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Background: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies., Methods: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA., Results: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors., Conclusions: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Novartis Pharma LLC. Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Skopinfarm LLC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41% of whom were born preterm. After lymphocyte subsets were assessed via flow cytometry, samples of 18 infants (0.09‰) were sent for whole exome sequencing. Confirmed genetic defects were consistent with autosomal recessive agammaglobulinemia in 1/18, severe combined immunodeficiency - in 7/18, 22q11.2DS syndrome - in 4/18, combined immunodeficiency - in 1/18 and trisomy 21 syndrome - in 1/18. Two patients in whom no genetic defect was found met criteria of (severe) combined immunodeficiency with syndromic features. Three patients appeared to have transient lymphopenia. Our findings demonstrate the value of implementing combined TREC/KREC NBS screening and inform the development of policies and guidelines for its integration into routine newborn screening programs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autosomal dominant hearing loss is represented by a large number of genetically determined forms. Over 50 genes associated with dominant nonsyndromic hearing impairments were described. Pathogenic variants in the CEACAM16 gene lead to the development of DFNA4B hearing loss. Currently, 8 pathogenic variants in this gene have been described. The objective of this study was to study the audiological and molecular genetic characteristics of a large family with CEACAM16-associated autosomal dominant nonsyndromic hearing loss. A detailed anamnesis was collected, and a comprehensive audiological examination was performed for 21 family members. Genetic testing was performed, including whole-genome sequencing for the proband's son and Sanger sequence analysis for the proband and for all available family members. In a large Russian family, including 5 generations, an autosomal dominant type of slowly progressing nonsyndromic late-onset hearing loss was observed. Eleven family members suffer from hearing impairment, which starts with tinnitus and threshold increase at high frequencies, since the age of 5-20 years. Hearing loss slowly progresses with age in each person and is similar to age-related hearing loss. We have detected the novel likely pathogenic variant с.419С>T (p.(Thr140Ile)) in exon 3 of the CEACAM16 gene, which segregates with late-onset nonsyndromic hearing loss in this family. The clinical data obtained in the examined family correspond with the phenotype in previously described cases. In general, the study widened the mutation spectrum of the gene, allowing to carry out medical genetic counseling and to answer the questions about the hearing impairment prognosis for future generations.

Cerebral aneurysms are diagnosed in 1-5% of people and cause 80-85% of subarachnoid hemorrhages (SAH). Aneurysmal hemorrhages are more common in people aged 30-50 years causing high socio-economic significance of this disease. Therefore, the outcomes of microsurgical clipping are an urgent problem in these patients., Objective: To evaluate the immediate and long-term results after microsurgical treatment of cerebral aneurysms in acute period of hemorrhage; to analyze functional results and long-term outcomes, including higher mental functions and return to previous work., Material and Methods: The study included 517 patients in acute period of subarachnoid hemorrhage between 2019 and 2022. Severity of hemorrhage was assessed using the Hunt-Hess scale while the Fisher scale was valuable to estimate dimensions of hemorrhage and predictions for vasospasm. All patients underwent microsurgical clipping of aneurysms. We assessed clinical status and outcomes immediately after microsurgical clipping, within 2 weeks, 1, 3, 6 and 12 months after surgery. The Modified Glasgow Outcome Scale, Modified Rankin Scale (mRS), EQ-5D-3L Quality of Life Questionnaire, Mini-Mental State Examination MMSE and Hamilton Anxiety Rating Scale were used., Results: After 1 month, mRS score 0 was observed in 22% of patients, score 1 - 17%, score 2 - 19.4%, score 3 - 6.2%, score 4 - 2.6%, score 5 - 1% of patients. Mortality rate was 6.4%. After 12 months, mRS score 0, 1, 2, 3 and 4 was observed in 67%, 15%, 8%, 3% and 0.4% of patients, respectively. After 12 months, 39 (8.3%) patients did not return to previous work. Among 427 (91.7%) patients who returned to previous work, 20% returned to work after 3 months, 65% after 6 months and 15% after 9 months., Conclusion: Short-term and long-term functional outcomes vary significantly. There were significantly better mRS scores in long-term period compared to early period. Analysis of immediate and long-term results after hemorrhage will allow us to determine the most important predictors of adverse functional outcomes, assess the prevalence, characteristics, modifiable risk factors and consequences of hemorrhage.

A male factor, commonly associated with poor semen quality, is revealed in about 50% of infertile couples. CFTR gene (Cystic Fibrosis Transmembrane Conduction Regulator) variants are one of the common genetic causes of azoospermia-related male infertility. Notably, the spectrum and frequency of pathogenic CFTR variants vary between populations and geographical regions. In this work, we made an attempt to evaluate the allele frequency (AF) of 12 common CFTR variants in infertile Russian men and healthy individuals from different districts of Russia. Because of the limited number of population-based studies on Russian individuals, we characterized the population AFs based on data from the Registry of Russian cystic fibrosis (CF) patients. In addition to the CF patient registry, we estimated the local frequencies of the same set of variants based on the results of genotyping of CF patients in local biocollections (from St. Petersburg and Yugra regions). AFs of common CFTR variants calculated based on registry and biocollection data showed good concordance with directly measured population AFs. The estimated region-specific frequencies of CFTR variants allowed us to uncover statistically significant regional differences in the frequencies of the F508del (c.1521_1523del; p.Phe508del) and CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb; p.Ser18ArgfsX) variants. The data from population-based studies confirmed previous observations that F508del, CFTRdele2,3(21kb), and L138ins (c.413_415dup; p.Leu138dup)variants are the most abundant among infertile patients, and their frequencies are significantly lower in healthy individuals and should be taken into account during genetic monitoring of the reproductive health of Russian individuals.

