A clinical case of severe Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene in a girl

Duchenne muscular dystrophy (DMD) is a hereditary progressive muscular dystrophy, mainly manifested in boys, is characterized by the onset at an early age, gradual symmetrical atrophy of the striated musculature of the limbs, trunk, as well as damage to the heart muscle. As a rule, girls and women inheriting a pathological mutation are classified only as its carriers and do not have clinical manifestations of the disease. Rare cases when women or girls show clinical manifestations of DMD may be due to chromosomal rearrangements involving the region of the short arm of the X chromosome (Xp21.2), deletions of this region, complete loss of the X chromosome (Shereshevsky-Turner syndrome), homogenous X chromosome dysomnia, compound heterozygous state for two pathogenic mutations in the DMD gene, nonequilibrium inactivation of the X chromosome. When female mutation carriers have DMD clinical symptoms, they usually manifest much milder than boys and young males. Descriptions of patients with the severe course and rapid progression of the disease, comparable in the rate of progression with boys, are rare. In this article, the authors share their experience of observing a girl patient who suffered from a severe form of DMD.

Dose selection of Incobotulinumtoxin A for the treatment of spasticity and sialorrhea in cerebral palsy: results of a retrospective multicenter study

Introduction. In patients with infantile cerebral palsy (CP), botulinum therapy is used to treat both muscle tone disorders and sialorrhea. Therefore, it is logical to use one preparation of botulinum toxin type A to treat spasticity and sialorrhea in one injection procedure. The aim of the work is to conduct a retrospective analysis of data from 15 centres that treat patients with cerebral palsy and use the botulinum therapy method to determine the optimal doses of IncobotulinumtoxinA (IBTA) for the treatment of spasticity and chronic sialorrhea in real clinical practice. Materials and methods. The treatment results of 389 children with cerebral palsy (including 211 (54.2%) boys) with IBTA were analyzed. The majority were children with bilateral forms of cerebral palsy - 312 (80.2%). The average age of the patients was 5.27 ± 3.71 years, the average weight of the patients was 18.8 ± 10.9 kg. Results. The total dose of IBTA in the group of 389 patients with cerebral palsy for the treatment of spasticity was 163.74 ± 80.65 U (25-550; 95% CI 155.7-171.7) and 10.4 ± 5.4 U/kg body weight (1,25-29.7; 95% CI 9.8-10.9). The total dose of IBTA in the group of patients with cerebral palsy with simultaneous treatment of spasticity and chronic sialorrhea (n = 16) was significantly higher: 267.18 ± 124.57 U (115-570; 95% CI 200.8-333.6) and 13, 0 ± 7.1 U/kg (5.8-24.6; 95% CI 9.2-16.8). In the lower extremities, the most frequent target muscles were the gastrocnemius (55.0% of cases; 95% CI 49.9-60.0) and semitendinosus / semimembranous muscle (46.3% of cases; 95% CI 41.2-51.4 ), and in the upper limbs - pronator teres (48.6% of cases; 95% CI 43.5-53.7) and biceps brachii (28.8% of cases; 95% CI 24.3-33.6). Limitations of the study. The limitations of our work are the use of an open retrospective study format, a relatively small sample of patients with chronic sialorrhea, the absence of long-term follow-up of patients and the results of repeated IBTA injections. Conclusion. If it is necessary to use botulinum therapy for the treatment of spasticity and sialorrhea in a child with CP, it is optimal to use the product IncobotulinumtoxinA, which will allow correction of two pathological manifestations in one procedure and can shorten the intervals between repeated injection cycles.

Selective screening and molecular characteristics of Russian patients with Pompe disease

Introduction. Pompe disease (PD) or type II glycogenosis is a rare multisystem hereditary accumulation disease caused by a deficiency of the enzyme acid maltase (acid alpha-1,4-glucosidase), which leads to reduced activity to the accumulation of glycogen in various organs and tissues of the body. The aim of the study is to develop a high-performance method of early biochemical diagnosis of PD and optimization of its molecular genetic diagnosis. Materials and methods. The characteristics of the relative frequencies and spectrum of the detected mutations were studied using a sample of 7670 patients with suspected Pompe disease admitted to the National Medical Research Center of Children’s Health of the Ministry of Health of Russia as part of the selective screening, as well as eight patients with PD, whose laboratory diagnosis was made outside the framework of this selective screening. Results. As a result of selective screening of PD in Russian patients from high-risk groups, the detectability was 0.47%. PD’s clinical and age characteristics in both children and adults are described. The relative frequencies are calculated, and the spectrum of 47 pathogenic variants of the GAA gene responsible for the occurrence and development of Pompe disease in 44 patients is characterized. Seventeen new mutations of the GAA gene, unknown previously, have been identified and described, adding 2.7% to the HGMD database. Conclusion. Optimization of the algorithm of molecular diagnosis of Pompe disease in Russian patients is proposed.

