) after approval of the Ethics Committee. Two tissue sections were stereologically localised after brain fixation, slice preparation, and comparison with ultrasound imaging. We studied the periventricular white matter and the corresponding cortical region in each brain. Conventional histological stains were used. In addition, apoptosis was detected using a neuronal-specific terminal deoxynucleotidyl transferase-mediated nick end-labelling (TUNEL) method (NeuroTACS). A semiquantitative evaluation was performed to compare regions close to brain lesions with injury-free areas. Neuronal apoptosis was low in both cortical and in periventricular regions. No glial apoptosis was detected. Apoptosis in neurones was, however, detected in preterm brains with bacterial or mycotic infection. These results point out to the ambiguity of the TUNEL-reactive neurons in the diseased premature infants using fine-tuned ultrasound-guided neuropathological analysis, support the probable coexistence of neuronal TUNEL-reactivity and infection, and suggest that the association between apoptosis and HIE should overall be viewed with more caution.

Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X

Purpose Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, we describe a new genotype-phenotype correlation attributed to rare exon 3 interchange haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes (L- and M-opsin genes). Methods A multigenerational family with X-linked high myopia and cone dystrophy was investigated. Results Affected male patients had infantile onset myopia with normal visual acuity and color vision until their forties. Visual acuity decreased thereafter, along with the development of severe protan and deutan color vision defects. A mild decrease in electroretinography response of cone photoreceptors was detected in childhood, which further deteriorated in middle-aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively. Conclusion Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone-rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X.

Leber congenital amaurosis: First genotyped Hungarian patients and report of 2 novel mutations in the CRB1 and CEP290 genes

Purpose To introduce the first Hungarian patients with genetically defined Leber congenital amaurosis (LCA) and to report 2 novel mutations. Methods Seven otherwise healthy patients (4-29 years, 5 male and 2 female) who had an onset of severe visual impairment before age 2 years were investigated. The diagnosis was established in all individuals by medical history, funduscopy, and full-field electroretinogram (ERG). Ocular examination included visual acuity testing, digital fundus photography, and in 6 patients retinal imaging with optical coherence tomography (OCT). Arrayed primer extension microarray screening was performed in all probands. In 2 patients, further Sanger sequencing and targeted next-generation sequencing revealed the second disease allele. Results A cone-rod type LCA was revealed in 4 patients and a rod-cone type disease in 3 patients. Five patients presented with maculopathy. Optical coherence tomography (OCT) imaging showed diffuse retinal thickening in 3 probands with severe macular atrophy in one. Full-field ERGs were undetectable or residual in all patients. Genetic screening revealed AIPL1, CRB1, and CEP290 gene-related pathology in 6 patients; in 1 proband, no mutation was found. Three homozygous and 3 compound heterozygous mutations were identified. Two novel variants were detected: c.2536G>T (p.G846X) in the CRB1 gene and c.4929delA (p.Lys1643fsX2) in the CEP290 gene. Conclusions Genetic subtypes identified are among the most common ones in LCA; the phenotypes are consistent with those reported previously. Both novel mutations are predicted to result in a premature translation termination. The phenotype related to the novel CRB1 mutation results in severe atrophic maculopathy.

Szaruhártya-lerakódások bizonytalan jelentőségű monoklonális gammopathiában. Irodalmi áttekintés és esetbemutatás

To summarize ophthalmological signs of monoclonal gammopathy of undetermined significance (MGUS) and to present a case report. Summary of the literature data and presentation of the history of a 46-year-old female patient. In MGUS, pathological, but non-malignant plasma cells produce abnormal monoclonal immunoglobulin. Its prevalence is 0.15%, but it increases with age. As yearly 1-2% of MGUS patients develop multiple myeloma, frequent hematological follow-up is necessary. Corneal opacifications in MGUS have been described in a few dozens of patients in the literature. These may be nummular or crystal-like, or even present with white or grey line-forming depositions in the stroma. They may be centrally or peripherally localized. In our patient, bilateral, branching, geographical corneal opacifications were detected predescemetally, that were progressing and reaching the optical centre during follow-up. With 0.15 best corrected visual acuity, penetrating keratoplasty was performed (postoperative best spectacle-corrected visual acuity 0.6). Masson trichrom staining of the explanted cornea verified protein deposition, immunhistochemistry identified kappa light chain immunglobulin deposition in the posterior stroma, surrounded with inflammatory cells. Serum electrophoresis and bone marrow biopsy of our patient proved MGUS, therefore, hematological follow-up is going on. In the case of progressive, atypical corneal opacification, the hematological diagnosis of monoclonal gammopathy must be excluded - monoclonal gammopathy of ocular significance -, as delay in proper diagnosis and treatment of the systemic disease may have devastating consequences. Orv Hetil. 2018; 159(39): 1575-1583.