Hypotonia Research Articles

Percutaneous thermal radiofrequency rhizotomy of L2-S1 spinal nerve roots in children with cerebral palsy.

This study presents the results of an evaluation of the effectiveness of percutaneous thermal radiofrequency (RF) ablation of spinal nerve roots to reduce spasticity and improve motor function in children with cerebral palsy (CP). A retrospective analysis was conducted on the surgical treatment outcomes of 26 pediatric patients with severe CP (Gross Motor Function Classification System levels IV-V). The assessment protocol included muscle tone assessment using the modified Ashworth scale (MAS), evaluation of passive and active range of motion, gait video recording, and locomotor status evaluation using the Gross Motor Function Measure (GMFM)-88 scale. Thermal RF rhizotomy (ablation of spinal nerve roots) was performed on all patients at the L2-S1 levels at 70°C for 90 seconds. The statistical data analysis was conducted using the t-test and Mann-Whitney U-test. A p value < 0.05 was considered statistically significant. Before the operation, the average level of spasticity in the lower-limb muscles of all patients was 3.0 ± 0.2 according to the MAS. In the early postoperative period, the spasticity level in all examined muscle groups significantly decreased to a mean of 1.14 ± 0.15 (p < 0.001). In the long-term postoperative period, the spasticity level in the examined muscle groups averaged 1.49 ± 0.17 points on the MAS (p < 0.001 compared to baseline, p = 0.0416 compared to the early postoperative period). Despite the marked reduction of spasticity in the lower limbs, no significant change in locomotor status according to the GMFM-88 scale was observed in the selected category of patients. In the long-term period, during the control examination of patients, the GMFM-88 level increased on average by 3.6% ± 1.4% (from 22.2% ± 3.1% to 25.8% ± 3.6%). The findings of this study offer preliminary yet compelling evidence that RF ablation of spinal nerve roots can lead to a significant and enduring decrease in muscle tone among children with severe spastic CP. Further studies and longer-term data of the impact on functionality and quality of life of patients with CP after spinal root RF ablation are needed.

Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention.

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland-3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland-3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland-3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub-domain analysis found the decline to be present across all modalities. In addition, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status, and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.

Every Picture Tells A Story: Managing Exertional Heatstroke with Rotating Ice Water Towels.

A 23-year-old woman completing her first marathon collapsed near the finish line at 4 hours 6 min with a rectal temperature of 41.8°C. She was in good health before the race with no recent illness, had completed a full training program, and was taking no medications or supplements. On the initial exam, she was unconscious with a response to painful stimulus, spontaneous breathing, rapid pulse, eyes closed, fully dilated pupils, poor muscle tone, and pale skin that was warm to touch. The medical team initiated whole-body cooling using rapidly rotating ice water towels and ice packs placed in the neck, axilla, and groin. She developed echolalia during active cooling. About 20 minutes into the cooling procedure, she "woke up," was able to answer questions coherently, and her pupils were normal size and reactive. She was discharged home with instructions to follow-up in 2 d for evaluation and blood chemistry testing.

Comparative characteristics of cervical sagittal balance parameters and atlantoaxial instability criteria in normal and Down syndrome children

BACKGROUND: Sagittal balance of the spine has received considerable development in recent years. However, most studies focused on the assessment of vertebral–pelvic parameters. The cervical spine has long received insufficient attention from researchers, but this trend has been changing. The study of cervical sagittal balance in children with Down syndrome is beneficial in approaching the preconditions of atlantoaxial instability. AIM: To perform a comparative analysis of cervical sagittal balance parameters and atlantoaxial instability criteria in normal and Down syndrome children. MATERIALS AND METHODS: Radiographs of the cervical spine in the neutral position in lateral projection and postural radiographs of 110 pediatric patients were analyzed retrospectively. The patients were divided into two groups: group 1 (normal), 60 children aged 4–17 years without spinal pathology, and group 2 (Down syndrome), 50 children aged 4–17 years with Down syndrome. The parameters of cervical sagittal balance (Oc-C2, Oc-C7, C1-C2, C2-C7, C2-C7H, C7S, Th1S, TIA, NT) and criteria for atlantoaxial instability (Nakamura angle, ADI, SAC-C1, SAC-C1/SAC-C4) were obtained, and data was statistically analyzed. RESULTS: Significant differences in the parameters C7S, Th1S, and TIA increased in children with Down syndrome. These parameters are involved in cervical lordosis; however, no significant differences in cervical lordosis angles were found. Furthermore, significant differences were noted in the criteria of atlantoaxial instability ADI, SAC-C1, and SAC-C1/SAC-C4 toward their decreasing in children with Down syndrome. CONCLUSION: In patients with Down syndrome, the indices of cervical lordosis are statistically greater than those in normal children. Moreover, the parameters of cervical lordosis in patients with Down syndrome do not differ from those in normal children. Therefore, during flexion, subcompensation of the cervical spine is observed in children with Down syndrome. Given the statistically smaller indicators ADI, SAC-C1, SAC-C1/SAC-C4, low neck muscle tone, and ligamentous hypermobility, these abnormalities can be considered as congenital predisposition factors for atlantoaxial instability in children with Down syndrome.

