Introduction. The problem of early diagnostics of orphan diseases is relevant for most countries of the world. The challenge for healthcare is to prevent new cases of orphan diseases by providing medical genetic testing and counseling at the stage of family planning. Department of psychoneurology of the State Intstitution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine" has been dealing with the problem of orphan diseases since 2012 and has significant experience in their diagnosis and treatment in children.The aim of paper: to develop an algorithm for the genetic diagnosis of epileptic and developmental encephalopathies in children with developmental delay and dimorphic features based on modern data on the application and interpretation of genetic methods. A case which demonstrate the complexity of interpreting the results and algorithms for early diagnosis of patients and the importance of medical and genetic counseling is presentedMaterial and methods: clinical and neurological examination, sleep video-EEG monitoring during night sleep, brain magnetic resonance imaging (3.0T), whole-exome sequencing (WES).Results. The article presents the algorithm of genetic diagnosis of orphan diseases in children with developmental and epileptic encephalopathies, developmental delay, and dimorphic features. A clinical case of a boy with general developmental delay and atonic epileptic seizures is presented. Sleep EEG-monitoring showed epileptiform activity in the stage of slow-wave sleep localized in the central-parietal and left temporal areas in the form of benign childhood epileptiform patterns.Whole-exome sequencing detected a variant of uncertain significance (VUS) c.5887C>T(p.Arg1963Cys) of SON gene in a heterozygous state, which leads to the replacement of arginine to cysteine. Mutations in the SON gene in the heterozygous state have been described in patients with Zhu-Tokita-Takenouchi-Kim syndrome (OMIM: 617140).Conclusions: It is important for pediatricians and neurologists to be aware of orphan diseases in children with developmental and epileptic encephalopaties and developmental delay. Genetic tests are wide available but they require competent interpretation by clinicists. After obtaining the results, it is important to compare the obtained result with the phenotype of patient. In case the phenotype of patient match and the results of genetic test, (detected VUS) this mutation could be etiological factor of the disease. In our case, the clinical signs coincided with those described in 2015 by the authors of the first description of Zhu-Tokita-Takenuchi-Kim syndrome, and therefore genetic testing helped to verify the final diagnosis. Therefore genetic counseling is extremely important for detection of etiology and prognosis of early developmental and epileptic encephalopathies/
This paper considers the pathogenesis and causes of increasing the prevalence of anxiety disorders and neuroticism in children, approaches to patient management, the role of pharmacological and non-pharmacological methods of correction for such disorders. Particular attention is paid to the definition and diagnosis of certain nosological forms of anxiety disorders in children. The results of own clinical observation of children with neurosis-like conditions, anxiety disorders and sleep disorders and the use of modern pharmacotherapy in the correction of these disorders are also presented.
Purpose - to determine the prevalence of sleep disorders in children with epileptic encephalopathies and autism spectrum disorder (ASD); to evaluate the effectiveness of neuroadaptogenic «Silenta» in the treatment of sleep disorders in children in this group. Materials and methods. We examined 50 children with clinical manifestations of ASD aged 2 to 8 years (mean age was 4.3 years±1.5), including 31 boys and 19 girls. The examination included anamnesis to clarify the features of the pre- and perinatal period, clinical and neurological examination, video EEG monitoring during night sleep for 8 hours, survey of parents on the quality of sleep in children using the Children’s Sleep Habits Questionnaire (CSHQ). All children were divided into 2 groups depending on clinical features: Group 1 - 28 children with ASD who had epileptic seizures at the time of examination or in the anamnesis (children with epileptic encephalopathies); Group 2 - 22 children with ASD without clinical epileptic seizures. Children from the 1st group were prescribed neuroadaptogen «Silenta» for 30 days. Results. Children with ASD and epileptic seizures had higher sub-scales «Difficulty falling asleep», «Parasomnia» and the overall score on the CSHQ-A scale. The results indicate a negative impact of epileptic seizures in children with ASD on sleep quality and the frequency of paroxysmal sleep disorders. The overall prevalence of sleep disorders in children with ASD was determined using the CSHQ-A questionnaire before and after treatment. The incidence of sleep disorders in children with ASD and epileptic seizures after treatment decreased from 85.7% to 53.6%, and in children with ASD without epileptic seizures - from 63.6% to 22.7%. In both groups statistically significant reduction in the proportion of children with sleep disorders after a course of treatment with neuroadaptogen «Silenta». Conclusions. It is shown that the frequency of sleep disorders in children with ASD and epileptic seizures is 85.7%, and in children with ASD without epileptic seizures - 63.6%. In children with ASD and epileptic seizures the incidence of sleep disorders during 30 days of the neuroadaptogen «Silenty» decreased to 53.6%, and in children with ASD and without epileptic seizures the incidence of sleep disorders decreased to 22.7%. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.
