Genetic Aspects of Pathogenesis of Congenital Spastic Cerebral Paralysis

Congenital spastic cerebral palsy (СР) is a large group of non-progressive disorders of the nervous system. The basis of the pathogenesis of these conditions is considered the impact of many factors. The clinical diversity of the disease and the syndromic principle of classification determine the existing uncertainties in the diagnosis of these diseases. The multifactorial nature of the underlying brain lesions is obvious and beyond doubt. The volume of information accumulated to date does not allow one to exclude the role and significance of the direct effect of acute asphyxiation in childbirth on a fetus normally formed during pregnancy, the role of infectious brain lesions, and disorders of neuronal migration. It is impossible to ignore the dependence of the clinical picture of the disease on what stage of ontogenesis the impact of the damaging agent occurs. As one of the pathogenetic factors, the genetic determinism of the phenotype of the clinical picture of a disease is fairly considered. This review focuses on the genetic aspects of the pathogenesis of this pathology. The information on monogenic mechanisms of inheritance is analyzed in detail. Such genetically determined mechanisms of pathogenesis as the inheritance of prerequisites for brain trauma in the perinatal period are considered separately. The new clinically significant variants of chromosomal mutations found in patients with CР are reviewed in detail,  the evidence of the influence of genetic factors on the development of cerebral palsy in the absence of a pronounced monogenic cause of the disease, obtained through twin studies, is reviewed.  Lit search of polymorphisms markers of predisposition to the development of cerebral palsy genes of the folate cycle, genes of glutamate receptors, the gene of apolipoprotein and of the gene for the transcription factor of oligodendrocytes (OLIG2) in Detail the role of epigenetic effects on the activity of genes coding for mitochondrial proteins

Новая мутация в гене TRIP4, ассоциированная с фенотипом врожденной мышечной дистрофии типа Давиньон–Шове (клинический случай)

Congenital muscular dystrophies are heterogeneous groups of neuromuscular diseases leading to hypotonia, progressive muscle weakness and dystrophic or structural signs in muscle biopsy. At the present time, 34 genes associated with congenital muscular dystrophy have been described. The clinical case of a rare form of congenital muscular dystrophia associated with a homozygous mutation in the TRIP4 gene in a patient with respiratory failure requiring respiratory support, neurological symptoms, muscular hypotonia, and multiple congenital malformations of skeletal system is presented for the first time in Russia. The undescribed pathogenic homozygous variant of the nucleotide sequence in the TRIP4 gene (chr15:64686179, c.136C>T, p.Arg46Ter, 2 exon, NM_016213.4) was detected by whole exome sequencing. The mutation in the TRIP4 gene was validated by Sanger sequencing in a child and its origin was investigated. The mother and father of the girl are carriers of the heterozygous variant in the TRIP4 gene. Identification of the genetic cause of a rare form of neuromuscular disease is important for determining the tactics of patient management and medical and genetic counseling of the family, as well as clarifying the pathogenesis of a rare pathology. Врожденные мышечные дистрофии и врожденные миопатии представляют собой гетерогенную группу нервно-мышечных заболеваний, приводящих к гипотонии, прогрессирующей мышечной слабости и дистрофическим или структурным признакам при мышечной биопсии. В настоящее время описано 34 гена, связанных с врожденной мышечной дистрофией. Впервые в России представляется клинический случай редкой формы врожденной мышечной дистрофии, обусловленной гомозиготной мутацией в гене TRIP4, у пациента с дыхательной недостаточностью, требующей респираторной поддержки, неврологической симптоматикой, мышечной гипотонией, множественными врожденными пороками развития опорно-двигательной системы. В результате проведенного полноэкзомного секвенирования выявлен ранее не описанный патогенный вариант нуклеотидной последовательности в гене TRIP4 в гомозиготном состоянии, приводящий к остановке синтеза полнофункционального белка (chr15:64686179, c.136C>T, p.Arg46Ter, 2 й экзон, NM_016213.4). Мутация в гене TRIP4 была валидирована методом секвенирования по Сэнгеру у ребенка, и исследовано ее происхождение. Мать и отец девочки являются носителями гетерозиготного варианта в гене TRIP4. Выявление генетической причины редкой формы нервно-мышечного заболевания важно для определения тактики ведения пациента и медико-генетического консультирования семьи, а также уточнения патогенеза редкой патологии