Early neurological signs in infants identified through neonatal screening for SMA: do they predict outcome?

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months. Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development.What is Known:• There is increasing evidence of heterogeneity among the SMA newborns identified via NBS.• The proposed nosology describes a clinically silent disease, an intermediate category (‘paucisymptomatic’) and ‘symptomatic SMA’.What is New:• The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay.• The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.

Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20.

Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays. Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14. Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression. Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children's families.

A New Mutation of Pompe Disease in a 2-Month-Old Infant

Pompe disease, also known as type 2 glycogen storage disease (GSD), is an autosomal recessive disorder. It occurs due to the deficiency of an enzyme, acid maltase, which degrades glycogen in lysosomes. This deficiency leads to glycogen accumulation in several tissues, such as cardiac muscle cells [1]. The disease is classified into infantile and late-onset types. Infantile Pompe disease (IPD) can manifest with feeding problems, hepatomegaly, generalized muscle weakness, hypotonia, macroglossia, and hypertrophic cardiomyopathy [1-3], from the first day to weeks of life [1]. If left untreated, IPD leads to cardiorespiratory failure and death within one year. Late-onset Pompe disease (LOPD), which includes juvenile-, childhood-, and adult-onset disease, is characterized by proximal muscle weakness, respiratory muscle involvement (especially the diaphragm), and arrhythmia. The prognosis of LOPD is less severe than that of IPD [1]. Diagnosis can be made by gene sequencing of the acid alpha-glucosidase (GAA) gene and enzyme assay in dried blood, muscle, skin, and blood cells [5,6]. During pregnancy, diagnosis can also be made by amniocentesis [1]. Treatment with enzyme replacement using recombinant human acid α-glucosidase is effective. As IPD is rapidly progressive, treatment should be initiated as soon as possible. Enzyme therapy can prevent and reverse cardiac and muscle involvement [1]. According to the information the authors have about Pompe disease, in most cases, the initial signs and symptoms are common with other diseases. In these cases, genetic testing significantly helps to definitively diagnose the disease. With the progress made in genetic tests, sometimes new mutations are added to the existing genetic bank. In this case report, the authors introduce a Pompe patient with a new genetic mutation of pathogenic types. This patient had presented with signs of severe hypotonia and cardiomegaly, increased cardiac enzymes, and abnormal liver tests. Despite enzyme therapy immediately after diagnosis, the patient died.

Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy.

Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.

Clinico-radiological characteristics of two patients with geroderma osteodysplasticum caused by new nucleotide variants in the GORAB gene

Geroderma osteodysplasticum (OMIM #231070) is a rare autosomal recessive disorder characterized by congenital wrinkled skin on the dorsal surface of the limbs and abdomen; marked osteoporosis in childhood. Pathogenic variants of the nucleotide sequence in the GORAB gene, which encodes the GORAB protein located in the Golgi apparatus and plays a crucial role in vesicle transport in the Golgi complex, lead to the disease. This is the first report of 2 patients with this disease in Russia. A detailed description of the clinical-radiological and genetic characteristics of these patients with new nucleotide variants in the GORAB gene in a compound heterozygous state is presented: c.170C&gt;G (p.Ser57Ter) and c.790G&gt;C (p.Ala264Pro); c.295C&gt;T (p.Gln99Ter) and heterozygous deletion on chromosome 1 (chr1:g.170531967–170539494del), affecting exons 1 and 2 of the gene. The main clinical manifestations of the syndrome were congenital wrinkled skin, sagging cheeks, hypoplasia of the cheekbones, prognathism, muscle hypotonia and joint hypermobility. Radiological signs included congenital bilateral dislocation of the hip, compression fractures of the vertebral bodies, and disruption of the continuity of the growth plate of the distal femur and proximal tibia, referred to as “insertion.” The rarity of the syndrome, as well as the similarity of clinical manifestations with a heterogeneous group of hereditary diseases accompanied by decreased skin elasticity, leads to a late correct diagnosis. This necessitates the description of the clinical-genetic characteristics of the disease, the study of the dynamics of the formation of its phenotypic manifestations, and the methods of molecular-genetic diagnostics.

