De novo CLCN3 variants affecting Gly327 cause severe neurodevelopmental syndrome with brain structural abnormalities.

A recent study revealed that monoallelic missense or biallelic loss-of-function variants in the chloride voltage-gated channel 3 (CLCN3) cause neurodevelopmental disorders resulting in brain abnormalities. Functional studies suggested that some missense variants had varying gain-of-function effects on channel activity. Meanwhile, two patients with homozygous frameshift variants showed severe neuropsychiatric disorders and a range of brain structural abnormalities. Here we describe two patients with de novo CLCN3 variants affecting the same amino acid, Gly327 (p.(Gly327Ser) and p.(Gly327Asp)). They showed severe neurological phenotypes including global developmental delay, intellectual disability, hypotonia, failure to thrive, and various brain abnormalities. They also presented with characteristic brain and ophthalmological abnormalities, hippocampal and retinal degradation, which were observed in patients harboring homozygous loss-of-function variants. These findings were also observed in CLCN3-deficient mice, indicating that the monoallelic missense variant may also have a dominant negative effect. This study will expand the phenotypic spectrum of CLCN3-related disorders.

Phenotypic features of 1q41q42 microdeletion including WDR26 and FBXO28 are clinically recognizable: The first case from Japan.

1q41q42 microdeletion syndrome has been established in 2007. Since then, more than 17 patients have been reported so far. The reported deletions showed random breakpoints and deletion regions are aligned as roof tiles. Patients with 1q41q42 microdeletion syndrome show intellectual disability, seizures, and distinctive features. Many genotype-phenotype correlation studies have been performed and some genes included in this region have been suggested as potential candidate genes. Recently, de novo variants in WDR26 and FBXO28 were identified in patients who showed consistent phenotypes with 1q41q42 microdeletion syndrome. Thus, both genes are now considered as the genes possibly responsible for 1q41q42 microdeletion syndrome. Here, the first case of a Japanese patient with a de novo 1q41q42 microdeletion is reported. Owing to the distinctive features, this syndrome would be clinically recognizable.

Comparison of Silent and Conventional MR Imaging for the Evaluation of Myelination in Children.

PURPOSE: Silent magnetic resonance imaging (MRI) scans produce reduced acoustic noise and are considered more gentle for sedated children. The aim of this study was to compare the validity of T1- (T1W) and T2-weighted (T2W) silent sequences for myelination assessment in children with conventional spin-echo sequences. MATERIALS AND METHODS: A total of 30 children (21 boys, 9 girls; age range: 1-83 months, mean age: 35.5 months, median age: 28.5 months) were examined using both silent and spin-echo sequences. Acoustic noise levels were analyzed and compared. The degree of myelination was qualitatively assessed via consensus, and T1W and T2W signal intensities were quantitatively measured by percent contrast. RESULTS: Acoustic noise levels were significantly lower during silent sequences than during conventional sequences (P < 0.0001 for both T1W and T2W). Inter-method comparison indicated overall good to excellent agreement (T1W and T2W images, κ = 0.76 and 0.80, respectively); however, agreement was poor for cerebellar myelination on T1W images (κ = 0.14). The percent contrast of silent and conventional MRI sequences had a strong correlation (T1W, correlation coefficient [CC] = 0.76; T1W excluding the middle cerebellar peduncle, CC = 0.82; T2W, CC = 0.91). CONCLUSIONS: For brain MRI, silent sequences significantly reduced acoustic noise and provided diagnostic image quality for myelination evaluations; however, the two methods differed with respect to cerebellar delineation on T1W sequences.

Prognostic factors for acute encephalopathy with bright tree appearance.

OBJECTIVE: To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. METHODS: We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. RESULTS: Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p=0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p<0.05) and minimal platelet counts were significantly lower (p<0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. CONCLUSIONS: Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability.

Cucurbita-5,23-diene-3beta,25-diol from Sicana odorifera.

The spectral data of a new triterpene, cucurbita-5,23-diene-3beta,25-diol, isolated from the seeds of Sicana odorifera, are reported.

