Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.

OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories. METHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations. RESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported. SIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2. PLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.

Crucial involvement of fast waves and Delta band in the brain network attributes of infantile epileptic spasms syndrome.

Objective: This study aims to describe the characteristics of the brain network attributes in children diagnosed with Infantile Epileptic Spasms Syndrome (IESS) and to determine the influence exerted by adrenocorticotrophic hormone (ACTH) or methylprednisolone (MP) on network attributes. Methods: In this retrospective cohort study, we recruited 19 infants diagnosed with IESS and 10 healthy subjects as the control from the Pediatric Neurology Department at the Third Affiliated Hospital of Zhengzhou University between October 2019 and December 2020. The first thirty-minute processed electroencephalograms (EEGs) were clipped and filtered into EEG frequency bands (2 s each). A comparative assessment was conducted between the IESS group and the controls as well as the pre- and post-treatment in the IESS group. Mutual information values for each EEG channel were collected and compared including characteristic path length (CPL), node degree (ND), clustering coefficient (CC), and betweenness centrality (BC), based on graph theory. Results: Comparing the control group, in the IESS group, there was an increase in CPL of the Delta band, and a decrease in ND and CC of the Delta band during the waking period, contrary to those during the sleeping period (P < 0.05), a decreased in CPL of the fast waves and an increase in ND and CC (P < 0.05) in the sleep-wake cycle, and a decrease in ND and CC of the Theta band in the waking phase. Post-treatment compared with the pre-treatment, during the waking ictal phase, there was a noted decrease in CPL in the Delta band and fast waves, while an increase was observed in ND and CC (P < 0.05). Conclusions: The Delta band and fast waves are crucial components of the network attributes in IESS. Significance: This investigation provides a precise characterization of the brain network in children afflicted with IESS, and lays the groundwork for predicting the prognosis using graph theory.

Corrigendum: Different frequency bands in various regions of the brain play different roles in the onset and wake-sleep stages of infantile spasms.

[This corrects the article DOI: 10.3389/fped.2022.878099.].

Different Frequency Bands in Various Regions of the Brain Play Different Roles in the Onset and Wake-Sleep Stages of Infantile Spasms.

Objective: The study aimed to identify the signatures of brain networks using electroencephalogram (EEG) in patients with infantile spasms (IS). Methods: Scalp EEGs of subjects with IS were prospectively collected in the first year of life (n = 8; age range 4-8 months; 3 males, 5 females). Ten minutes of ictal and interictal EEGs were clipped and filtered into different EEG frequency bands. The values of each pair of EEG channels were directly compared between ictal with interictal onsets and the sleep-wake phase to calculate IS brain network attributes: characteristic path length (CPL), node degree (ND), clustering coefficient (CC), and betweenness centrality (BC). Results: CPL, ND, and CC of the fast waves decreased while BC increased. CPL and BC of the slow waves decreased, while ND and CC increased during the IS ictal onset (P < 0.05). CPL of the alpha decreased, and BC increased during the waking time (P < 0.05). Conclusion: The transmission capability of the fast waves, the local connectivity, and the defense capability of the slow waves during the IS ictal onset were enhanced. The alpha band played the most important role in both the global and local networks during the waking time. These may represent the brain network signatures of IS.

An intractable epilepsy phenotype of ASNS novel mutation in two patients with asparagine synthetase deficiency.

BACKGROUND AND OBJECTIVE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease caused by variations of the ASNS gene. It manifests as microcephaly, severe developmental delay, and spastic quadriplegia. 71% of ASNSD patients died during early infancy. We aim to investigate mutations related to intractable epilepsy in one Chinese genealogy. MATERIAL AND METHODS: Head Magnetic Resonance Imaging (MRI), whole exome sequencing (WES), and Liquid Chromatography-Mass Spectrometry (LC-MS) to help 2 patients with intractable epilepsy find the underlying mechanisms of disease. RESULTS: These two patients had a compound heterozygous mutation (c.224A > G, p.N75S and c.1612A > G, p.M538V) in the ASNS gene, of which c.1612A > G was a novel mutation. The asparagine levels in patients' plasmas were normal. In addition, they had a later onset, longer survival, and were milder than previously reported ASNSD patients. CONCLUSIONS: Two patients were diagnosed with a milder form of ASNSD. Clinically, the asparagine level in the patient's plasma cannot be used as the only basis to diagnose this disease. This study has expanded the disease phenotype spectrum of ASNSD and broadened the variation profile of the ASNS gene, which can assist in the clinical diagnosis and treatment of ASNSD patients.

[Clinical and genetic analysis of two patients with CHARGE syndrome due to de novo variants of CHD7 gene].

OBJECTIVE: To analyze the clinical characteristics and genetic basis of two children patients with CHARGE syndrome. METHODS: The clinical features of the two patients were analyzed, and potential variants were detected by Trio whole exome sequencing (trio-WES) of the probands and their parents. RESULTS: Child 1 has manifested cerebellar vermis dysplasia, enlargement of cerebral ventricles, whereas child 2 manifested with infantile spasm and congenital hip dysplasia. Both children were found to harbor de novo heterozygous variants of the CHD7 gene, namely c.4015C>T (exon 17) and c.5050G>A (exon 22). Based on the guidelines of the American College of Medical Genetics and Genomics, the two variants were rated as pathogenic variants, and the related disease was CHARGE syndrome. Furthermore, child 2 was also found to harbor a novel heterozygous c.6161A>C (p.Gln2054Pro) missense variant of COL12A1 gene, which was rated as possibly pathogenic, and the associated disease was Bethlem myopathy type 2, which is partially matched with the patient' s clinical phenotype. CONCLUSION: The special clinical phenotypes shown by the two children harboring novel CHD7 variants have further expanded the phenotypic spectrum of CHARGE syndrome.

