Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6–6% of RP and 3–16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify ‘actionable’ genotypes—i.e., genotypes that may benefit from the treatment—and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients’ access to available therapeutic options.

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The purpose of the study was to search for causes that exert a negative effect on the mental development of patients with con­genital hypothyroidism (CH). A total of 85 children aged 5-17 years (65 patients with CH and 20 healthy individuals of the same age from their families) were examined. Their mental de­velopment was assessed by the D. Veksler test in the presence of clinical and hormonal compensation. The results have demon­strated that the start of therapy at month 1 of life provides high adaptive capacities and results in the normal level of mental development in children with CH (the mean IQ, 103±4 scores). The adequacy of the therapy performed also affects the mental development of patients with CH in future: children with normal intellect (IQ > 90 scores) received adequate hormonal replace­ment therapy within the first year of life in 90% of cases whereas hormonal compensation within the first year of life was noted only in 38% of the children with borderline intellectual deficiency (IQ = 70-89 scores). Perinatal pathology was more frequently de­tected in children with mental retardation: in children with oli­gophrenia and those with normal intellect, their maternal path­ological pregnancy was observed in 56 and 22%, respectively. Birth asphyxia was noted in 33% versus 15%. Familial and so­cialfactors played a role (but not decisive) in the formation of the intellectual level of a child with CH. It is concluded that the time of initiation and the adequacy of therapy play the leading role in the formation of intellect. The authors 'findings show it necessary to optimize a follow-up system for children with CH: a stricter clinical and hormonal monitoring of patients by an endocrinol­ogist and consulting of children with CH by a neurologist and a medical psychologist from their infancy.

Investigation of risk factors for glucocorticoid induced (GI) osteoporosis, which is one of the most frequent and serious complications of long term systemic glucocorticoid (SGC) therapy for bronchial asthma, is a topical issue of preventative medicine. In the present work, allele specific hybridization on a bio chip was used to determine the allele and genotype frequencies of eight candidate genes for GI osteoporosis in 137 patients with bronchial asthma receiving long term SGC therapy. The MTHFR polymorphism 677C>T showed a significant association with the proximal femur mineral density (Z score) in patients treated with SGC (nonparametric Kruskal-Wallis ANOVA, p = 0.0013). On the other hand, carriers of the null genotype by the GSTM1 insertion-deletion polymorphism had lower bone mineral density Z scores than carriers of at least one functional GSTM1 allele (Mann-Whitney U test with the Bonferroni correction, p = 0.034). Anal ysis of gene-gene interactions showed that the MTHFR 677C/C/GSTM1 null genotype combination was associated with significantly lower bone mineral density Z scores than other genotype variants (KruskalWallis ANOVA, p = 0.0012). Thus, the MTHFR and GSTM1 alleles can modulate the risk of GI osteoporosis in patients with bronchial asthma, which is very important for the identification of patients at a high risk of osteoporosis among individuals receiving SGC, as well as inhaled glucocorticoids.