Purpose - to analyze the clinical and genetic characteristics of young children with developmental and epileptic encephalopathies and to determine their role in the formation of autism spectrum disorders (ASD). Materials and methods. The study included 58 children aged 0-3 years with the onset of epileptic seizures in the first year of life, clinical manifestations of developmental and epileptic encephalopathies with genetic etiology. The examination included assessment of neurological status, collection of anamnesis, assessment of semiology and determination of seizure type, assessment of development and screening for ASD at the age of 18 and 24 months, night sleep electroencephalography (video EEG), brain magnetic resonance imaging (MRI), screening for pathogenic variants by whole-exome sequencing or examination of relevant gene panels. Pathogenic variants of 33 different genes were found in the examined children. Pathogenic variants of genes responsible for the function of ion channels (41.3%), intracellular signaling systems (17.2%), organelles and intracellular membranes (12.1%) were most frequently found. 44.8% of children had symptoms of ASD at the age of 18 months, and 68.9% of children at the age of 24 months. The predominant types of epileptic seizures were myoclonic (37.9%) and focal clonic (34.4%). According to video EEG monitoring, interictal focal (39.6%) and multifocal (22.4%) epileptiform changes dominated in the examined children. According to MRI, structural changes of the brain were found in 86.2% of children. Conclusions. It is shown that children with a history of myoclonic seizures (RR=1.264) and infantile spasms (RR=1.44) have a high risk of developing ASD at 24 months. It has been established that there is a positive relationship between the presence in the child of mutations in the genes responsible for the functioning of ion channels (RR=1.32), as well as for the functioning of synapses, neurotransmitters and receptors (RR=1.5) and the development of ASD in 24 months. The research was carried out in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Bioethics and Deontology Commission. Informed consent of the children’s parents was obtained for the research. No conflict of interests was declared by the authors.
Abstract. The problem of early diagnosis and treatment of orphan (rare) diseases is unresolved in the world medical community. This is mainly due to the fact that some of this cohort of diseases have an incidence of less than 1:1,000,000. In most cases, the diagnosis is made after the height of the disease and quite often in the presence of irreversible changes. Department of Psychoneurology, State Institution «Institute of Pediatrics, Obstetrics and Gynecology named after acad. O. M. Lukyanova of the NAMS of Ukraine» has been engaged in the diagnosis and treatment of orphan diseases since 2012 and has experience in the diagnosis and treatment of orphan diseases, 80 % of which are manifested by neurological symptoms. A large number of orphan diseases in children occur under the clinical «masks» of diseases such as cerebral palsy, hydrocephalus, epilepsy, mental retardation and autism spectrum disorders. It is important that the pediatrician be vigilant about orphan diseases and approach the diagnosis from the etiology and pathogenesis of development, rather than clinical manifestations. In recent years, doctors have armed themselves with modern diagnostic techniques such as MRI, MR spectroscopy, next generation sequencing (NGS), whole exome sequencing (WES), and whole genome sequencing (WGS). But the question remains about the interpretation of the results obtained, the algorithm for early diagnosis and the patient's clinical route. In this publication, we would like to share our experience in the diagnosis and treatment of orphan diseases, taking into account modern protocols and data based on our own observations and international scientific sources. We give an example of a rare (orphan) disease caused by a POLG mutation and describe the entire diagnostic process from the appearance of the first symptoms of the disease to the establishment of the final diagnosis Keywords: orphan diseases, perinatal neurology, mitochondrial diseases, leukodystrophies, complete exome sequencing
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