An otorhinolaryngologist's view on the problem of children with submucous cleft palate

Today, congenital cleft lip and palate (CCLP) is the most common congenital malformation of the maxillofacial area. According to different authors, the incidence of the defect among infants is 1 per 500--1000 depending on the region. In most cases, CCUPP is not difficult to diagnose; it is detected in the maternity hospital, and child with its parents is sent to a specialized institution for surgical treatment. However, there is a type of isolated cleft palate which may be very difficult to diagnose due to absence of evident defect of the palate. This is hidden (submucosal) congenital cleft palate. [1, 7]

THE GENETIC SUSCEPTIBILITY TO ATHEROSCLEROSIS

Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Atherosclerosis is the main cause of death and disability in developed countries, while in developing countries the incidence of this pathology is growing rapidly. Advances in techniques of molecular genetics have revealed that genetic polymorphisms significantly influence susceptibility to atherosclerotic vascular diseases. A large number of candidate genes, genetic polymorphisms and susceptibility loci associated with atherosclerotic diseases have been identified in recent years and their number is rapidly increasing. In recent years, there is significant interest in identifying additional factors of genetic risk for atherosclerosis. In recent years, a large number of genetic studies have been carried out to prove the genetic effect on the atherosclerotic process. Rapid progress in the sequencing of the human genome and molecular genetic methods have helped in the definition of susceptibility loci and associated candidate genes with atherosclerosis and concomitant diseases. The association of a large number of susceptibility genes with atherosclerosis reflects the enormous complexity of the disease. Multiple factors, including endothelial dysfunction, lipid metabolism defects, inflammation and immune responses, oxidative stress, cell proliferation, tissue remodeling and hemostatic defects are involved in the pathogenesis of atherosclerosis. In this review we focus and discuss on some of the major candidate genes and genetic polymorphisms associated with human atherosclerotic vascular diseases

Mutation of the ALDH7A1 gene in a patient with pyridoxal phosphate-dependent neonatal epileptic encephalopathy: a clinical case

The article presents a clinical case of severe infantile generalized idiopathic epilepsy with status-like seizures, muscular dystonia and developmental delay. The examination included a phenotypic analysis: the course of the perinatal period, the nature of seizures, cognitive and behavioral disorders; video electroencephalography, and brain MRI. Using the targeted exome sequencing of genes associated with epileptic encephalopathy (NGS), we detected a nucleotide heterozygous variant of the ALDH7A1 gene (previously not described). This mutation led to the appearance of a stop codon in position 82 of the protein p.Arg82Ter and the amino acid substitution in position 399 of the protein p.Glu399Gln. This clinical observation demonstrates the importance of DNA-based diagnosis involving the targeted exome sequencing to identify molecular defects, especially in severe neonatal drug-resistant seizures. In the case of confirmed mutations in the ALDH7A1 gene, the patient should be given vitamin B6 at the therapeutic doses for seizure relief

Experience of application of proproceptive modeling of walking in children of early age with motor disorders