First Chinese patient with mental retardation-40 due to a de novo CHAMP1 frameshift mutation: Case report and literature review.

Mental retardation-40 (MRD40) is a rare autosomal dominant neurodevelopmental disorder with a poor prognosis that is caused by a heterozygous mutation in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). It was previously considered a non-syndromic disease due to the lack of specific external features. Only limited international reports describing CHAMP1 mutations are currently available. The present case study was the first to report on a Chinese patient with MRD40. The patient presented with severe global development delay with significant craniofacial dysmorphia. Using trio whole-exome sequencing, a novel de novo frameshift mutation in CHAMP1, NM_032436.2: c.530delCinsTTT, was identified, which expands the spectrum of the known pathogenic variants. The present case report helps to improve the syndromic profile of the rare MRD40 disorder and provides an example for the clinical diagnosis of MRD40.

MicroRNA-135a participates in the development of astrocytes derived from bacterial meningitis by downregulating HIF-1α.

Accumulating evidence has highlighted the potential of microRNAs (miRs) as biomarkers in various human diseases. However, the roles of miRs in bacterial meningitis (BM), a severe infectious condition, still remain unclear. Thus, the present study aimed to investigate the effects of miR-135a on proliferation and apoptosis of astrocytes in BM. Neonatal rats were injected with Streptococcus pneumoniae to establish the BM model. The expression of miR-135a and hypoxia-inducible factor 1α (HIF-1α) in the BM rat models were characterized, followed by determination of their interaction. Using gain- and loss-of-function approaches, the effects of miR-135a on proliferation, apoptosis, and expression of glial fibrillary acidic protein (GFAP), in addition to apoptosis-related factors in astrocytes were examined accordingly. The regulatory effect of HIF-1α was also determined along with the overexpression or knockdown of HIF-1α. The results obtained indicated that miR-135a was poorly expressed, whereas HIF-1α was highly expressed in the BM rat models. In addition, restored expression levels of miR-135a were determined to promote proliferation while inhibiting the apoptosis of astrocytes, along with downregulated Bax and Bad, as well as upregulated Bcl-2, Bcl-XL, and GFAP. As a target gene of miR-135a, HIF-1α expression was determined to be diminished by miR-135a. The upregulation of HIF-1α reversed the miR-135a-induced proliferation of astrocytes. Taken together, the key findings of the current study present evidence suggesting that miR-135a can downregulate HIF-1α and play a contributory role in the development of astrocytes derived from BM, providing a novel theoretical perspective for BM treatment approaches.

MiR-301a-3p in the pathogenesis of bacterial meningitis by targeting Cx43.

Gap junction (GJ) is concerned with cell growth, differentiation, immune response, as well as many physiological and pathological processes. Cx43, as an important GJ protein, is associated with a variety of diseases. This study investigated the effect of miR-301a-3p in bacterial meningitis by targeting the Cx43 gene. The negative correlation between Cx43 and miR-301a-3p was because of the abnormal expression of related genes. MiR-301a-3p agomir was transfected into astrocytes for higher expression; CCK8 assay and flow cytometry showed that the high expression of miR-301a-3p would inhibit apoptosis and induces proliferation of astrocytes, whereas miR-301a-3p antagomir would inhibit proliferation and induce apoptosis. Bioinformatics analysis showed that Cx43 was the target gene of miR-301a-3p, and dual-luciferase assay and experiments repeated showed that miR-301a-3p regulated the expression of Cx43 on the 3'-untranslated region seed region. Therefore, miR-301a-3p played a biological role in the development of bacterial meningitis by regulating the expression of the target gene Cx43.

Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis.

Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×10(7) cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX+DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX+DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX+DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.

[NMDAR expression in the cochlear nucleus and hearing damage in neonatal rats with hyperbilirubinemia].

OBJECTIVE: To study the role of N-methyl-D-aspartate-receptor (NMDAR) expression in the development of hearing damage in neonatal rats with hyperbilirubinemia. METHODS: Sixty seven-day-old Sprague-Dawley rats were randomly injected with bilirubin of 100 microg/g (low-dose treatment group) or 200 microg/g (high-dose treatment group) or normal saline (control group). Auditory brainstem response (ABR) was examined. The concentrations of bilirubin in blood and brain were measured. NMDAR expression in the cochlear nucleus slices was examined by immunohistochemistry assay. RESULTS: ABR reflecting threshold obviously increased, and I, II and III wave latency as well as I-II, II-III and I-III interval were more prolonged in the two bilirubin treatment groups when compared with the control group. The NMDAR expression in the cochlear nucleuse in the two bilirubin treatment groups was obviously lower than that in the control group. The NMDAR expression in the cochlear nucleuse was negatively correlated with the brain bilirubin content and the ABR reflecting threshold in the two bilirubin treatment groups. CONCLUSIONS: An increased NMDAR activity may play an important role in hearing damage following hyperbilirubinemia.

[Miniature quadrupole mass spectrometer array and its applications in manned spaceflight].

This paper explained the working method of the quadrupole mass spectrometer array and its features of volume, weight, power, sensitivity to many kinds of gases as well as flexibility when used together with a miniature gas chromatograph (GC) and a thermal-conductivity detector (TCD). Three types of structure formed in its development are also described. Finally, the applications of the quadrupole mass spectrometer array in the field of manned spaceflight were summarized.