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4 -related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4 -related retinal dystrophies in this specific population.

Ectodermal dysplasia (ED) is a heterogeneous group of hereditary diseases of the skin and its appendages, which are characterized by impaired development and/or homeostasis of two or more ectoderm derivatives, including: hair, teeth, nails, sweat glands and their modifications (mammary glands, for instance). The overall prevalence of ectodermal dysplasia remains precisely unknown not only in Russia, but also in the world, nor is known the contribution of individual genes to its structure. This complicates the DNA diagnosis establishment of this disease due to the lack of an accurate diagnostic algorithm and a universal cost-effective method of analysis. To date, the most highly-researched genes involved in the development of anhydrous or hypohidrotic forms of ED are EDA, EDAR, EDARADD and WNT10A. The ectodysplasin A (EDA) gene is the cause of the most common X-linked form of ED, a gene from the Wnt family (WNT10A) is responsible for the autosomal recessive form of the disease, and two other genes (EDAR and EDARADD) can cause both autosomal recessive and autosomal dominant forms. This review provides the characteristics of the genes involved in ED, their mutation spectra, the level of their expression in human tissues, as well as the interrelation of the aforementioned genes. The domain structures of the corresponding proteins are considered, as well as the molecular genetic pathways in which they are involved. Animal models for studying this disorder are also taken into consideration. Due to the cross-species genes conservation, their mutations cause the disruption of the development of ectoderm derivatives not only in humans, but also in mice, cows, dogs, and even fish. It can be exploited for a better understanding of the etiopathogenesis of ectodermal dysplasias. Moreover, this article brings up the possibility of recurrent mutations in the EDA and WNT10A genes. The review also presents data on promising approaches for intrauterine ED treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © AUTHORS.)

Background and Importance: The supraorbital "keyhole" approach has been described for the treatment of basilar artery aneurysms. Transpalpebral approach (TPA) is an alternative minimally invasive route to aneurysms of the Circle of Willis with excellent functional and cosmetic outcomes., Clinical Presentation: 53-years-old female who presented with an incidentally found 6.3 mm BA aneurysm with 3.1 mm neck diameter, admitted to our department of neurovascular surgery. Clipping was performed through TPA, with endoscope assistance and intraoperative ICG angiography. The patient's postoperative course was uneventful and was discharged home on postoperative day 5 without any complications., Conclusion: First time in the literature described keyhole TPA with eyelid incision to BA aneurysm. TPA is technically difficult and requires some experience to work through deep and limited surgical corridor. This technique can be good alternative to traditional fronto-lateral, supraorbital keyhole craniotomies.

We examined a cohort of 93 cystic fibrosis (CF) male patients who were pancreatic-sufficient (PS-CF; n=40) or pancreatic-insufficient (PI-CF; n = 53). Complex semen examination was performed, including standard semen analysis, quantitative karyological analysis (QKA) of immature germ cells (IGCs), transmission electronic microscopy (TEM), biochemical analysis, and sperm DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) assay. Azoospermia was diagnosed in 83 (89.2%) patients. The other 10 (10.8%) patients were found to be nonazoospermic and showed various spermatological diagnoses (asthenozoospermia, n = 2; asthenoteratozoospermia, n = 3; oligoasthenozoospermia, n = 1; oligoasthenoteratozoospermia, n = 3; and normozoospermia, n = 1) with no specific morphological abnormalities. Oligospermia was detected in 89.2% azoospermic and 30.0% nonazoospermic patients. Low seminal pH (<7.0) was found in 74 (89.2%) of 83 azoospermic patients. Moderate leukocytospermia (2.0 × 10 6 -2.2 × 10 6 ml -1 ) was revealed in 2.4% azoospermic and 40.0% nonazoospermic semen samples. The signs of partial meiotic arrest at prophase I were found in 4 of 6 nonazoospermic patients examined by QKA of IGCs. The content of fructose and citrate was low in oligospermic and normal in nonoligospermic semen samples. An increased percentage (>30%) of spermatozoa with noncondensed ("immature") chromatin was revealed in 2 of 6 nonazoospermic semen samples analyzed by TEM., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Wire arc additive manufacturing (AM) is able to replace the traditional manufacturing processes of Ti alloys. At the same time, the common drawback of Ti workpieces produced by AM via wire deposition welding is the formation of a coarse-grained dendritic structure, its strong anisotropy and, consequently, lower strength as compared to a monolithic alloy. In this work, a new method is proposed for the enhancement of the strength properties of the Ti-6Al-4V alloy synthesized by AM via wire deposition welding, which involves the use of a wire with an initial ultrafine-grained (UFG) structure. The UFG wire is characterized by a large number of defects of the crystalline lattice and grain boundaries, which will enable increasing the number of "crystallization centers" of the α-phase, leading to its refinement. The macro- and microstructure, phase composition and microhardness of the Ti-6Al-4V alloy samples were investigated. The microhardness of the alloy produced by layer-by-layer deposition welding using a UFG wire was shown to be on average 20% higher than that of the samples produced by a deposition welding using a conventional wire. The nature of this phenomenon is discussed, as well as the prospects of increasing the mechanical characteristics of Ti alloys produced by additive manufacturing.

