Nervous System Abnormalities Research Articles

MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research.

Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.

Joubert syndrome presenting bilateral peroneal neuropathies: A case report.

Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing. A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS. This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

E031 Retinal vasculitis with Libman-Sacks endocarditis as presenting features of a systemic lupus erythematosus with antiphospholipid antibody syndrome patient

Abstract Background/Aims Ocular manifestations of systemic lupus erythematosus (SLE) are rarely reported at the time of disease onset. Retinal vasculitis is usually associated with the active generalised disease. We report a case of a 22-year-old lady who was diagnosed with SLE with antiphospholipid antibody syndrome (APS) as the initial presentation of retinal vasculitis and Libman-Sacs endocarditis. Methods A 22-year-old lady with a background history of benign hypermobility spectrum disorder, presented to the eye casualty with a 4-week history of right-sided visual disturbances and was diagnosed with retinal vasculitis associated with uveitis, central retinal vein occlusion with multiple emboli in the retinal artery of the right eye and a single embolus in the left eye. In terms of family history, both father and brother were diagnosed with spondyloarthropathy, and the maternal uncle had Sjogren’s syndrome. She was then referred to the medical team for proper evaluation. On query, she mentioned photosensitive rash on her face getting worse in sunlight, a history of Raynaud’s phenomenon, significant hair loss, and one miscarriage before the 10 weeks of gestation. On examination, mild alopecia and a faint butterfly rash on the face were noted. Cardiac auscultation revealed pansystolic murmur. The rest of the systemic examinations were unremarkable. Results The blood test showed thrombocytopenia (130 u/L), positive antinuclear antibody (1:80, speckled pattern) with anti-double stranded DNA (26 IU/L), low complement (C3-0.74, C4- 0.12), markedly raised anticardiolipin antibody IgG (2016 u/ml), anti beta 2 glycoprotein 1 IgG ( >6100 u/ml) including presence of lupus anticoagulant. Her urinary protein creatinine ratio was 66mg/mmol. 3 sets of blood cultures came back negative. Transthoracic echo showed vegetation on the posterior mitral valve leaflet (0.95x 1.2cm) with moderate mitral regurgitation while transesophageal echo additionally found the possibility of perforation at the junction of leaflets of the mitral valve which was later confirmed by cardiac magnetic resonance imaging (MRI). The head MRI scan did not show any central nervous system abnormality. She was initially treated with 500mg intravenous methylprednisolone for 3 days followed by 20mg oral prednisolone daily with gradual tapering. Hydroxychloroquine and mycophenolate mofetil were added. Her case was discussed in the cardiology multidisciplinary team meeting and an opinion from the cardiothoracic surgery was taken to consider valve replacement in the future. Due to aspirin allergy, only warfarin was considered for APS. She had 2 sessions of pan-retinal photocoagulation as well. In subsequent follow-up, it was noted significant improvements in terms of her symptoms. Conclusion Vaso-occlusive retinopathy is a rare, potentially vision-threatening initial manifestation of SLE, which can be an indicator of active disease. Early identification of patients is necessary for timely intervention and multidisciplinary team involvement is required for comprehensive treatment plans. Disclosure M. Islam: None. S. Quddus: None. M. Hughes: None. R. Kumar: None.

Fetal and neonatal outcomes of posterior fossa anomalies: a retrospective cohort study

The primary aim of this study was to estimate the incidence of posterior fossa anomalies (PFA) and assess the associated outcomes in King Abdulaziz Medical City (KAMC), Riyadh. All fetuses diagnosed by prenatal ultrasound with PFA from 2017 to 2021 in KAMC were analyzed retrospectively. PFA included Dandy–Walker malformation (DWM), mega cisterna magna (MCM), Blake's pouch cyst (BPC), and isolated vermian hypoplasia (VH). The 65 cases of PFA were 41.5% DWM, 46.2% MCM, 10.8% VH, and 1.5% BPC. The annual incidence rates were 2.48, 2.64, 4.41, 8.75, and 1.71 per 1000 anatomy scans for 2017, 2018, 2019, 2020, and 2021, respectively. Infants with DWM appeared to have a higher proportion of associated central nervous system (CNS) abnormalities (70.4% vs. 39.5%; p-value = 0.014) and seizures than others (45% vs. 17.9%; p-value = 0.041). Ten patients with abnormal genetic testing showed a single gene mutation causing CNS abnormalities, including a pathogenic variant in MPL, C5orf42, ISPD, PDHA1, PNPLA8, JAM3, COL18A1, and a variant of uncertain significance in the PNPLA8 gene. Our result showed that the most common PFA is DWM and MCM. The autosomal recessive pathogenic mutation is the major cause of genetic disease in Saudi patients diagnosed with PFA.

