Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia)

Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and с.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes.

Thalassemia Major and Associated Psychosocial Problems: A Narrative Review

Thalassemia is an inherited disease that causes the production of damaged hemoglobin chains. Patients are diagnosed with thalassemia major due to major clinical signs and deep anemia. This study aimed to examine the major thalassemia and psychosocial aspect of it, which is such an important issue, to serve as a roadmap for better handling these patients and to contribute to the literature. The method used in this study was narrative review. A literature review was conducted by searching the materials published in databases including Web of Science, PubMed, Scopus, and Google Scholar search engine from 2001 to 2020. Besides WHO website was searched. Thalassemia major damages the heart, liver, lungs and endocrine organs due to anemia and iron accumulation. In addition, the patient may experience mental and social problems due to the congenital nature of the disease and its lifelong duration. The psychosocial problems and treatment burdens of thalassemia patients are very high. There are many studies about the prevalence and physical consequences of thalassemia. However, there are not enough articles and researches describing the psychosocial effects of thalassemia on patients and what can be done about these effects. For this reason, this paper focuses on the process of thalassemia and the psychosocial problems it creates to contribute to the literature and to be a roadmap for better handling these patients.

The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

Guidelines for genetic testing of healthy adults who deposit samples and related data in bioresource collections and biobanks

Currently, a significant part of research in the fields of human and medical genetics is carried out using tissue samples, genealogical, population, medical and personal data. Their use is of particular relevance in the “genome era”, since only joint analysis of genomic data and health status of the population is crucial for understanding how genes are associated with health and disease. Genetic studies of adults without symptoms of diseases are carried out to obtain data on a possible predisposition to multifactorial diseases, to establish the carrier status of autosomal recessive mutations as part of preconception care and to assess individual sensitivity to drugs. In addition, healthy individuals can be tested to detect an inherited disease at presymptomatic stage. This situation increasingly emphasizes the importance of storing data on genome sequencing or any other patient tests for subsequent data reanalysis, as well as their safety, including biosamples from an individual and one’s family. The review article, based on international experience, summarizes guidelines for genetic testing of healthy individuals. The options for storing biological samples and related data are considered.

Successful Anesthetic Management of Myotonic Dystrophy Type I Using Sugammadex: A Case Report

Myotonic dystrophy (DM) is an uncommon inherited disease. Anesthesia for DM patients is tough due to its potency of cardiogenic and pulmonary problems, but a series of studies have shown how to manage and avoid complications and situations. We describe a case of a 33-year-old male patient who was scheduled for an elective excision & biopsy on the left axillae for hidradenitis suppurativa with DM type I. Anesthesia was induced and maintained with propofol, remifentanil, and rocuronium. Sugammadex is used as a reversal agent of neuromuscular blockade. He didn’t show myotonia during surgery and emergence. He also didn’t show postoperative pulmonary complications.

Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in CFTR, the most frequent of which is F508del. F508del causes ER retention and degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life at the plasma membrane. Despite the recent successes with small-molecule CFTR modulator drugs, the folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment of polarized bronchial epithelial monolayers with the VX-809+VX-770 combination resulted in epithelial dedifferentiation effects that we found were caused specifically by VX-809. Moreover, prolonged VX-770 exposure also led to the destabilization of VX-809-rescued F508del-CFTR. Notably, co-treatment with the physiological factor HGF prevented VX-809-mediated epithelial differentiation and reverted the destabilizing effect of VX-770 on VX-809-rescued CFTR. Here, we show that prolonged treatment with VX-661, a second-generation corrector developed based on VX-809 structure, does not perturb epithelial integrity of polarized bronchial epithelial monolayers. Yet, its efficacy is still affected by co-exposure to VX-770, the potentiator present in all VX-661-containing combination therapies approved in the United States and Europe for treatment of F508del-CFTR carriers. Importantly, we found that co-treatment with HGF still ameliorated the impact of VX-770 in F508del-CFTR functional rescue by VX-661, without increasing cell proliferation (Ki-67) or altering the overall expression of epithelial markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight the importance of evaluating the cellular effects of prolonged exposure to CFTR modulators and suggest that the benefits of adding HGF to current combination therapies should be further investigated.

ADHD from Chıldhood to Adulthood

ttention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in childhood, characterized by inattention, impulsivity, and hyperactivity. Recognizing and diagnosing ADHD in children is mostly during the school period. ADHD negatively affects children's skills necessary for academic success and social adaptation in the school environment. ADHD symptoms are at the forefront of the situations in which the child, not only the parents but also the teachers, directs the family to seek treatment or help. ADHD appears to affect 5-10% of children and 4.4% of adults worldwide. ADHD is a genetically inherited disease that emerges with the effect of genetic factors. For this reason, problems may arise in family functions when there is more than one person with ADHD at home. In this study, DSM-5 diagnostic criteria, models developed for the diagnosis of adult ADHD and what families can do when living with ADHD are shared.

