Neurophysiological and brain structural insights into cyclin-dependent kinase-like 5 deficiency disorder: Visual and auditory evoked potentials and MRI analysis.

OBJECTIVE: CDKL5 deficiency disorder (CDD), an epileptic encephalopathy for which novel therapeutics are under development, lacks valid and reliable measures of therapeutic efficacy. We aimed to elucidate the neurophysiological and brain structural features of CDD patients and identify objective indicators reflecting the clinical severity. METHODS: Twelve CDD patients and 12 healthy controls (HCs) participated. The clinical severity of CDD was scored using the CDD severity assessment (CDD-SA). The participants underwent visual evoked potential (VEP), auditory brainstem response (ABR), structural MRI, and diffusion tensor imaging (DTI) analyses. Measurements from each modality were compared with normal values of age-matched cohorts (VEP and ABR) or statistically compared between CDD patients and HCs (MRI). RESULTS: VEP showed a significant correlation between P100 latency and CDD-SA in CDD patients. ABR showed abnormalities in six patients (50%), including prolonged V-wave latency (n = 2), prolonged inter-peak latency between waves I and V (n = 3), and mild hearing loss (n = 4). Structural MRI showed a significant reduction in cortical volume in the left pars triangularis and right cerebellum compared with HCs. DTI showed a widespread decrease in fractional anisotropy and an increase in mean and radial diffusivity compared with HCs. CONCLUSION: CDD patients had reduced cortical volume in the left pars triangularis, a brain region crucial for speech, and one-third of patients had mild hearing loss. These changes may be involved in language impairments in CDD patients. Additionally, P100 latency significantly correlated with the clinical severity. These features can be used to assess the clinical severity of CDD.

Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study.

OBJECTIVE: To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI). METHODS: Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs) underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI). The measurements obtained from each modality were statistically compared between RTTs and HCs and examined for their correlation with the clinical severity of RTTs. RESULTS: Structural MRI imaging revealed volume reductions in most cortical and subcortical regions of the brain. Remarkable volume reductions were observed in the frontal and parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus, and corpus callosum. DTI analysis revealed decreased white matter integrity in broad regions of the brain. Fractional anisotropy values were greatly decreased in the superior longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI analysis showed decreased functional connectivity in the interhemispheric dorsal attention network, and between the visual and cerebellar networks. The clinical severity of RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and cerebellar peduncles. CONCLUSION: Regional volume and white matter integrity of RTT brains were reduced in broad areas, while most functional connections remained intact. Notably, two functional connectivities, between cerebral hemispheres and between the cerebrum and cerebellum, were decreased in RTT brains, which may reflect the structural changes in these brain regions.

Novel NARS2 variant causing leigh syndrome with normal lactate levels.

Leigh syndrome is the most genetically heterogenous phenotype of mitochondrial disease. We describe a patient with Leigh syndrome whose diagnosis had not been confirmed because of normal metabolic screening results at the initial presentation. Whole-exome sequencing identified pathogenic variants in NARS2, the gene encoding a mitochondrial asparaginyl-tRNA synthetase. One of the biallelic variants was novel. This highlights the essential role of genetic testing for a definite diagnosis of Leigh syndrome.

Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathy is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability, in which there is additional developmental impairment independent of epileptic activity. Biallelic variants of SZT2, a known seizure threshold regulator gene, have been linked to a wide spectrum of clinical features, ranging from severe intellectual disability with refractory seizures to mild intellectual disability without seizures. Here, we describe a child with developmental and epileptic encephalopathy whose genetic testing led to the identification of novel biallelic variants of SZT2, a paternally inherited c.2798C>T, p.(Ser933Phe) variant and a maternally inherited c.4549C>T, p.(Arg1517Trp) variant. Our patient showed common clinical and radiographic features among patients with SZT2-related encephalopathy. However, neonatal-onset seizures and suppression-burst EEG activity, not previously associated with SZT2-related encephalopathy, were observed in this case. Although the seizures were controlled with carbamazepine, the developmental consequences remained profound, suggesting that the developmental impairments might be attributed to a direct effect of the SZT2 variants rather than the epileptic activity. We propose that SZT2 variants should be regarded among those that are believed to cause neonatal-onset developmental and epileptic encephalopathy with a suppression-burst pattern on EEG.

The role of molecular analysis of SLC2A1 in the diagnostic workup of glucose transporter 1 deficiency syndrome.