Huanglian Jiedu decoction alleviates neurobehavioral damage in mice with chronic alcohol exposure through the RAS-RAF-MEK-ERK pathway

ObjectiveLong-term alcohol consumption can cause organic damage to the brain, resulting in mental and nervous system abnormalities and intellectual impairment. Huanglian Jiedu decoction (HLJDD) is the classic representative of clearing heat and detoxifying. This study aimed to explore the effects and possible mechanisms of HLJDD on brain injury in chronic alcohol-exposed mice. MethodsThe alcohol-exposed mice were treated with different doses of HLJDD to observe behavioral changes, hippocampal Aβ1-42 deposition, number and ultrastructural changes of neurons in the hippocampus and prefrontal cortex, and expressions of synaptic proteins. On this basis, transcriptome sequencing was used to analyze the differentially expressed genes in different treatment groups, and functional enrichment analysis was performed. Then, WB and RT-PCR were used to verify the expression of the pathway. ResultsChronic alcohol exposure reduced body weight in mice, led to motor cognitive impairment, increased Aβ1-42 in the hippocampus, decreased the number of neurons in the hippocampus and prefrontal cortex, and the expression of PSD95 and SYN in the hippocampus. HLJDD significantly improved the cognitive dysfunction of mice and alleviated the damage of the hippocampus and prefrontal cortex. Transcriptome sequencing results showed that the regulatory effects of HLJDD on chronic alcohol-exposed mice may be related to the RAS pathway. Further experiments confirmed that chronic alcohol exposure caused a significant increase in protein and gene expressions of the RAS-RAF-MEK-ERK pathway in mouse, and this activation was reversed by HLJDD. ConclusionHLJDD may ameliorate brain damage caused by chronic alcohol exposure by regulating the RAS-RAF-MEK-ERK pathway.

Клинические случаи ранней офтальмологической диагностики септо-оптической дисплазии

Identification of a genetic variant of a hereditary disease of the visual organ is necessary not only to determine the features of clinical manifestations and course of the disease, but also to carry out preventive measures to prevent the birth of a sick child. Therefore, the identification of ophthalmopathology requires a mandatory assessment of the condition of the patient's body as a whole. The article presents two clinical cases of ophthalmological diagnosis of septo-optic dysplasia. It is a clinically heterogeneous condition representing a combination of hypoplasia of the optic nerves, pituitary hypoplasia and abnormal formation of structures along the midline of the brain. The diagnosis is established in the presence of two or more signs of the classical triad. Hypoplasia of the optic nerves leads to decreased vision, amblyopia. Violation of the hypothalamic-pituitary system requires hormone replacement therapy. The prognosis of mental development depends on central nervous system abnormalities, if any, mental retardation occurs. The first clinical case: a boy R., 11 months old, was directed by a neurologist due to the presence of a pendulum-like nystagmus, hypoplasia of the optic nerves of both eyes, uneven caliber and convoluted course of retinal vessels were also revealed upon examination. The lag in physical and neuropsychic development drew attention to itself. To clarify the diagnosis, the child was recommended to perform an MRI of the head, which revealed aplasia of the septum pellucidum. Septo-optic dysplasia was diagnosed on the basis of the revealed disorders. The second patient, a girl, 2 days old, was referred to an ophthalmologist by a neurologist, the absence of a septum pellucidum was revealed on the neurosonogram, hypoplasia of the optic nerves and tortuosity of the retinal vessels were found on examination of the fundus. Septo-optic dysplasia was diagnosed. Thanks to the early detection of this severe hereditary pathology, timely maintenance and replacement therapy by a neurologist and endocrinologist, and observation by a geneticist, it is possible not only to prevent complications of the disease itself, but also to prevent the re-birth of a sick child in the family. Keyword: septo-optic dysplasia; hypoplasia of the optic nerves; aplasia of the septum pellucidum

Preliminary Proteomic Study of the Porcine Pituitary Gland under Heat Stress.