The authors present a patient with petroclival meningioma complicated by trigeminal neuralgia. Resection of tumor via anterior transpetrosal approach with microvascular decompression of the trigeminal nerve was performed. A 48-year-old female patient presented with left-sided (V1-V2) trigeminal neuralgia. Magnetic resonance imaging revealed a tumor 33´27´25 mm with a base adjacent to the top of petrous part of the left temporal bone, tentorium cerebelli and clivus. Intraoperative examination revealed true petroclival meningioma extending to trigeminal notch of petrous part of temporal bone. There was additional compression of trigeminal nerve by caudal branch of superior cerebellar artery. Total resection of tumor was followed by disappearance of vascular compression of trigeminal nerve and regression of trigeminal neuralgia. Anterior transpetrosal approach provides early devascularization and resection of true petroclival meningioma, as well as wide imaging of anterolateral surface of the brainstem, identification of neurovascular conflict and vascular decompression.

At present, researchers pay great attention to the development of metastable β-titanium alloys. A task of current importance is the enhancement of their strength and fatigue properties. An efficient method for increasing the strength of such alloys could be severe plastic deformation. The object of this study was a medical metastable β-titanium alloy Ti-15Mo (ASTM F2066). The alloy in the (α + β) state was for the first time deformed by combined processing, including equal channel angular pressing-conform and drawing. Such processing enabled the production of long-length rods with a length of 1500 mm. The aim of the work was to study the effect of the combined processing on the alloy's microstructure and mechanical properties. An ultrafine-grained structure with an average size of structural elements less than 100 nm was obtained. At the same time, high strength and ductility (σ uts = 1590 MPa, δ = 10%) were achieved, which led to a record increase in the endurance limit (σ -1 = 710 MPa) under tension-compression terms.

Introduction: Nowadays, due to universal newborn hearing screening (UNHS) the number of children with mild-to-moderate hearing loss diagnosed in the first year of life has increased significantly. Aside from that, identification of the genetic cause improves the genetic counselling of the families and allows to reveal possible comorbidities which may need a special approach., Objective: To present the characteristics of the early audiologic phenotype in hearing impaired patients with biallelic mutations in the USH2A gene based on systematic analysis of the audiological data., Patients and Methods: 13 patients with mutations in the USH2A gene underwent audiological examination. Most of them were found among a large group of infants with bilateral nonsyndromic sensorineural hearing loss (SNHL) examined under 12 months., Results: Eight out of eleven children failed UNHS and were initially diagnosed as having bilateral nonsyndromic SNHL. Seven children underwent an audiological assessment before the age of 9 months. The earliest audiological examination was carried out at 1 and 3 months. The children with pathogenic variants in the USH2A gene in our examined group were identified in the first year of life via UNHS. The hearing threshold levels (HTL) for the USH2A group are compactly distributed between 51.25 dB and 66.25 dB, quartiles are 54 dB and 63.4 dB, with a median of 60 dB. The audiological profile of patients with biallelic USH2A mutations differs from audiograms of patients who had STRC-related hearing loss. We have not found any significant elevation in hearing thresholds in the first decade of life. We also estimated the prevalence of the USH2A and STRC mutations among GJB2-negative infants with bilateral nonsyndromic SNHL examined under 12 months, and it was 7.5% and 16.1%, respectively., Conclusion: According to our results, the early hearing phenotype in pediatric patients with biallelic mutations in the USH2A- gene is characterized by nonsyndromic mild-to-moderate SNHL in the first decade of life. Our results indicate that the presence of mutations in the USH2A or STRC genes can be expected in a child with congenital mild-to-moderate nonsyndromic SNHL. This information is of practical importance for parents, as they have to know the prognosis of hearing loss for their child from the very beginning. Post-screening follow-up should include adequate clinical, genetic, and social support for children and their parents., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nephropathic cystinosis is a rare autosomal recessive disorder characterized by amino acid cystine accumulation and caused by biallelic mutations in the CTNS gene. The analysis methods are as follows: tandem mass spectrometry to determine the cystine concentration in polymorphonuclear blood leukocytes, Sanger sequencing for the entire coding sequence and flanking intron regions of the CTNS gene, multiplex PCR to detect a common mutation-a 57 kb deletion, and multiplex ligation-dependent probe amplification to analyze the number of exon copies in the CTNS gene. Haplotype analysis of chromosomes with major mutations was carried out using microsatellite markers D17S831, D17S1798, D17S829, D17S1828, and D17S1876. In this study, we provide clinical, biochemical, and molecular genetic characteristics of 40 Russian patients with mutations in the CTNS gene, among whom 30 patients were selected from a high-risk group of 85 people as a result of selective screening, which was carried out through cystine concentration measurement in polymorphonuclear blood leukocytes. The most common pathogenic variant, as in most described studies to date, was the 57 kb deletion, which represented 25% of all affected alleles. Previously non-described variants represented 22.5% of alleles. The founder effect in the Karachay and Chechen ethnic groups was shown for the following major variants: c.1015G > A and c.518A > G., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Savostyanov, Pushkov, Shchagina, Maltseva, Suleymanov, Zhanin, Mazanova, Fisenko, Mishakova, Polyakov, Balanovska, Zinchenko and Tsygin.)