Can newborn screening be cost benefit procedure if preventing serious complications of cystic fibrosis?

Cystic Fibrosis (CF) is a common inherited disease with reported mean prevalence of 0.737/10,000 in 27 EU countries (Farrell J Cyst Fibros. 2008). Still, many EU countries have not implemented CF in the Newborn Screening (NBS) programme, including our country. We report the case of a 7-month-old boy whose presenting signs of CF were life-threatening neurological symptoms caused by severe metabolic alkalosis and hypoelectrolytemia. By presenting this case, we argue hoping to persuade the authorities in any country that the available newborn screening for CF is the cost benefit procedure in preventing life treating consequences with the obvious impact on the long-term prognosis of this chronic disease.

Two Novel Mutations in the SI Gene Associated With Congenital Sucrase-Isomaltase Deficiency: A Case Report in China

Background: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive inherited disease that leads to the maldigestion of disaccharides and is associated with mutation of the sucrase-isomaltase (SI) gene. Cases of CSID are not very prevalent in China or worldwide but are gradually being identified and reported.Case Presentation: We report a case involving a 14-month-old male who presented with failure to thrive that had begun after food diversification and was admitted for chronic diarrhea. We used a whole-exome sequencing (WES) approach to identify mutations in this patient's genome. WES revealed two novel heterozygous mutations in the SI gene, c.2626C > T (p.Q876*) and c.2872C > T (p.R958C), which were confirmed by Sanger DNA sequencing. With a strict sucrose- and starch-restricted diet, the patient's diarrhea was resolved, and he began to gain weight.Conclusions: We report a case of novel variants in the SI gene that caused CSID. This report provides valuable information for the clinical field, especially in China.

527 An incidental diagnosis in a patient with SARS-CoV-2 pneumonia

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic disease of the myocardium, with a prevalence of 1:500 cases in the general population. The salient feature is a hypertrophy, symmetrical or not, of the walls of the left ventricle (mainly the septum, but also less typical locations, such as the apex or the infero-lateral wall), not linked to abnormal load conditions. HCM is mostly an autosomal dominant inherited disease with incomplete penetrance and variable expressivity, mainly linked to mutations in genes coding for sarcomeric proteins. Several studies have shown an up-regulation of the ACE-2 gene, perhaps indicative of a compensatory anti-hypertrophic and anti-fibrotic response of the myocardium, in hypertrophic cardiomyopathy. Being the ACE-2 receptor target of the SARS-CoV-2 virus, these patients may have an increased risk of infection and a worse outcome. A 47-year-old man, with no known comorbidities, was hospitalized in our Emergency Medicine Department for bilateral SARS-CoV-2 pneumonia. Noninvasive mechanical ventilation c-PAP (FiO2 60%, PEEP 7.5 cmH2O) was started for hypoxemic respiratory failure and an ECG showed diffuse ventricular repolarization abnormalities suggestive of left overload (asymmetric negative T waves V4–V6, in I, II, and aVL, flat in aVF. Figure 1), with a deep Q wave in III. The patient was asymptomatic for chest pain and equivalents and D-dimer and indices of myocardionecrosis were normal. Echocardiographic evaluation was performed, with evidence of marked asymmetric concentric hypertrophy of the left ventricle (interventricular septum: 16 mm), without significant anomalies in segmental kinetics, noteworthy valvulopathies, and pericardial effusion. The family and personal medical history were negative for syncope, sudden cardiac death, and resuscitated cardiac arrest and the estimated risk of sudden cardiac death at 5 years (HCM Risk-SCD) was <4% (1.33%). The diagnostic hypothesis of non-obstructive hypertrophic cardiomyopathy was advanced. During hospitalization, ECG monitoring showed no sustained ventricular arrhythmias and the patient remained asymptomatic for dyspnoea, chest pain, and equivalents. Subsequent echocardiograms showed no new changes. A progressive weaning from oxygen support was carried out and, after 30 days, the patient was discharged to home fiduciary isolation, with optimal cardiological therapy and indication to study with cardiac magnetic resonance to the negativization of the nasal swab for SARS-CoV-2. MRI, performed about 2 months later, confirmed the suspicion of hypertrophic cardiomyopathy, with no signs of late enhancement in T1-weighted sequences (Figure 2). The patient was then referred to a genetic study and cardiological follow-up, still in progress.