Although numerous studies have shown that the hypothalamic-pituitary-adrenal axis plays a vital role in the response to environmental stress by mediating the production of a series of hormones, the mechanism underlying these effects has not been elucidated. This study used proteomics techniques to investigate the differentially expressed proteins (DEPs) in the pituitary glands of pigs and to elucidate the potential changes in the immune-neuroendocrine system under heat stress (HS). In total, 2517 peptides corresponding to 205 proteins were detected. A comparison of the expression patterns between HSs and healthy controls revealed 56 DEPs, of which 31 were upregulated and 25 were downregulated. Ingenuity pathway analysis (IPA) was used to reveal the subcellular characteristics, functional pathways, regulatory networks, and upstream regulators of the identified proteins. The results showed that these differentially expressed proteins were involved in intercellular communication, interactions, apoptosis, nervous system development, functions, abnormalities and other functions, and in the regulatory network. Moreover, the upstream regulators of the differentially expressed proteins were mainly transcriptional regulators, hormones, and cytokines. Thus, the functional network and pathway analyses could provide insights into the complexity and dynamics of HS-host interactions and may accelerate our understanding of the mechanisms underlying HS.

Evaluation of Congenital Cytomegalovirus Infection in Pregnant Women Admitted to a University Hospital in Istanbul.

Cytomegalovirus (CMV) can cause serious complications in immunocompromised individuals and fetuses with congenital infections. These can include neurodevelopmental impairments and congenital abnormalities in newborns. This paper emphasizes the importance of concurrently evaluating ultrasonography findings and laboratory parameters in diagnosing congenital CMV infection. To examine the prenatal characteristics of CMV DNA-positive patients, we assessed serum and amniotic fluid from 141 pregnant women aged 19-45 years, each with fetal anomalies. ELISA and PCR tests, conducted in response to these amniocentesis findings, were performed at an average gestational age of 25 weeks. Serological tests revealed that all 141 women were CMV IgG-positive, and 2 (1.41%) had low-avidity CMV IgG, suggesting a recent infection. CMV DNA was detected in 17 (12.05%) amniotic fluid samples using quantitative PCR. Of these, 82% exhibited central nervous system abnormalities. Given that most infections in pregnant women are undetectable and indicators non-specific, diagnosing primary CMV in pregnant women using clinical findings alone is challenging. We contend that serological tests should not be the sole means of diagnosing congenital CMV infection during pregnancy.

Risk factors associated with congenital central nervous system abnormalities in the National Hospital of Zinder, Niger

IntroductionCongenital malformations of the central nervous system (CNS) are morphological abnormalities of the brain and spinal cord that occur during fetal development. They constitute the second most common congenital disability, after congenital cardiac defects. Many risk factors have been identified; however, these studies included various types of congenital abnormality. Furthermore, there is a lack of information on risk factors for congenital CNS malformation, and notably in the Zinder region of Niger. ObjectiveThis study aimed to identify the risk factors associated with congenital CNS malformations in the Zinder region. MethodsIn a case-control design, patients with congenital CNS malformation were enrolled between June 2022 and April 2023 in the Department of Neurosurgery of the National Hospital of Zinder. ResultsFamily history of malformation (aOR:3.31, 95% CI:1.25−8.78) and consanguine marriage (aOR:2.28, 95% CI:1.23−4.20) were significantly associated with congenital CNS malformation. In contrast, folic acid supplementation (aOR:0.34, 95% CI:0.13, 0.89), multiparity (aOR:0.34, 95% CI:0.13, 0.89), and grand multiparity (aOR, 0.47; 95% CI:0.23, 0.97) had a protective effect. ConclusionRisk factors such as family malformation history and consanguine marriage increased the risk of developing congenital malformations of the central nervous system. In contrast, folic acid supplementation in the index period and multiparity had a significant protective effect.

The subgenomic flaviviral RNA suppresses RNA interference through competing with siRNAs for binding RISC components.