Objectives: The present study investigated the stability of furosemide under space-flight conditions on board the International Space Station, as well as its pharmacokinetics and pharmacodynamics under conditions simulating exposure to some space-flight factors., Methods: Quantitative analysis of furosemide tablets by HPLC was performed before spaceflight (background), then after six months storage under normal ground conditions (control) and under spaceflight conditions (SF). The pharmacokinetics and pharmacodynamics of furosemide were studied in six healthy volunteers after a single oral dose of 40 mg under normal conditions (background) and under anti-orthostatic hypokinesia (ANOH)., Results: Quantitative content of furosemide in tablets before SF was 40.19 ± 0.28 mg (100.47 ± 0.71%), after 6 months storage: under normal conditions (control) - 39.9 ± 0.39 mg (99.73 ± 0.98%), under SF - 39.24 ± 0.72 mg (98.11 ± 1.80%), which was within the prescribed limits. Studying basic hemodynamic parameters showed that in ANOH conditions 6 h after furosemide administration there was a statistically significant increase of the stroke volume (SV) (+36.5 Δ%), a tendency for increasing of the stroke index (SI) (+36.5 Δ%) and decreasing of the total peripheral resistance (TPR) (-21.9 Δ%) compared to baseline study., Conclusions: It has been established that various factors of space flight (overloading, excessive vibration, microgravity, etc.) do not negatively influence the stability of furosemide in tablet form during storage for 6 months on board the International Space Station., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Gyrate chorioretinal atrophy (GCA) is a rare hereditary disease with certain complications; one extremely rare complication of GCA is foveoschisis. For the first time in Russian ophthalmology, a 10-year-old female child has been described to have genetically verified GCA associated with the OAT gene in combination with ornithinemia and foveoschisis. The diagnosis was made on the basis of fundus examination, perimetry data, autofluorescence, optical coherence tomography, fluorescence angiography, electroretinography, mass spectrometry with confirmation by molecular genetic research. The presented clinical case illustrates the need for an interdisciplinary approach to the diagnosis of GCA with diagnostic algorithm involving various examination methods and doctors of different specialties.

Objective: To present a patient with brainstem abscess treated by microsurgical resection., Case Presentation: A 53-years-old female patient admitted to the neurosurgical department in a severe condition with symptoms of intracranial hypertension, hyperthermia, general infectious signs and laboratory manifestations of infectious process. Contrast-enhanced MRI revealed a large brainstem lesion (abscess). Retrosigmoid craniotomy with total microsurgical resection of the abscess was performed. External ventricular drainage was incerted on the second postoperative day due to progressive hydrocephalus with clinical deterioration, it was removed in 8 days. Slow positive dynamics was observed in postoperative period. The patient was discharged in 2 weeks after surgery., Conclusion: There are no established algorithm for the treatment of brainstem abscesses. Therapeutic approach is advisable for small abscesses. There are 2 neurosurgical options for this lesion: stereotactic drainage and microsurgical resection with or without external ventricular drainage. Treatment strategy depends on location and size of abscess, as well as clinical state of the patient.