Somatoneurological and psycho-pedagogical features of children with cerebral palsy in the context of their readiness for training in Paralympic sports

Introduction. Currently, Russia does not have a scientifically grounded medical and psychological support system for disabled children (DC), which allows involving them in classes in children and youth schools of adaptive physical education, preparing the country’s Paralympic DC reserve. Aim of the study. To develop and create a medical support system for the Paralympic DC reserve, capable of improving their quality of life and forming a medical and social lift. Materials and methods. Children aged from 1 year to 18 years had cerebral palsy (CP) with impaired motor functions of levels I and II according to the global motor function assessment system and the Manual Abilities Classification system and their families were monitored. A comprehensive assessment of the somatic, neurological, mental and nutritional status of CP children) was carried out, and a wide range of comorbid pathology was described. After the rehabilitation treatment with the use of complex personalized rehabilitation programs, dynamic monitoring of the condition of patients with cerebral palsy was carried out, followed by an assessment of the effectiveness of rehabilitation treatment and the impact on it the psychological readiness of patients, their parents to engage in Paralympic sports, as well as the socio-economic level of the family. The attitude of CP children and their parents to participate in the Paralympic movement was studied. All patients underwent a comprehensive study of somatic, neurological, orthopaedic, psychological and nutritional status. The socio-hygienic characteristics of families and the rehabilitation potential of DC and their families have been determined. Results. Children with cerebral palsy have a wide range of comorbid pathology, which requires the involvement of specialists of different profiles in the curation of patients. The use of complex personalized rehabilitation programs allows achieving positive dynamics after 14 days of rehabilitation treatment. Early introduction of botulinum therapy in the rehabilitation program of CP patients provides higher efficiency of rehabilitation treatment. Treatment of protein-energy deficiency in CP children should include correction of the diet using specialized products, metabolic therapy, enzyme and complex vitamin preparations. Differentiated medical, psychological and pedagogical counselling of parents of CP children will allow optimizing the solution of the state problem regarding the timely inclusion of persons with disabilities in adaptive physical education classes. Conclusion. The development and creation of a comprehensive medical and psychological support system solve an urgent medical and social problem, ensuring the integration of DC into society and improving the quality of life of both a sick child and his family members.

Sleep disorders in children and adolescents with tension-type headaches

Introduction. Tension-type headache (TTH) represents a widespread and recurrent disease in adults, children, and adolescents, adversely affecting the quality of life, learning achievements, and social functioning. In recent publications, a high incidence of comorbid disorders in patients with TTH is discussed, in particular sleep disorders. The aim of the study was to assess the nature and prevalence of sleep disorders in children and adolescents with frequent episodic TTH and chronic TTH. Materials and methods. One hundred fifty patients aged from 8 years to 16 years 11 months with TTH were examined. Of them, 91 (49 boys, 42 girls) had frequent episodic TTH, 59 (26 boys, 33 girls) had chronic TTH. There was used Sleep Disturbance Scale for Children including 26 questions for parents. Results. The present study confirms the high incidence of sleep disorders among TTH children and adolescents. TTH was diagnosed in 129 (86.0%) out of 150 patients. The most frequently diagnosed varying degrees of severity (clinically relevant and borderline, when assessing sleep disorders in children) were insomnia (disorders of initiating and maintaining sleep) - in 65.3% of patients (including 60.4% with frequent episodic TTH and 72.9% with chronic TTH), excessive somnolence - in 74.7% (67.1% and 86.4%), sleep breathing disorders - in 26.7% (23.1% and 32.2%), disorders of arousal/nightmares - in 46.0% (42.9% and 50.8%), sleep-wake transition disorders - in 65.3% (67.1% and 62.7%), sleep hyperhidrosis - in 31.3% (26.4% and 39.0%). Thus, all sleep disorders (except for sleep-wake transition disorders) were significantly more common among the patients with chronic TTH. At the same time, in the subgroup of patients with TTH and any sleep disorders, significantly more prominent indicators of the frequency, the intensity of TTH and its negative impact on the daily activity were revealed, compared to patients with TTH lacking sleep disorders. Conclusion. The results of the assessment of children and adolescents with TTH show that when planning preventive therapy for TTH and evaluating its results, not only main clinical characteristics of TTH should be taken into account, but also the manifestations and severity of comorbid disorders, including sleep disorders observed in most patients with TTH. The revealed prevalence of various sleep disorders in the subgroup of patients with chronic TTH confirms that sleep disorders and anxiety disorders refer to significant risk factors for the transition of TTH to a chronic form, and such patients need more active multimodal treatment.