During the life cycle of mosquito-borne flaviviruses, substantial subgenomic flaviviral RNA (sfRNA) is produced via incomplete degradation of viral genomic RNA by host XRN1. Zika virus (ZIKV) sfRNA has been detected in mosquito and mammalian somatic cells. Human neural progenitor cells (hNPCs) in the developing brain are the major target cells of ZIKV, and antiviral RNA interference (RNAi) plays a critical role in hNPCs. However, whether ZIKV sfRNA was produced in ZIKV-infected hNPCs as well as its function remains not known. In this study, we demonstrate that abundant sfRNA was produced in ZIKV-infected hNPCs. RNA pulldown and mass spectrum assays showed ZIKV sfRNA interacted with host proteins RHA and PACT, both of which are RNA-induced silencing complex (RISC) components. Functionally, ZIKV sfRNA can antagonize RNAi by outcompeting small interfering RNAs (siRNAs) in binding to RHA and PACT. Furthermore, the 3' stem loop (3'SL) of sfRNA was responsible for RISC components binding and RNAi inhibition, and 3'SL can enhance the replication of a viral suppressor of RNAi (VSR)-deficient virus in a RHA- and PACT-dependent manner. More importantly, the ability of binding to RISC components is conversed among multiple flaviviral 3'SLs. Together, our results identified flavivirus 3'SL as a potent VSR in RNA format, highlighting the complexity in virus-host interaction during flavivirus infection.IMPORTANCEZika virus (ZIKV) infection mainly targets human neural progenitor cells (hNPCs) and induces cell death and dysregulated cell-cycle progression, leading to microcephaly and other central nervous system abnormalities. RNA interference (RNAi) plays critical roles during ZIKV infections in hNPCs, and ZIKV has evolved to encode specific viral proteins to antagonize RNAi. Herein, we first show that abundant sfRNA was produced in ZIKV-infected hNPCs in a similar pattern to that in other cells. Importantly, ZIKV sfRNA acts as a potent viral suppressor of RNAi (VSR) by competing with siRNAs for binding RISC components, RHA and PACT. The 3'SL of sfRNA is responsible for binding RISC components, which is a conserved feature among mosquito-borne flaviviruses. As most known VSRs are viral proteins, our findings highlight the importance of viral non-coding RNAs during the antagonism of host RNAi-based antiviral innate immunity.

Urinary tract infections in pediatric orthopedic surgical patients: a Single Institution National Surgical Quality Improvement Program Study.

Perioperative urinary tract infections (UTIs) are poorly studied among pediatric orthopedic surgical patients. We evaluated the incidence of and risk factors for UTI in a large volume of pediatric orthopedic surgical patients. Children <18 who underwent orthopedic surgery between March 2015 and December 2018 were analyzed using our institution's National Surgical Quality Improvement Program (NSQIP) data. Demographic, perioperative and outcome data of patients who developed a UTI within 30 days of surgery were compared to patients without UTI. NSQIP data were available for 520 surgeries (324 girls and 196 boys). Median age at surgery was 13.5 years. A Foley was placed in 301/520 cases (88/196 boys and 213/324 girls) in 264 children. Six cases of UTI occurred within 30 days of surgery (1.2% of surgeries). The UTI rate among patients with a Foley was 2.3%, and among girls with a Foley was 2.8%. No UTIs occurred without a Foley, nor any in boys. All six occurred in the American Society of Anesthesiologists Class 2 females, ages 7-15 undergoing elective surgery with Foley for over 48 h. Factors associated with an increased odds of developing UTI included: higher BMI [OR, 1.12 (CI, 1.01-1.22; P = 0.03)], developmental delay [OR, 7.82 (CI, 1.40-43.7; P = 0.02)], structural central nervous system abnormality [OR, 17.5 (CI, 3.89-90.4; P = 0.01)], longer duration with Foley [OR, 1.68 (CI, 1.22-2.32; P = 0.002)] and hospital readmission within 30 days [OR 14.2 (CI, 2.32-87.3; P = 0.004)]. Risk of UTI is low after pediatric orthopedic surgery. Girls with comorbidities including structural central nervous system abnormality, developmental delay and higher BMI with prolonged Foley catheterization may have higher postoperative UTI risk. Level of Evidence: II.