Objectives: To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions., Methods: The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied., Results: The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in V z for verapamil (-54 Δ%), furosemide (-20 Δ%), propranolol (-8 Δ%), and acetaminophen (-9 Δ%), but a statistically significant increase in V z was found for etacizine (+39 Δ%); there was an increasing trend in Cl t for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Cl t for etacizine, verapamil, and furosemide (-22, -23 and -9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (-5 and -12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (-19 and -20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC 0-∞ (-57 Δ%), C max (-53 Δ%), relative bioavailability of acetaminophen (-52 Δ%) and a sharp increase in Cl t (+147 Δ%), T max (+131 Δ%) as well as a trend towards a significant decrease in T 1/2 (-53 Δ%), MRT (-36 Δ%) and a moderate increase in V z (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC 0-∞ , Cl t , T 1/2 , MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for C max , T max , V z were found in ANOH and SP compared to background studies., Conclusions: The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The issue of point prevalence, cumulative prevalence (CP), and burden of rare hereditary diseases (RHD), comprising 72-80% of the group of rare diseases, is discussed in many reports and is an urgent problem, which is associated with the rapid progress of genetic technology, the identification of thousands of genes, and the resulting problems in society. This work provides an epidemiological analysis of the groups of the most common RHDs (autosomal dominant, autosomal recessive, and X-linked) and their point prevalence (PP) and describes the structure of RHD diversity by medical areas in 14 spatially remote populations of the European part of Russia. The total size of the examined population is about 4 million. A total of 554 clinical forms of RHDs in 10,265 patients were diagnosed. The CP for all RHDs per sample examined was 277.21/100,000 (1:361 people). It is worth noting that now is the time for characterizing the accumulated data on the point prevalence of RHDs, which will help to systematize our knowledge and allow us to develop a strategy of care for patients with RHDs. However, it is necessary to address the issues of changing current medical classifications and coding systems for nosological forms of RHDs, which have not kept pace with genetic advances., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MM declared a past co-authorship with the authors RZ, EG, AM, NP, TV, and SK to the handling editor., (Copyright © 2021 Zinchenko, Ginter, Marakhonov, Petrova, Kadyshev, Vasilyeva, Alexandrova, Polyakov and Kutsev.)

Free from toxic elements biomaterial potentially applicable for load bearing biomedical implants was obtained for the first time by laser cladding of S520 bioactive glass onto ultrafine-grained commercially pure titanium. The cladding process affected the refined structure of the substrate inducing martensitic transformation near its surface. The α' acicular martensite gradually passes into relatively large grains with increasing distance from the substrate surface, which subsequently are transformed into smaller grains of about 2 μm in diameter. Both the melted zone, where the martensite crystalline structure was found, and the HAZ are characterised by relatively lower hardness in comparison with that of the substrate core indicating increased ductility. Such a combination of zones with different properties may have a synergistic effect and is beneficial for the obtained biomaterial. A characteristic region in the form of about 3 μm width band was formed in the melted zone at about 10 μm below the titanium surface. The results of EDS analysis indicate that several glass elements moved into the region while the titanium content in the same area was decreased. High bioactivity of the coated S520 glass was revealed by in vitro testing with SBF solution and almost complete reduction of P concentration occurred after 14 days., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background.  This study deals with a rare (orphan) monogenic connective tissue disorder - Ehlers-Danlos syndrome kyphoscoliotic type 2 (EDSKS2). Kyphoscoliotic type 2 Ehlers-Danlos syndrome is an autosomal recessive disorder caused by mutations in the FKBP14 gene (7p14.3), which encodes the FKBP22 protein. According to the 2017 classification, this type is in group seven - collagen spatial structure and cross-linking defects. We present results of clinical examination and molecular genetic analysis for five patients with age varying from two to fifteen years.  Methods.  Five patients were examined using clinical and laboratory methods. DNA samples used for the analysis were extracted from whole blood samples using a Wizard® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol.  Results.  The major clinical findings were kyphoscoliosis, early motor development delay, muscular weakness, hypotonia and hearing loss. Molecular genetic analysis detected a homozygous c.362dupC duplication in exon 3 of the FKBP14 gene in all five patients. This mutation is common in various countries. Differential diagnostics were carried out to exclude other Ehlers-Danlos syndrome types and myopathies.  Conclusions.  Literature analysis and examination of five EDSKS2 patients demonstrated the involvement of major organs and systems, such as joints, spine, muscles, cardiovascular system, respiratory system, hearing, and vision, into the pathological process. Kidney mobility increases and nephroptosis seems to be secondary caused by muscular weakness. During molecular genetic analysis, to verify EDSKS2 it is recommended to initially search for the c.362dupC duplication, which appears to be common in European countries, including Russia., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Semyachkina AN et al.)