Dyslexia as the most prevalent form of specific learning disabilities

Dyslexia is the most common form of specific learning disabilities. Dyslexia is observed in 5-17.5 % of schoolchildren, and among children with specific learning disabilities, it accounts for about 70-80 %. Usually, dyslexia manifests itself as the inability to achieve an appropriate level of reading skills development that would be proportional to their intellectual abilities and writing and spelling skills. Secondary consequences of dyslexia may include problems in reading comprehension and reduced reading experience that can impede the growth of vocabulary and background skills. The review discusses neurological management of reading and writing as complex higher mental functions, including many components that are provided by various brain areas. The principles of dyslexia classification, the main characteristics of its traditionally defined forms are given: phonemic, optical, mnestic, semantic, agrammatic. The article analyzes the cerebral mechanisms of dyslexia development, the results of studies using neuropsychological methods, functional neuroimaging, and the study of the brain connectome. The contribution to dyslexia development of disturbances in phonological awareness, rapid automated naming (RAN), the volume of visual attention (VAS), components of the brain executive functions is discussed. The origin of emotional disorders in children with dyslexia, risk factors for dyslexia development (including genetic predisposition) are considered. Dyslexia manifestations in children are listed, about which their parents seek the advice of a specialist for the first time. In the process of diagnosing dyslexia, attention should be paid to the delay in the child’s speech development, cases of speech and language development disorders and specific learning disabilities among family members. It is necessary to consider possible comorbidity of dyslexia in a child with attention deficit hyperactivity disorder, dyscalculia, developmental dyspraxia, disorders of emotional control and brain executive functions. Timely diagnosis determines the effectiveness of early intervention programs based on an integrated multimodal approach.

Differential diagnosis of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

Anti-NMDA receptor encephalitis

Autoimmune diseases of the central nervous system (CNS) are one of the most socially and economically significant problems of neurology. Despite the identification of new nosological forms of autoimmune encephalitis, the creation of diagnostic panels for the verification of autoantibodies in biological fluids, and the use of highly effective pathogenetic therapy, the number of diagnostic errors remains high, which poses a threat to the patient’s life and a high risk of developing severe complications. Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis) is autoimmune encephalitis caused by the presence of antibodies (Ab) to the NR1 subunit of NMDA-receptors (NMDAR) characterized by the development of severe mental and neurological deficits in a previously healthy person. This article summarizes the recent literature on anti-NMDAR encephalitis. The literature search was carried out using the Scopus, Web of Science, Pubmed, CyberLeninka databases. The review presents the facts of the history of the study of the disease, epidemiological data, modern ideas about the pathogenetic mechanisms of the development of the disease, the spectrum of clinical manifestations and various forms of the course of the disease. The diagnostic criteria and research methods used to confirm the diagnosis are described, approaches to the treatment of anti-NMDAR encephalitis are outlined. Anti-NMDAR encephalitis is clinically manifested by a combination of mental disorders, epileptic seizures, speech and extrapyramidal disorders, and disturbances in the rhythm of sleep and wakefulness. The disease occurs at any age. The development of the disease can be associated with such immunological triggers as oncological process and herpetic encephalitis, or be idiopathic in nature. There are features of the course of the clinical picture depending on the age of the patient, paraneoplastic or postherpetic aetiology of the disease. The diagnostic algorithm, along with neuroimaging, determination of specific antibodies, electroencephalography, should also include the search for an oncological process. The recovery of patients can take from several months to years. In some cases, persistent neurological deficits develop. Predictors of a favourable outcome include early initiation and use of combination therapy, detection and removal of neoplasms, a low titer of anti-NMDAR antibodies, and age of patients over 12 years of age. In up to 25% of cases, a relapsing course of the disease is possible, and therefore requires long-term monitoring of these patients.

The role of external factors in realizing of the natural progress of the child’s motor development within the first year of life

Introduction. The development of a child in the first year of life provides the basis for their further harmonious growth. Motor development occurs in parallel with the ongoing gradual development of the nervous system. The transition to a new motor milestone is associated with the emergence of new skills; therefore, stimulation of motor development should occur in accordance with the next milestone of the nervous system development. Intervention in the natural process of the skills gaining without considering the developmental nervous system milestone leads to a change in the trajectory of motor progress of the child. Aim of the study was to assess the significance of individual elements of motor development for the function of balance and walking, as well as to identify the role of non-physiologic (contradicting motor ontogenesis) stimulation of motor skills in the evolvement of non-optimal motor patterns and impaired balance and walking function. Materials and methods. In total, 43 children aged ≥ 12 months admitted to the «Consultative Diagnostic Department» of the Federal State Autonomous Institution «National Medical Research Center for Children’s Health» of the Ministry of Health of Russia were examined within the framework of dispensary observation in the period from December 2016 to June 2019. The assessment of motor development was carried out according to the tests and questionnaires developed. The children were divided into two groups: the treatment group, in which the intervention was carried out, and the control group. Results. The frequency of realization of physiological patterns in children in the treatment group was 65.5%, and in the control group was 89.6%. The occurrence of the functional disorders of the musculoskeletal system was as follows: pathological functional kyphosis in the lumbar spine in children in the treatment group occurred in 73.1%, and in the control group in 26.9%; sitting on the sacrum occurred in 73.1% in the treatment group, and 26.9 % in the control group; impaired coordination in the treatment group occurred in 53.9%, and in 46.1% in the control group; decreased balance function in the treatment group occurred in 61.5%, and in 38.5% in the control group. Conclusion. Correct interaction with a child in the first year of life, in combination with physiological stimulation corresponding to the developmental milestones of the nervous system, allows the child to implement their motor skills in a timely manner, without disrupting the natural sequence of motor development, and minimizes the risks of functional disorders of the musculoskeletal system.