Prenatal diagnosis of non-typical Chiari malformation type I associated with de novo Nuclear Factor I A gene mutation: a case report

BackgroundChiari malformation is one of the most common Central nervous system (CNS) abnormalities that can be detected in routine fetal scanning. Chiari malformation type I (CMI) is a congenital defect characterized by a displacement of the cerebellar tonsils through the foramen magnum. The etiology of CMI has not been well established and suggested having multifactorial contributions, especially genetic deletion. Clinical characteristics of this anomaly may express in different symptoms from neurological dysfunction and/or skeletal abnormalities in the later age, but it is rarely reported in pregnancy.Case presentationWe present a case in which the Chiari malformation type I was diagnosed with comorbidities of facial anomalies (flatting forehead and micrognathia) and muscular-skeletal dysmorphologies (clenched hands and clubfeet) at the 24+6 weeks of gestation in a 29-year-old Vietnamese pregnant woman. The couple refused an amniocentesis, and the pregnancy was followed up every 4 weeks until a spontaneous delivery occurred at 38 weeks. The newborn had a severe asphyxia and seizures at birth required to have an emergency resuscitation at delivery. He is currently being treated in the intensive neonatal care unit. He carries the novel heterozygous NFIA gene mutation confirmed after birth. No further postnatal malformation detected.ConclusionCMI may only represent with facial abnormalities and muscle-skeletal malformations at the early stage of pregnancy, which may also alert an adverse outcome. A novel heterozygous NFIA gene mutation identified after birth helps to confirm prenatal diagnosis of CMI and to provide an appropriate consultation.

Central Precocious Puberty in Italian Boys: Data From a Large Nationwide Cohort.

There are only a few nationwide studies on boys with central precocious puberty (CPP) and the last Italian study is a case series of 45 boys that dates back to 2000. We aimed to evaluate the causes of CPP in boys diagnosed during the last 2 decades in Italy and the relative frequency of forms with associated central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) compared to idiopathic ones. We performed a national multicenter retrospective study collecting data from 193 otherwise normal healthy boys with a diagnosis of CPP. Based on MRI findings, the patients were divided into: Group 1, no CNS abnormalities; Group 2, mild abnormalities (incidental findings) unrelated to CPP; and Group 3, causal pathological CNS abnormalities. The MRI findings show normal findings in 86%, mild abnormalities (incidental findings) in 8.3%, and causal pathological CNS abnormalities in 5.7% of the cases. In Group 3, we found a higher proportion of patients with chronological age at diagnosis < 7 years (P = .00001) and body mass index greater than +2 SDS (P < .01). Gonadotropin-releasing hormone analogue therapy was started in 183/193 subjects. The final height appeared in the range of the target height in all groups and in 9 patients in whom the therapy was not started. In our study on a large nationwide cohort of boys referred for precocious puberty signs, the percentage of forms associated with CNS abnormalities was one of the lowest reported in the literature.

Abstract 20: Axonal Neuropathy and Inflammatory Response in Peripheral Nerves of a Murine Cerebral Amyloid Angiopathy Model

