A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings

Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a very rare recessive hereditary disorder. At the moment, ten CMS22 patients are described, with the disorder caused by nine different Loss-of-Function mutations and 14 gross deletions in the PREPL gene. The materials for our study were DNA samples of five family members: two patients with myasthenia, their healthy sibling and parents. Clinical exome analysis was carried out for one patient, then the whole family was checked for target variants with Sanger sequencing, quantitative multiplex ligation-dependent probe amplification, and chromosome 2 microsatellite markers study. To determine the functional significance of the splicing variant, we applied the minigene assay. The cause of the proband’s disorder is a compound heterozygous state of two previously non-described pathogenic PREPL variants: a c.1528C>T (p.(Arg510Ter)) nonsense mutation and a c.2094G>T pseudo-missense variant, which, simultaneously with a p.(Lys698Asn) amino acid substitution, affects splicing, leading to exon 14 skipping in mRNA. The second patient’s disorder was caused by a homozygous nonsense c.1528C>T (p.(Arg510Ter)) mutation due to maternal uniparental disomy (UPD) of chromosome 2. In this study, we describe a unique case, in which two siblings with a rare disorder have different pathologic genotypes

Dynamics of kidney disorders in children with juvenile idiopathic arthritis taking into account therapy resume

Introduction. In the study of the course and consequences of rheumatic diseases much attention is paid to comorbid conditions that significantly affect the function of internal organs, including kidneys. According to the concept of cardiorenal ratios, even minor renal impairment can be an independent risk factor for cardiovascular events and death. Objective. To determine the features of functional disorders of the kidneys in children and adolescents with juvenile idiopathic arthritis (JIA), taking into account the nature of the disease and therapy. Materials and methods. 85 children (8–18 years) with JIA, oligo- (61.5 %) and polyarthritis (38.5 %), 63 girls and 22 boys were examined. The average duration of the disease was 84.13 ± 6.28 months. The study was conducted twice with an interval of one year. Determination of renal status included studies of urinary sediment, concentration and nitrogen excretion capacity of the kidneys (fluctuations in specific weight during the day, daily proteinuria, creatinine and urea in the blood, glomerular filtration rate (GFR)). Statistical processing of the material was performed using parametric (Student's t-test (p), Fisher's angular transformation) and non-parametric parameters (Wilcoxon-Mann-Whitney), correlation and regression analysis. Results. Changes in renal function did not depend on the sex of patients and included proteinuria (9.09 %), namely microalbuminuria, which occurred in all variants of arthritis; reduction of GFR (8.26 %) – only in polyarthritis and uveitis-associated variants. Comparison of the frequency of renal changes in patients with varying degrees of disease activity showed their absence in the inactive stage of JIA. With active inflammatory process functional disorders of the kidneys occurred from 16.67 % to 26.32 % of cases, regardless of the degree of activity One year later there are positive changes: increased glomerular filtration rate (p ≤ 0.05), a tendency to decrease serum creatinine (p ≤ 0.1) on the background of basic methotrexate therapy up to 15 mg/m2/week. The combination of methotrexate therapy with the anti-TNF immunobiological drug (adalimumab) showed greater efficacy in improving renal function, a significant increase in GFR (p ≤ 0.05), a decrease in serum creatinine (p ≤ 0.05) and proteinuria (р ≤ 0,05). Conclusions. Children with JIA have changes in renal function, more often with uveitis-associated arthritis and methotrexate over 15 mg/m2/week. The inclusion of immunobiological drugs in the treatment not only reduces the activity of the disease, but also reduces the risk of concomitant comorbid lesions of internal organs, including kidneys

Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

Intellectual development disorder (IDD) is characterized by a general deficit in intellectual and adaptive functioning. In recent years, there has been a growing interest in studying the genetic structure of IDD. Of particular difficulty are patients with non-specific IDD, for whom it is impossible to establish a clinical diagnosis without complex genetic diagnostics. We examined 198 patients with non-specific IDD from 171 families using whole-exome sequencing and chromosome microarray analysis. Hereditary forms of IDD account for at least 35.7% of non-specific IDD, of which 26.9% are monogenic forms. Variants in the genes associated with the BAF (SWI/SNF) complex were the most frequently identified. We were unable to identify phenotypic features that would allow differential diagnosis of monogenic and microstructural chromosomal rearrangements in non-specific IDD at the stage of clinical examination, but due to its higher efficiency, exome sequencing should be the diagnostic method of the highest priority study after the standard examination of patients with NIDD in Russia