Type 1 kyphoscoliotic Ehlers–Danlos syndrome caused by mutations of the PLOD1 gene: analysis of own observations

Kyphoscoliotic type of Ehlers–Danlo syndrome occurs in the practice of doctors of different specialties. The main manifestations of the disease are congenital muscular hypotonia, progressive kyphoscoliosis, generalized joint hypermobility, dislocation/subluxation of the joints. In recent years, special attention has been paid to the fragility of blood vessels characteristic of patients, which usually has serious consequences. Purpose: the study aims at clarifying the clinical characteristics of type 1 kyphoscoliotic Ehlers–Danlo syndrome based on the analysis of the clinical findings observed in 2 patients with severe vascular disorders. Data from clinical and molecular genetic examination of 2 children (girl and boy) 17 and 13 years old from unrelated families are presented. The diagnosis of type 1 kyphoscoliotic Ehlers–Danlo syndrome was established in accordance with the diagnostic criteria according to the International Classification 2017. Children showed severe vascular disorders in the neonatal period, ruptures of medium-caliber arteries in adolescence. Genomic sequencing in both patients revealed a pathogenic nucleotide variant in the PLOD1 gene — duplication of the 11959421–11968422 chromosome 1 region in the homozygous state. The results of literature analysis and own observations of 2 patients with type 1 kyphoscoliotic Ehlers–Danlo syndrome indicate the severity and rather high incidence of vascular disorders, which should be considered when developing recommendations for the medical management of patients.

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Background and aimsThe occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders. Material and methodsThe selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative. ResultsThe first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene. ConclusionsCollectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

A nonsense CC2D1A variant is associated with congenital anomalies, motor delay, hypotonia, and slight deformities

BackgroundAutosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients. MethodsWe described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene. ResultsThe patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database. ConclusionsThis study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

Differential diagnosis of acute flaccid paralysis in children with Guillain—Barré syndrome and neuromyelitis optica spectrum disorder: Clinical cases

Background. Acute flaccid paralysis is a clinical syndrome characterized by a sudden onset of weakness in one or more limbs with decreased or absent tendon reflexes in the affected limbs. This condition may be a manifestation of such pathologies as Guillain-Barré syndrome and neuromyelitis optica spectrum disorder. Clinical cases description. We describe two clinical cases of Guillain-Barré syndrome in patient M., 7 years old, and neuromyelitis optica spectrum disorder in patient D., 3 years old. In both children, the main clinical manifestation was acute flaccid paralysis. Patient M. was admitted to the Neurological Department of the Moscow Regional Center for Maternity and Childhood Protection with complaints of sharp pronounced weakness in the limbs, inability to walk. According to the disease history, the patient had an acute respiratory viral infection in October 2022. The conducted neurologic examination revealed decreased muscle tone and muscle strength in all limbs, absence of reflexes from the lower limbs. A liquor test was conducted, which revealed increased protein contents. Electroneuromyography detected a pronounced axonal lesion of all motor fibers in the arms and legs. The formulated diagnosis was “Guillain-Barré syndrome, variant of acute motor axonal neuropathy.” The treatment with plasmapheresis and intravenous immunoglobulins showed positive dynamics. In the second case, patient D. was admitted to the Pediatric Infectious Disease Department of Naro-Fominsk Hospital with similar complaints of sharp weakness in the limbs. Neurological examination showed a diffuse decrease in muscle tone, absence of reflexes from all limbs. Elevated protein contents were determined in the liquor. MRI of the cervical spinal cord showed myelitis of segments C3–C7. Negative antibodies to aquaporin-4 were found. The patient was treated with ceftriaxone, methylprednisolone, and plasmapheresis. Then he was transferred to the Neurological Department of the Moscow Regional Center for Maternity and Childhood Protection, where a repeated MRI of the cervicothoracic spinal cord revealed, in addition to myelitis at the level of C3–C7, a lesion of segments from the level of C2 to the medulla oblongata. The formulated diagnosis was “Neuromyelitis optica spectrum disease, seronegative form. Flaccid tetraparesis.” The continued treatment with prednisolone and intravenous immunoglobulin produced positive effect. Conclusion. The presented clinical cases will help neurologists to improve timely diagnosis and treatment of causes of acute flaccid paralysis in children, thereby reducing possible complications, disability, and mortality.

The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.