A timely detection of patients with tetrahydrobiopterin (BH4) -deficient types of hyperphenylalaninemia (HPABH4) is important for assignment of correct therapy, allowing to avoid complications. Often HPABH4 patients receive the same therapy as phenylalanine hydroxylase (PAH) -deficiency (phenylketonuria) patients-dietary treatment-and do not receive substitutive BH4 therapy until the diagnosis is confirmed by molecular genetic means. In this study, we present a cohort of 30 Russian patients with HPABH4 with detected variants in genes causing different types of HPA. Family diagnostics and biochemical urinary pterin spectrum analyses were carried out. HPABH4A is shown to be the prevalent type, 83.3% of all HPABH4 cases. The mutation spectrum for the PTS gene was defined, the most common variants in Russia were p.Thr106Met-32%, p.Asn72Lys-20%, p.Arg9His-8%, p.Ser32Gly-6%. We also detected 7 novel PTS variants and 3 novel QDPR variants. HPABH4 prevalence was estimated to be 0.5-0.9% of all HPA cases in Russia, which is significantly lower than in European countries on average, China, and Saudi Arabia. The results of this research show the necessity of introducing differential diagnostics for HPABH4 into neonatal screening practice., Competing Interests: The authors have declared that no competing interests exist. The fact that Kanivets I. is an employee of the company Genomed does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background. Brain aneurysms are found in 1-2% of population and cause subarachnoid hemorrhage (SAH) in 80-85% of cases. In recent decades, the incidence of unruptured aneurysms has increased due to widespread availability of CT and MRI. Microsurgery is still essential in the treatment of cerebral aneurysms., Objective: To assess the effectiveness and safety of minimally invasive approaches in microsurgical treatment of brain aneurysms in comparison with traditional approaches, to clarify the indications and contraindications for minimally invasive approaches., Material and Methods: There were 394 patients with cerebral aneurysms for the period 2014-2019. All patients were divided into 2 groups depending on surgical approach: traditional approach (TrA) ( n =171, 43.4%) and minimally invasive approach (MiniAp) ( n =223, 56.6%). In the TrA group, pterional ( n =85), orbitozygomatic ( n =23) and lateral supraorbital approaches ( n =63) were used. In the MiniAp group, transbrow supraorbital ( n =88), mini-pterional ( n =62), transbrow transorbital ( n =37) and transpalpebral transorbital approaches ( n =36) were used. Treatment outcomes were compared in both groups for patients with ruptured and unruptured aneurysms. We evaluated intra- and postoperative complications, surgery time and postoperative hospital-stay. Neurological outcomes were assessed using the Glasgow Outcome Scale (GOS) and the modified Rankin Scale (mRs). Cosmetic outcomes were compared using the visual analogue cosmetic scale. Unilateral hypesthesia and eyebrow movement were assessed separately after 3, 6 and 12 months., Results: In acute period of SAH, surgery time was significantly less in the MiniAp group ( p =0.001). There were no significant between-group differences in the incidence of intraoperative rupture, surgical and neurological complications ( p >0.05). Postoperative hospital-stay was significantly less in the MiniAp group ( p =0.006). In this group, neurological outcomes were slightly better ( p <0.001), there was no mortality, adverse outcomes occurred in 5.3% of cases ( n =5). In the TrA group, 1 patient died from postoperative hematoma, adverse outcomes were noted in 9 (8.7%) patients. Cosmetic outcomes were significantly better in the MiniAp group ( p <0.001). In delayed period of SAH and unruptured aneurysms, surgery time was less in the MiniAp group ( p =0.051). Incidence of intra- and postoperative complications was similar in both groups ( p >0.05). Hospital-stay was significantly shorter in the MiniAp group ( p <0.001). Functional outcomes were comparable in both groups. Cosmetic outcomes were significantly better in the MiniAp group ( p <0.05)., Conclusion: MiniAp and TrA are characterized by similar efficacy in microsurgical treatment of cerebral aneurysms. MiniAp is recommended only for experienced neurosurgeons in a specialized hospital. Safety and effectiveness of MiniAp are achieved by careful selection of patients, individual neuroimaging and preoperative planning.

Familial adenomatous polyposis (FAP) is a hereditary syndrome characterized by the presence of multiple adenomatous polyps in the colon. The main cause of the disease is a germline mutation in the APC gene. Here we report 4 unrelated FAP patients with different large deletions in the APC gene detected by Multiplex Ligation-dependent Probe Amplification (MLPA) method: deletion of exons 7-15, deletion of promoters B, A, and 5'-UTR region and deletion of promoter B (in 2 patients). The deletion of promoters B, A, and 5'-UTR was not described in the literature earlier, so we report it for the first time. In 2 families with promoter B deletion, we could identify the tendency for decreasing the age of disease manifestation in each next generation, in contrast to the previous one. The incidence of large deletions in APC among Russian patients with FAP reached 4.8% and our finding suggests the need to study this gene by MLPA in "no mutation patients" after Sanger's sequencing.

Congenital sensorineural hearing loss is related to mutations in numerous genes encoding the structures of the inner ear in majority of the cases. Mutations in GJB2 gene are the most frequently identified causes of congenital nonsyndromal hearing loss. GJB2 gene testing became a routine clinical tool. For GJB2-negative patients new genetic approaches including methods based on new generation sequencing give a chance to identify mutations in other genes. The frequent reason of mild-to-moderate hearing loss such as the deletions/mutations of the gene STRC encoding stereocilin protein were recognized (OMIM: 606440)., Objectives: To evaluate the audiological features in hearing impaired patients with deletions and point mutations in the STRC gene., Patients and Methods: The group of 28 patients from 21 unrelated families with pathological mutations in the STRC gene underwent audiological examination. The description and analysis of the results of full audiological examination was provided., Results: All patients initially had bilateral nonsyndromal sensorineural hearing loss. Among 11 homozygotes of large deletion harboring STRC to CATSPER2 genes were 7 male individuals indicating the presence of male infertility syndrome. In general, 7 children failed audiological screening and 4 children underwent audiological assessment in the age of 3 and 6 months. The most frequently hearing thresholds were registered between 35 and 55 dB that corresponds to mild-to-moderate hearing impairment. The average age of diagnostics was 7.9 years (ranged from 3 months to 45 years). In the majority of patients the audiological profiles were flat or descending with elevation of thresholds at middle and high frequencies and relatively preserved thresholds at low frequencies. Hearing thresholds are symmetric and stable with age., Conclusion: STRC-linked hearing loss is congenital, of mild and moderate severity. Special clinical and genetic approach for children who failed newborn hearing screening with mild-to-moderate hearing loss is necessary., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient. Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells. Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels. Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype., (Copyright © 2020 Altamura, Ivanova, Imbrici, Conte, Camerino, Dadali, Polyakov, Kurbatov, Girolamo, Carratù and Desaphy.)