Effect of adrenocorticotropic hormone therapy for epileptic spasms developing after the age of 1 year.

PURPOSE: Epileptic spasms sometimes begin after the first year of life, and such seizures are recognized as late-onset spasms (LOS). The prognosis of LOS is poor, and a treatment strategy has not been established. This study aimed to assess the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for LOS. METHODS: We investigated the rate of LOS in 22 patients (14 boys and 8 girls) treated with ACTH therapy. The age at onset of LOS and at the start of ACTH therapy ranged from 12 to 94 months (median, 31.6 ± 22.1 months) and from 12.5 to 116 months (median, 37.5 ± 23.7 months), respectively. We investigated the response rate of LOS treated with ACTH therapy, and compared the clinical features between responders (short-term) and nonresponders. RESULTS: Nine (41%) of the 22 patients showed cessation of epileptic spasms within 3 months. The epileptic spasms ceased in four of these nine patients for more than 1 year. The age at onset of LOS was significantly associated with short-term seizure cessation (p<0.05). Patients who achieved short-term cessation of seizures received ACTH therapy within 6 months from the onset of LOS. CONCLUSION: ACTH therapy is a potentially effective treatment when started within 6 months from the onset of LOS. A younger age at onset of LOS is associated with a favorable outcome.

All-trans Arachidonic acid generates reactive oxygen species via xanthine dehydrogenase/xanthine oxidase interconversion in the rat liver cytosol in vitro.

We previously reported that the all-cis isomer of arachidonic acid, the most naturally occurring isoform of this fatty acid, reduced cuprous copper ion-induced conversion of xanthine dehydrogenase into its reactive oxygen species generating form, xanthine oxidase. In the present study, the effects of all-trans isomer of arachidonic acid, in comparison with cis isomer of arachidonic acid, on the xanthine dehydrogenase/xanthine oxidase interconversion were explored. cis isomer of arachidonic acid alone did not have any significant effect on the activities of xanthine dehydrogenase and xanthine oxidase, but it inhibited the cuprous copper ion-induced conversion of xanthine dehydrogenase to xanthine oxidase in rat liver cytosol in vitro. In contrast, trans isomer of arachidonic acid elicited an increase in xanthine oxidase activity concomitant with a decrease in xanthine dehydrogenase activity, and further potentiated the cuprous copper ion-induced xanthine dehydrogenase/xanthine oxidase interconversion. In primary rat hepatocyte cultures, trans isomer of arachidonic acid increased 2',7'-dichlorofluorescein-fluorescence intensity in the cytosolic fraction from 2',7'-dichlorodihydrofluorescein, an indicator of reactive oxygen species generation. The pretreatment of allopurinol, an xanthine oxidase inhibitor, diminished the trans isomer of arachidonic acid-induced increase in the 2',7'-dichlorofluorescein-fluorescence intensity, indicating the role of xanthine dehydrogenase/xanthine oxidase in mediating trans isomer of arachidonic acid-induced reactive oxygen species generation. These observations suggest that, in contrast to all-cis arachidonic acid, all-trans arachidonic acid has the potential to enhance reactive oxygen species generation via xanthine dehydrogenase/xanthine oxidase interconversion in the liver cytosol in vitro.

Biosynthesis of acaterin: mechanism of the reaction catalyzed by dehydroacaterin reductase.

Dehydroacaterin reductase is an enzyme which catalyzes the final step of acaterin biosynthesis, that is, the reduction of the C-4/C-5 double bond of dehydroacaterin. The mechanism of the reduction was investigated with a cell-free preparation obtained from the acaterin-producing microorganism, Pseudomonas sp. A 92. Incubation of dehydroacaterin in the presence of [4,4- 2H2]NADPH or D2O followed by 2H NMR analysis of the resulting acaterin revealed that the deuterium atom from NADPH was incorporated into the C-5 position of acaterin, while the deuterium atom from D2O was introduced into the C-4 position. It was further demonstrated that the pro-R hydrogen at C-4 of NADPH was stereospecifically utilized in this reduction.