Investigation of electromyography of the masseter and temporal muscles in children with Down syndrome aged 2 to 12 years during maximal voluntary isometric contraction and rest

Background. Muscle weakness and low muscle tone may cause chewing and swallowing disorders in people with Down syndrome. This study investigated the electromyography of the masseter and temporal muscles in children with Down syndrome, aged 2 to 12, during maximal voluntary isometric contraction and rest. Methods. The current descriptive-analytical and case-control study investigated the electromyography frequency indicators of the masseter and temporal muscles at maximum voluntary contraction and resting states in 15 children aged 2 to 12 with Down syndrome and 15 normal children of the same age. Results. The average frequency of the mean and median in the electrical signal of the masseter and temporal muscles on the left and right sides and in two different positions in children with Down syndrome is lower than in normal children. In comparing the average frequency of the mean, except for the left and right temporal muscles in the maximum voluntary isometric contraction and the left master muscle during rest, there is a significant difference in the rest. Also, in comparing the average frequency of the median, except for the left and right temporal muscles in the resting state, there are non-significant differences in the rest of the cases. Conclusion. The average frequency of the electrical signal of the masseter and temporal muscles in children with Down syndrome is lower than that of normal children. Unlike typically developing children, those with Down syndrome struggle with chewing and swallowing. Practical Implications. The data obtained from this study contributes to the enhancement of interventions and treatments for patients with Down syndrome.

ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet

BackgroundResearch has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring. MethodsThe clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature. ResultsThe infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD). ConclusionCHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.

Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning

GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development.

КАЧЕСТВО ЖИЗНИ ДЕТЕЙ С НАСЛЕДСТВЕННЫМИ НАРУШЕНИЯМИ РАЗВИТИЯ СОЕДИНИТЕЛЬНОЙ ТКАНИ И ИХ РОДИТЕЛЕЙ В ПРОЦЕССЕ ДИНАМИЧЕСКОГО КОНТРОЛЯ В УСЛОВИЯХ ПОЛИКЛИНИКИ

Purpose of the study. To assess the quality of life of children with hereditary disorders of connective tissue development and their parents during dynamic monitoring in a polyclinic. Material and methods. In the period from 2020 to 2023, the patients were under dispensary observation. The main group of patients (n=30) and the comparison group (n=30) are presented. At the beginning of treatment, the average age was 4.7±0.5 years. For patients of the two groups, therapeutic measures were proposed, which included back massage (ten sessions once in 4 months), electrical stimulation of the back muscles (ten sessions once in 6 months), and a physical therapy complex. Additionally, patients from the main group were prescribed sessions at the school "Posture Correction", swimming, bracing, additional physiotherapy complexes (electrical stimulation of the back – 3 courses of 10 sessions per year), back massage (10 sessions every month), diet and vitamin therapy for 3 years. The quality of life was assessed using the PedsQL questionnaire. Results. It was statistically significantly proved that during the period of dispensary observation, the patients of the main group and their parents improved physical parameters in 65.0% of cases (in the comparison group in 20.3% of cases), p=0.016; emotional parameters improved in 59.8% of cases (in the comparison group in 21.0% of cases), p=0.014. At the same time, a satisfactory muscular corset was visualized, which was confirmed by additional examination methods (electroneuromyography, stabilometry); complications from the osteoarticular system were reduced. In patients from the comparison group and their parents, the quality of life did not change statistically significantly. The patients noted hypotonia of the back muscles in 53% of cases and pain on palpation along the spine in the thoracic region in 37.3% of cases (p&lt;0.001). Conclusions. Over time, in the main group, the number of complications from the osteoarticular system was minimized and the quality of life in patients of the main group and their parents significantly improved.

Electromyography reveals the etiology of floppy infant in developing country

Background. Floppy infants are correlated with the extensive differential diagnosis. It can make diagnostic approach become more challenging. Case report. We report a 10-months-old infant referred from Pediatrician to electromyography (EMG) laboratory presenting with floppy and developmental delays. The central and motor neuron manifestations also increased of CPK levels bring ambiguity for the diagnosis. EMG may distinguish the cause from myopathy, anterior horn cell, neuromuscular junction (NMJ) or central origin when genetic testing is not routinely done in developing country. Conclusion. EMG helps clinician to distinguish the diagnosis of floppy infant.

Gene Therapy for Genetic Muscle Diseases

Genetic muscle diseases encompass a group of conditions where genetic alterations affect skeletal muscles, leading to muscle weakness and hypotonia. Presently, the focus of treatment is on managing symptoms rather than addressing the root cause of the disease. However, recent advancements in gene therapy offer potential cure for these diseases, with over 180 genes identified as contributing factors. Encouraging results have emerged from preclinical trials conducted using animal models, prompting the initiation of several clinical trials aimed at assessing the safety and efficacy of gene therapy in human patients. In this review, we aim to provide an overview of the fundamental concept of gene therapy and discuss ongoing clinical trials that hold promise for curing genetic muscle diseases.