Background. In the pathogenesis of cerebral palsy, the pathology of the proprioceptive modality plays an important role. Proprioceptive correction is an effective method for habilitation of children suffering from this disease. "Stimulation of the feet" is one of the methods of proprioceptive correction. In the process of treatment, pressure is applied to the receptor zones of the feet with pneumatic elements. The pressure is produced in walking mode and simulates the effect of the step on the foot. Objective: the rehabilitation treatment of children with the consequences of perinatal damage to the central nervous system and various forms of cerebral palsy.Materials and methods. The results of the rehabilitation treatment of 51 children with the consequences of perinatal damage to the central nervous system in 2 age groups: from 7 months to 1 year and from 1 year to 2 years are described. The average age of children was 1.8 ± 0.054 years, standard deviation 0.385. Among them, 27 (52.9 %) were boys, 24 (47.1 %) girls. The children had various motor dysfunctions. Children with a predominance of spasticity in the muscles of the lower extremities were 70.6 %, children with a predominance of reduced tone in the muscles of the lower extremities were 29.4 %. Rehabilitation treatment was carried out from the simulator of the base load "Сorvit". The course of basic stimulation was 10 procedures lasting from 10 to 15 minutes. The mode of stimulation was selected individually as in the classroom for physiotherapy. The duration and intensity of the pressure on the foot were selected.Results. As a result of treatment, positive dynamics of motor functions was noted. It was expressed in the normalization of muscle tone and with its decrease, and with an increase. The effect of tonic reflexes decreased. In the older group, normalization of the step structure was revealed. A reliable positive dynamics of speech and mental development was recorded. In children aged 7 months to a year with severe spastic paresis, it was statistically significant (p <0.05).Conclusions. Support stimulation is an effective and safe method of physical habilitation of children with the effects of perinatal brain lesions and cerebral palsy

Significance of exome sequencing for diagnosis of epilepsy in children

Introduction. Epilepsy is a neurological disorder characterized by periodic seizure attacks. Around 70–80% of epilepsy cases have a hereditary component.Aim: to identify the genetic factors of pharmacoresistant epilepsy in children.Materials and methods. Fifty two patients with epilepsy and psychomotor / speech retardation were examined. We used the next generation sequencing (NGS) technique, which is the targeted exome sequencing, the “Hereditary epilepsy” panel of genes, and the whole exome sequencing assay.Results. Mutations were detected in 30 (57.7%) patients, while 22 patients had no mutations. In the latter cases, either epilepsy was of non-hereditary nature or the tested nucleotide sequence was located in the non-coding part of the gene (intron); in addition, a chromosomal rearrangement could be involved.Conclusion. The obtained data illustrate a diagnostic significance of the whole exome sequencing and encourage the interaction between an epileptologist and a geneticist in the diagnostic procedure. Identification of the genetic base of the disease is of great importance for genetic counseling and for selecting an antiepileptic therapy in this group of patients.The authors declare about the absence of conflict of interest with respect to this publication. Authors contributed equally to this article

Helsmoortel-van der Aa syndrome syndrome in a patient with epilepsy, developmental delay, intellectual disability, and autism spectrum disorder

Autism spectrum disorders (ASDs) are a group of complex disintegrative disorders of mental development, characterized by a lack of ability to social interaction, communication, stereotyped behavior, leading to social maladaptation. We present a rare clinical case of a delay in psychomotor and speech development, specific facial dysmorphia, impaired behavior, and a detected mutation in the ADNP gene. When conducting targeted exomic sequencing, we revealed a previously undescribed variant of the nucleotide sequence in the ADNP gene (p.Ala1017fs). Mutations in the ADNP gene in a heterozygous state were described for patients with Helsmoortel-van der Aa syndrome (OMIM: # 615873). Mutations in the ADNP gene are the genetic cause of ASD in 0.17% of cases. When interpreting the data of new generation sequencing (NGS) in patients with epileptic encephalopathy, ASD, and characteristic phenotype, it is advisable to take into account that the ADNP gene is one of the key genes responsible for embryonic neurodevelopment

An allelic variant of congenital Salih myopathy

The paper describes the steps and problems of diagnosing congenital myopathy with early respiratory disorders. While differentially diagnosing, the authors consider congenital myopathies, in which early cardiac involvement is encountered. Since the course of the disease in an observed female patient differed from that of such nosological entities and appeared as not only muscle weakness, but also as early respiratory disorders, we could not identify what nosological entity the disease belonged to in view of its clinical presentation and the results of muscle histological examination and we decided to perform exome sequencing. Molecular genetic testing could find heterozygous mutations in the titin (TTN) gene. The findings are suggestive of congenital proximal myopathy with early respiratory failure, which is an allelic variant of Salih myopathy. This case is the first and so far only description of this disease in Russia

Pediatric encephalopathy: cinical, biochemical and cellular insights into the role of Gln52 of GNAO1 and GNAI1 for the dominant disease

Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1