Introduction: Cerebral amyloid angiopathy (CAA) induces intracerebral hemorrhages, small vessel disease, and cognitive decline in elderly individuals. CAA is also associated with slower walking speed and abnormal gait rhythms compared to healthy controls. Little is known regarding the impact of peripheral nervous system abnormalities on CAA-associated gait disturbance. Furthermore, it is unknown whether peripheral nerves pose extracerebral targets of amyloid-related endoneurial inflammation. Hypothesis: Gait disturbance in a CAA model is associated with peripheral neuropathy through endoneurial inflammation related to amyloid accumulation. Methods: Aged (19-24 months) Tg-SwDI mice (CAA mice) of both sexes harboring mutations of human amyloid precursor protein (APP) were used as a CAA model. Age-matched C57BL/6 wild-type (WT) mice were used as controls (n=6-11/grp). Gait disturbance and sensorimotor function were assessed via DigiGait and grip strength testing. Flow cytometry was used to analyze immune cells in the sciatic nerve. Tibial nerve morphometry was performed to assess for neuropathy. Results: CAA mice had weaker grip strength ( CAA: 97.7 ± 17.6 g, WT 111.5 ± 8.1 g, p=0.039 ) and evidence of neuropathic gait disturbances, reflected by increased paw angles ( CAA: 21.1 ± 4.8°, WT 11.7 ± 3.4°, p=0.0002 ) and reduced paw areas ( CAA: 0.4 ± 0.05 cm 2 , WT 0.5 ± 0.06 cm 2 , p=0.013 ) impacting the ground when walking compared to WT mice. Tibial nerve morphometry showed a reduced number of myelinated nerve fibers ( CAA: 1023 ± 230.1, WT 1318 ± 45.8, p=0.0047 ) suggesting potential axonal degeneration in CAA mice. Flow cytometry showed an increase in the count of macrophage (both M1 and M2 subtypes) lineage cells ( M1 CAA: 102.3 ± 29.2, WT 57.9 ± 36.3, p=0.009 ) as well as M1 macrophage associated pro-inflammatory cytokine TNF-α ( CAA: 99.7 ± 28.3, WT 53.8 ± 12.2, p=0.009 ) in sciatic nerves of CAA mice compared to WT mice. Conclusions: CAA mice display an enhanced inflammatory response within the endoneurium which may contribute to observed axonal degeneration, ultimately impairing sensorimotor function and gait. Further studies are needed to unravel the mechanistic interplay between amyloid pathology, endoneurial inflammation, and axonal neuropathy in this CAA model.

DNMT1 Y495C mutation interferes with maintenance methylation of imprinting control regions

Hereditary Sensory and Autonomic Neuropathy Type 1E (HSAN1E) is a rare autosomal dominant neurological disorder due to missense mutations in DNA methyltransferase 1 (DNMT1). To investigate the nature of the dominant effect, we compared methylomes of transgenic R1wtDnmt1 and R1Dnmt1Y495C mouse embryonic stem cells (mESCs) overexpressing WT and the mutant mouse proteins respectively, with the R1 (wild-type) cells. In case of R1Dnmt1Y495C, 15 out of the 20 imprinting control regions were hypomethylated with transcript level dysregulation of multiple imprinted genes in ESCs and neurons. Non-imprinted regions, minor satellites, major satellites, LINE1 and IAP repeats were unaffected. These data mirror the specific imprinting defects associated with transient removal of DNMT1 in mESCs, deletion of the maternal-effect DNMT1o variant in preimplantation mouse embryos, and in part, reprogramming to naïve human iPSCs. This is the first DNMT1 mutation demonstrated to specifically affect Imprinting Control Regions (ICRs), and reinforces the differences in maintenance methylation of ICRs over non-imprinted regions. Consistent with nervous system abnormalities in the HSAN1E disorder and involvement of imprinted genes in normal development and neurogenesis, R1Dnmt1Y495C cells showed dysregulated pluripotency and neuron marker genes, and yielded more slender, shorter, and extensively branched neurons. We speculate that R1Dnmt1Y495C cells produce predominantly dimers containing mutant proteins, leading to a gradual and specific loss of ICR methylation during early human development.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Synonymous variants in the ATP6AP2 gene may lead to developmental and epileptic encephalopathy.

To the literature, variants in the ATP6AP2 gene may cause abnormal nervous system development and associated neurological symptoms. We report a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G > A (p.Ala286=) synonymous variant. In addition, an overview of reported patients with the same variant were collected and summarized to compare our findings. The patient started experiencing tonic seizures at 3.5 months of age, and magnetic resonance imaging (MRI) indicated impaired brain white matter development and reduced left hippocampal volume. Furthermore, electroencephalography showed multifocal interictal epileptiform discharges. Treatment with various anti-seizure medications yielded unsatisfactory results, and the disorder eventually developed into epileptic spasms. An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. A review of previously reported ATP6AP2-related DEE patients found that synonymous variants in the ATP6AP2 gene can cause early DEE onset, progressive changes in early-life MRI, and exon skipping in all ATP6AP2-related DEE patients. We found that synonymous variants in ATP6AP2 may have significant pathogenicity and are highly correlated with DEE. Due to increased isoform production, ATP6AP2 synonymous variants may cause nervous system developmental disorders by competitively reducing the generation of full-length transcripts, resulting in defects in ATP6AP2-related physiological processes.

Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes.

There is a considerable overlap between the clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in a general group of patients with PCC and in a group of patients with ME/CFS whose disease was not related to COVID-19. We hypothesize that the similarity in the chronic symptoms of patients with PCC and ME/CFS extends to objective autonomic nervous system abnormalities. Synchronous recordings of an electrocardiogram and continuous dynamics of blood pressure in the digital artery using the Penaz method were obtained using the spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting the PCC definition and 32 healthy controls. Heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) were assessed at rest and in tests with fixed respiratory rates. Indicators of baroreflex regulation (baroreflex effectiveness index and baroreflex sensitivity) were additionally determined at rest. The total power and power of low-frequency and high-frequency of RR interval variability at rest as well as baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to healthy controls. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing, the HRV parameters returned to normal in PCC but not in ME/CFS patients. The correlation analysis revealed a close relationship of HRV, BPV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in the ME/CFS and PCC patients. A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependent dysautonomia was identified in the ME/CFS and PCC patients. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationships between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

Clinical characteristics of 13 cases of Coronavirus infection complicated with severe central nervous system lesions in Shanxi children’s hospital

BackgroundThe new coronavirus Omicron variant strain spread rapidly worldwide and is currently the primary mutant strain prevalent in the world.ObjectiveTo explore the clinical features of severe central nervous system lesions in children infected with novel coronavirus Omicron mutant strain, so as to provide a reference for clinical diagnosis and treatment.Materials and methodsThe clinical data of 13 children diagnosed with novel coronavirus Omicron variant strain complicated with severe central nervous system infection from December 13, 2022, to January 31, 2023, in the Children’s Intensive Care Medicine Department of Shanxi Children’s Hospital were retrospectively analyzed.ResultsAmong the 13 children, there were 9 males (69%) and 4 females (31%); the ages ranged from 1-year-old 16 days to 13 years old, with a median age of 9 years old, and most of them were school-age children (84.6%). The 13 children were usually healthy, but this time they were all positive for the new coronavirus nucleic acid test. The 13 children had obvious signs of the abnormal nervous system when they were admitted to the hospital, among which 12 cases (92.3%) showed convulsions, 11 children had obvious disturbance of consciousness (84.6%) when they were admitted to the hospital, and 5 children had circulatory disorders (38.4%). Among the 13 children, 2 were cured (15.3%), 5 children had serious sequelae (38.4%) when they were discharged from the hospital, and 6 children died of severe illness (46.3%).ConclusionThis study illuminates the clinical characteristics of severe central nervous system complications in children with coronavirus variant infection, highlighting rapid onset, swift progression, relatively poor prognosis, and notable symptoms such as high fever, convulsions, altered consciousness, elevated interleukin-6 levels, increased cerebrospinal fluid lactate levels, and early imaging changes.

Clinical outcomes and risk factors of Acinetobacter baumannii meningitis in pediatric patients at a tertiary hospital in China.

To summarize the clinical characteristics, outcomes and identify risk factors of Acinetobacter baumannii (AB) meningitis in children. This was a single-center, retrospective study. Children hospitalized between January 2016 and December 2021 who were diagnosed with AB meningitis were included. The clinical characteristics and outcomes were reviewed. Risk factors were determined using univariate analyses (chi-square and Mann-Whitney U tests). Seventeen patients were included; 15 cases were secondary to neurosurgery, and two were neonates with primary bacterial meningitis. Common symptoms included fever, convulsions and nervous system abnormalities. Cerebrospinal fluid (CSF) tests typically showed increased white blood cell counts dominated by neutrophils, reduced glucose levels and elevated protein levels. Ten patients were successfully treated (successful treatment [ST] group); seven had failed treatment (failed treatment [FT] group). Univariate analyses revealed that mechanical ventilation, routine white cell counts in the peripheral blood, procalcitonin, protein in the CSF, septic shock and carbapenem-resistant AB (CRAB) differed significantly between the groups. AB meningitis in children has a high mortality rate. FT was associated with mechanical ventilation, septic shock, CRAB, lower peripheral leukocyte counts, higher protein levels in the CSF and procalcitonin. Larger studies are needed to identify independent risk factors for adverse outcomes.