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population., Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel 'spastic paraplegias' with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing., Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others., Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

Background: The evolution of skull base approaches associated with individualization of surgical corridor and minimizing the collateral damage. Achieving the radical removal of tumor and preserving the neurological status of the patient is possible, both with the traditional approaches and keyhole approaches. Our work presents experience using the transpalpebral approach (TPA) for microsurgical removal of tuberculum sellae meningioma (TSM)., Materials and Methods: A total of 15 patients with meningiomas underwent microsurgical removal of TSM through TPA. Ten patients were women and five were men. The standard preoperative diagnostic protocol includes magnetic resonance imaging with contrast enhancement, brain computed tomography for neuronavigation. We assess surgical complications, functional and cosmetic outcomes, and surgical parameters, including the time of surgery and intraoperative blood loss., Results: Visual impairment was finding in 100% patients, including slight decrease of vision (46,7%, seven patients), partial vision field loss (six patients, 40%), and serious visual impairment (two patients 13.3%). Visual improvement was noted in ten cases (66.7%), there was no improvement in four cases (26.7%), and one case (6.6%) had transient visual worsening for 4 days and slow improvement in 1 month. Headache disappeared in three patients (50%). There were no cases of cerebrospinal fluid leak. Transient frontal hypoesthesia was noted in all patients (100%) without permanent deficit. Transient palsy of the frontal muscle was noted in four patients for 4-6 months. Histological examination revealed WHO Grade I meningioma in 14 cases and in 1 case WHO Grade II meningioma. No deaths were identified in follow-up at 12 months. The average value of the Modified Rankin Scale was 1.4. The mean length of stay in hospital was 5., Conclusion: TPA is technically difficult and requires some experience to work in deep structures in a small surgical corridor. This technique can be good alternative to traditional fronto-lateral, supraorbital keyhole craniotomies, and endoscopic endonasal approaches., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Asian Journal of Neurosurgery.)

We studied pharmacokinetics and bioavailability of verapamil, propranolol, and ethacizine in healthy volunteers after single oral administration under normal conditions and on the second day of simulated antiorthostatic hypokinesia modeling some effects of microgravity. Under conditions of antiorthostatic hypokinesia, a tendency to a decrease in half-elimination period, mean retention time, and volume of distribution and an increase in the rate of absorption, ratio of maximum concentrations, and relative rate of absorption of verapamil and propranolol were revealed. For ethacizine, a statistically significant increase in the time of attaining maximum concentration and volume of distribution and a decrease in the maximum concentration, rate of absorption, ratio of maximum concentrations, and relative rate of absorption under conditions of antiorthostatic hypokinesia were found.

Pathogenic variants in the HINT1 gene lead to hereditary axonopathy with neuromyotonia. However, many studies show that neuromyotonia may remain undiagnosed, while axonopathy is the major clinical finding. The most common cause of neuromyotonia and axonopathy, especially in patients of Slavic origin, is a c.110G>C (p.Arg37Pro) pathogenic variant in homozygous or compound heterozygous state. In this study, we analyzed a peripheral neuropathy caused by pathogenic variants in the HINT1 gene and evaluated its contribution to the hereditary neuropathy structure. The studied group included 1596 non-related families diagnosed with hereditary motor and sensory neuropathy (HMSN). The results show that HINT1 gene pathogenic variants make a significant contribution to the hereditary neuropathy epidemiology in Russian patients. They account for at least 1.9% of all HMSN cases and 9% of axonopathy cases. The most common HINT1 pathogenic variant in Russian patients is the c.110G>C (p.Arg37Pro) substitution. Its allelic frequency is 0.2% (95% CI 0.19-0.21%), carrier frequency is 1 in 250 people in Russian Federation, and the estimated disease incidence is 1 in 234,000 individuals. It was determined that the cause of this pathogenic variant's prevalence is the founder effect.