The study aimed to investigate the role of molecular analysis of SLC2A1 in the diagnostic workup of glucose transporter 1 deficiency syndrome (Glut1DS). During 2006-2020, we received 100 requests for SLC2A1 variant analysis of patients clinically suspected for Glut1DS. Pathogenic variants were detected in 37 patients, among whom 11 were familial cases. Most patients presented with epilepsy (n = 31; 84%), movement disorders (MD) (n = 28; 76%), and intellectual disabilities (ID) (n = 29; 78%). Moreover, paroxysmal dyskinesias (PD) (n = 10; 27%) were more frequently seen in familial cases (55%) than in sporadic cases (15%) (p < .05). The Glut1DS patients with ID typically had either epilepsy or MD. The presence of MD, particularly when associated with epilepsy or ID, indicated Glut1DS (p < .05). The cerebrospinal fluid (CSF) glucose levels were at or below the 10th percentile in all 32 SLC2A1-positive patients but only in 16 of 52 (31%) SLC2A1-negative patients (p < .05). Thus, CSF analysis is an essential tool in the diagnostic workup of Glut1DS. SLC2A1 molecular analysis should be performed in patients with a family history of Glut1DS or with at least one of the following clinical features, such as epilepsy, MD, and PD with or without ID, and low CSF glucose level. This would help in precise molecular diagnosis of the disease and facilitate effective treatment and appropriate genetic counseling.

Spiky-shaped niobium pentoxide nano-architecture: highly stable and recoverable Lewis acid catalyst.

Niobium pentoxide particles with a complex three-dimensional (3D) nanostructure consisting of a spiky structure have been developed as recyclable and recoverable Lewis acid catalysts. The morphology of the niobium pentoxide was successfully controlled from 1D to 3D via a bridging-ligand-assisted hydrothermal treatment, without changing the crystal structure. Compared with dispersed one-dimensional (1D) niobium pentoxide nanorods with a major-axis length and minor-axis length of 20 nm and 5-8 nm, respectively, the spiky-shaped niobium pentoxide composed of 300 nm spherical cores and nanorods with a minor-axis length of 5 nm maintained its surface nanostructure even after calcination at 400 °C in air. The 400 °C-calcined spiky particles exhibited the highest production rate of 2-((4-methoxyphenyl)amino)-2-phenylacetonitrile (0.115 mmol m-2) in a Strecker reaction, resulting in a nanoscale and ordered surface structure of spiky particles that simultaneously exhibit high specific reactivity and high structural stability. Acid site analysis and Raman spectroscopy revealed that stable nanorods that grew in the (001) orientation functioned as Lewis acid catalysts and that the origin of the acidity was a flexible Nb-O polyhedral structure in the single-nanoscale (<10 nm) niobium oxide rods. This study proposes that the spiky-shaped niobium pentoxide exhibits sintering resistivity and high activity and has potential applications as a recoverable and recyclable solid acid catalyst.

Atypical Rett syndrome in a girl with mosaic triple X and MECP2 variant.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls, resulting from a loss-of-function variant in X-linked MECP2. Here, we report a rare case of a girl with RTT with an X chromosome mosaic karyotype (46,XX/47,XXX). METHODS: Fluorescent in situ hybridization (FISH) was carried out to confirm the mosaic karyotype. Sanger sequencing was carried out to genetically diagnose RTT. Furthermore, we assessed the X chromosome inactivation (XCI) pattern. MECP2 expression levels were examined via RT-PCR. RESULTS: The patient presented with preserved speech variant, the milder form of RTT. Genetic examination revealed a de novo, heterozygous, truncating variant of MECP2. FISH revealed mosaicism in the 47,XXX karyotype in 6% of her cells. The XCI assay revealed unbalanced inactivation with skewing in favor of the paternal X chromosome. MECP2 was downregulated to only 84% of the control, indicating that the patient's variant was probably of paternal origin. Unbalanced XCI in this patient might have contributed to the alleviation of the phenotype. However, her supernumerary X chromosome was derived from maternal X chromosome harboring the wild-type allele and might have had no preferential effect on her RTT-related phenotype. CONCLUSION: The present results indicate that phenotypic effects of X chromosome aneuploidy depend on the nature of the supernumerary X chromosome, the pattern of mosaicism, and XCI status.

MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. Its causative gene is the X-linked MECP2 encoding the methyl-CpG-binding protein 2 (MeCP2). The gene comprises four exons and generates two isoforms, namely MECP2_e1 and MECP2_e2. However, it remains unclear whether both MeCP2 isoforms have similar function in the brain. METHODS: We report a case of a boy with typical RTT. Male cases with MECP2 variants have been considered inviable, but somatic mosaicism of the variants can cause RTT in males. Whole-exome sequencing was performed to search for the genetic background. RESULTS: A novel nonsense and mosaic variant was identified in exon 1 of MECP2, and the variant allele fraction (VAF) was 28%. Our patient had the same level of VAF as that in reported male cases with mosaic variants in MECP2 exon 3 or 4, but manifested RTT symptoms that were milder in severity compared to those in these patients. CONCLUSION: This is probably because the variants in MECP2 exon 3 or 4 disrupt both isoforms of MeCP2, whereas the variant in exon 1, as presented in this study, disrupts only MeCP2_e1 but not MeCP2_e2. Therefore, our findings indicate that MeCP2_e2 may partially compensate for a deficiency in MeCP2_e1.

Comparison of insulin glargine 300 U/mL and insulin degludec using flash glucose monitoring: A randomized cross-over study.

AIMS/INTRODUCTION: We compared the efficacy and safety of insulin glargine 300 U/mL (Gla300) and insulin degludec U100 (Deg) using a flash glucose monitoring system. MATERIALS AND METHODS: A total of 24 Japanese patients with type 2 diabetes were randomized to receive once-daily Gla300 (n = 12) or Deg (n = 12) in the morning. The primary end-points were the mean percentage of time in the target glucose range (70-179 mg/dL) and hypoglycemia (<70 mg/dL), as measured using flash glucose monitoring during the last 7 days of each 14-day period. RESULTS: The percentages of time with glucose levels <70 mg/dL were not significantly different between the two insulin treatments. No significant differences were observed in the percentages of time with glucose levels of 70-179 mg/dL or ≥180 mg/dL. The percentage of time with nocturnal hypoglycemia with Gla300 was significantly lower than that with Deg treatment (P = 0.021). This difference might be attributable to the difference in the duration of action between the two formulations, and the incidence of nocturnal hypoglycemia with Deg treatment was associated with the concomitant use of metformin (P = 0.035). CONCLUSIONS: The two formulations were comparable in efficacy, whereas the incidence of nocturnal hypoglycemia was significantly lower with Gla300. Thus, the present study suggests that, although Gla300 and Deg are comparable long-acting insulin analogs, Gla300 is safer with respect to the incidence of hypoglycemia.

Acute Pharyngitis Associated With Streptococcus dysgalactiae Subspecies equisimilis in Children.

BACKGROUND AND OBJECTIVES: The importance of Streptococcus dysgalactiae subsp. equisimilis (SDSE) in causing sporadic pharyngitis in children remains controversial. The aims of this study were (1) to report the incidence and (2) to compare the epidemiologic and clinical features of patients with SDSE to those with Streptococcus pyogenes (SP). METHODS: A prospective study was conducted on acute pharyngitis associated with SDSE in children over a 2-year period. SDSE was identified using a phenotypic method, M protein gene (emm) analysis and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Patients with positive SDSE or SP cultures received cephalosporins for 5 days and were followed up. The emm genotyping and specific virulence genes analyses were performed. RESULTS: From 3416 throat cultures, 67 isolates (2.0%) were identified as SDSE and 515 (15.1%) were identified as SP. The mean age of patients with SDSE (8.3 years) was older than those with SP (6.6 years; P < 0.01). There was minimal seasonal variation in the isolation rates of SDSE. The febrile patients' rates, gender distribution, cervical lymph node adenopathy rates, hospitalization rates, eradication and failure rates and the nonsuppurative sequelae between patients with SDSE and SP were similar. All SDSE isolates possessed important virulence genes. The emm genotyping of SDSE showed high strain diversity. CONCLUSIONS: The incidence of acute pharyngitis associated with accurately identified SDSE was 2/15 of that with SP. Epidemiologic and clinical features of acute pharyngitis associated with SDSE are indistinguishable from those with SP, with the exception of age and seasonal variation.

Desymmetrization of aziridine with malononitrile using cinchona alkaloid amide/zinc(ii) catalysts.

The catalytic enantioselective desymmetrization of aziridines with malononitrile has been developed. Good yield and enantioselectivity were obtained by using cinchona alkaloid amide/Zn(ii) catalysts. The obtained product can be converted to ß-aminoester, ß-aminoamide and triamide compounds.

Highly efficient synthesis of quinoxalinone-N-oxide via tandem nitrosation/aerobic oxidative C-N bond formation.

An efficient method for constructing quinoxalinone-N-oxides from cyanoacetanilides has been developed. This transformation can be achieved using inexpensive reagents and molecular oxygen under mild conditions, thus offering a practical pathway to quinoxalinone-containing pharmaceuticals such as ataquimast and opaviraline.