Prevalence and allelic heterogeneity of hereditary diseases (HDs) could vary significantly in different human populations. Current knowledge of HDs distribution in populations is generally limited to either European data or analyses of isolated populations which were performed several decades ago. Thus, an acknowledgement of the HDs prevalence in different modern open populations is important. The study presents the results of a genetic epidemiological study of hereditary diseases (HDs) in the population of the Karachay-Cherkess Republic (KChR). Clinical screening of a population of 410,367 people for the identification of HDs was conducted. The population surveyed is represented by five major ethnic groups-Karachays, Russians, Circassians, Abazins, Nogais. The study of the populations was carried out in accordance with the proprietary protocol of genetic epidemiological examination designed to identify >3500 HDs easily diagnosed during clinical examination by qualified specialists specializing in the HDs. The protocol consists of the population genetic and medical genetic sections and is intended for comprehensive population analysis based on the data on different genetic systems, including the genes of HDs, DNA polymorphisms, demographic data collected during hospital-based survey. 8950 families (with 10,125 patients) with presumably the HDs were initially identified as a result of the survey and data collection through various sources of registration (from 1156 medical workers from 163 medical institutions). A diagnosis of hereditary pathology was established in 1849 patients (from 1295 families). Two hundred and thirty nosological forms were revealed (in 1857 patients from 1295 families). The total prevalence of HDs was 1:221. Differences between populations and ethnic groups were identified: 1:350 in Russians, 1:195 in Karachays, 1:199 in Circassians, 1:218 in Abazins, 1:135 in Nogais. Frequent diseases were determined, the presence of marked genetic heterogeneity was identified during the confirmatory DNA diagnosis. To explain the reasons for the differentiation of populations by load of HD, a correlation analysis was carried out between the F ST (random inbreeding) in populations and HDs load values. This analysis showed genetic drift is probably one of the leading factors determining the differentiation of KChR populations by HDs load. For the first time, the size of the load and spectrum of HDs in the populations of the KChR are determined. We have demonstrated genetic drift to be one of the main factors of the population dynamics in studied population. A significant genetic heterogeneity of HDs, both allelic and locus, was revealed in KChR.

Objective: The description of a clinical picture and audiological features at the hearing loss caused by changes of a STRC gene, coding protein stereocillin (MIM: 606440). Mutations in the numerous genes responsible for the inner ear proteins are the reason for congenital sensorineural hearing loss. The main cause of congenital bilateral sensorineural hearing loss in the Russian Federation are mutations in GJB2 gene it reaches up 68% of cases identified in infancy. GJB2 gene tests already became routine around the world. Possibilities of new methods based on sequencing of new generation (NGS, next generation sequencing) allow to conduct a research of more rare genes connected with a hearing impairment. The most often among GJB2 negative patients reveal mutations and deletion of a gene of STRC ., Patients and Methods: Full audiological examination of 5 children and one adult with a hearing loss from 2 unrelated families is provided. Mutations in STRC gene were identified. All children are examined aged before 8 years, and 3 children failed universal audiological screening in maternity hospital, to two children screening was not carried out as they were born till 2009., Results: The children with the sensorineural hearing loss connected with mutations and deletion of STRC gene failed hearing screening in maternity hospital because of the OAE is not registered, what indicates the congenital nature of a hearing loss. Recently it could not be noticed earlier because of slight increase of hearing thresholds and was regarded only as the early onset. Our data emphasize that the of thresholds from 35 to 60 dB in frequencies 0,5-4 kHz is common for mutations/deletions of STRC gene., Conclusion: The development of molecular genetics methods confirms the hereditary causes of GJB2 -negative patients and expands indications for family counseling. Special approach for child with hearing loss so early revealed is necessary and the consultation of parents frightened of screening results is very important.

Otoferlin ( OTOF ) gene mutations are the most common cause of hereditary ANSD according to investigations in several countries., The Aim: Of this study was to estimate the prevalence of OTOF mutations in Russian children with ANSD and evaluate audiological and clinical features of OTOF -related ANSD., Patients and Methods: 28 children with bilateral ANSDwere enrolled in the investigation. Two step genetic testing was performed: first step - GJB2 gene testing to exclude GJB2 -related hearing loss; second step - NGS-based sequencing to explore another 35 hearing loss genes (including OTOF )., Results: OTOF mutations, including 6 new variants, were found in 5 children with ANSD (18%). All 5 children had no risk factors for hearing loss and passed hearing screening. OAE and cochlear microphonics were present till the last testing at the age of 4-5 years. ABR were not detectable. The ASSR were measurable bilaterally at all frequencies in all cases, but they did not correlate with behavioral thresholds that revealed severe hearing loss. Hearing thresholds were stable during follow up period. 3 children underwent cochlear implantation. After cochlear implantation auditory nerve action potentials to electric stimulation were detected within normal range., Conclusion: Genetic testing of children with ANSD and first of all OTOF testing enables to reveal hearing loss etiology and provide the optimal rehabilitation approach, including cochlear implantation, as early as possible.

Introduction: Cavernous malformation (cm) of the optic nerve is a rare condition It is clinically presented by the so-called chiasmal apoplexy. Microsurgical removal of cavernous malformation is the method of choice., Material and Methods: Authors present a clinical case of the removal of cavernous malformation of the left optic nerve., Results: The presented case demonstrates the successful removal of the CM of the left optic nerve from the lateral supraorbital access. In the postoperative period, visual disorders did not worsen. Control MRI of the brain showed total removal of cavernoma., Conclusion: Presented clinical case demonstrates the radical removal of CM of the optic nerve. Early and correct diagnosis makes it possible to adequately treat the patient and preserve his/her visual functions.