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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., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Pathogenic variants of HECW2 have been reported in cases of neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; OMIM #617268). A novel HECW2 variant (NM_001348768.2:c.4343 T > C,p.Leu1448Ser) was identified in an NDHSAL infant with severe cardiac comorbidities. The patient presented with fetal tachyarrhythmia and hydrops and was postnatally diagnosed with long QT syndrome. This study provides evidence that HECW2 pathogenic variants can cause long QT syndrome along with neurodevelopmental disorders., (© 2023. The Author(s).)

Objective: In a study using a mouse model of CDKL5 deficiency disorder (CDD), seizures are specific to female mice heterozygous for Cdkl5 mutations and not observed in hemizygous knockout males or homozygous knockout females. The aim of this study was to examine whether the clinical phenotype of patients with CDD can be impacted by the type of genetic variant., Methods: Eleven CDD patients (six females and five males) were included in this study. The molecular diagnosis of hemizygous male patients was performed using digital PCR and their clinical phenotypes were compared with those of patients with mosaic or heterozygous CDKL5 variants. The severity of clinical phenotypes was graded by using CDKL5 Developmental Score and the adapted version of the CDKL5 Clinical Severity Assessment. The effect of cellular mosaicism on the severity of CDD was studied by comparing the clinical characteristics and comorbidities between individuals with hemizygous and mosaic or heterozygous CDKL5 variants., Results: One of the five male patients was mosaic for the CDKL5 variant. All patients developed seizures irrespective of their genetic status of the pathogenic variant. However, cellular mosaicism of CDKL5 deficiency was associated with lesser severity of other comorbidities such as feeding, respiratory, and visual functional impairments., Significance: This study provided evidence that cellular mosaicism of CDKL5 deficiency was not necessarily required for developing epilepsy. CDD patients not only exhibited clinical features of epilepsy but also exhibited the developmental consequences arising directly from the effect of the CDKL5 pathogenic variant., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abstract: Myofibrillar myopathy is a clinically and genetically heterogeneous group of muscle disorders characterized by myofibrillar degeneration. Bcl-2-associated athanogene 3 (BAG3)-related myopathy is the rarest form of myofibrillar myopathy. Patients with BAG3-related myopathy present with early-onset and progressive muscle weakness, rigid spine, respiratory insufficiency, and cardiomyopathy. Notably, the heterozygous mutation (Pro209Leu) in BAG3 is commonly associated with rapidly progressive cardiomyopathy in childhood. We describe a male patient with the BAG3 (Pro209Leu) mutation. The patient presented at age 7 years with muscle weakness predominantly in the proximal lower limbs. Histologic findings revealed a mixture of severe neurogenic and myogenic changes. His motor symptoms progressed rapidly in the next decade, becoming wheelchair-dependent by age 17 years; however, at the age of 19 years, cardiomyopathy was not evident. This study reports a case of BAG3-related myopathy without cardiac involvement and further confirmed the wide phenotypic spectrum of BAG3-related myopathy., Competing Interests: Supported in part by the Grant-in-Aid for Scientific Research C from the Japan Society for the Promotion of Science (19 K08268), Intramural Research Grants (2–5, 29–4) for Neurological and Psychiatric Disorders of NCNP, and a research grant for Initiative on Rare and Undiagnosed Diseases in Pediatrics (IRUD-P) from Japan Agency for Medical Research and Development. The authors report no conflict of interest. The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2022. The Author(s).)

This study aimed to elucidate the clinical characteristics of MECP2 duplication syndrome (MDS), particularly at initial presentation, and to provide clinical clues for the early diagnosis of this condition. We conducted a nationwide survey for MDS by sending questionnaires to 575 hospitals where board-certified pediatric neurologists were working and 195 residential hospitals for persons with severe motor and intellectual disabilities in Japan. This survey found 65 cases of MDS, and clinical data of 24 cases in which the diagnosis was genetically confirmed were analyzed. More than half of the patients (52%) had visited a hospital at least once during infancy due to symptoms associated with MDS, with a median age at the initial visit of 7 months. The symptoms that were frequently prevalent at the first visit were facial dysmorphic features, hypotonia, motor developmental delay, and recurrent infections. Dysmorphic features included small mouth, tented upper lip, tapered fingers, and hypertelorism. Other symptoms, including epilepsy, intellectual disabilities, autistic features, stereotypic movements, and gastrointestinal problems, generally appeared later with age. Some symptoms of MDS were found to be age-dependent and may not be noticeable in infancy. Recognition of these clinical characteristics may facilitate the early diagnosis and proper treatment of patients with MDS, improve their long-term outcomes, and help adapt appropriate genetic counseling., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features., (© 2020 International League Against Epilepsy.)

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., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

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&#95;e1 and MECP2&#95;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&#95;e1 but not MeCP2&#95;e2. Therefore, our findings indicate that MeCP2&#95;e2 may partially compensate for a deficiency in MeCP2&#95;e1., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

A heterozygous mutation in the fibroblast growth factor 12 (FGF12) gene, which elevates the voltage dependence of neuronal sodium channel fast inactivation, was recently identified in some patients with epileptic encephalopathy. Here we report 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). These 2 patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole-exome sequencing. This mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy. One of our cases exhibited EIMFS, and this case responded to phenytoin and high-dose phenobarbital (PB). FGF12-related epileptic encephalopathy may exhibit diverse phenotypes and may respond to sodium channel blockers or high-dose PB., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency., Materials and Methods: A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation., Results: The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 G>A and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate., Conclusion: POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

Objective: To evaluate the parameters associated with significant gastrointestinal (GI) involvement in Henoch-Schönlein Purpura (HSP), and construct a scoring system for the identification of patients at high risk of gross blood in stools., Study Design: Data for HSP patients hospitalized at each of seven institutes were retrospectively analyzed. Patients were divided into four groups according to the consequent severity of GI involvement. Identification of laboratory parameters at the time of admission were then used to differentiate the groups, and a scoring system to predict gross intestinal bleeding was constructed. Prognostic efficiency, correlation with the subsequent duration of abdominal pain, and association with manifestations excluding abdominal pain were also analyzed., Results: An analysis of variance (ANOVA) test showed significant intergroup differences in white blood cell (WBC) count, neutrophil count, serum albumin, potassium, plasma D-dimer and coagulation factor XIII activity. A scoring system consisting of these parameters showed a good prognostic value for gross intestinal bleeding in a receiver operating characteristic (ROC) analysis, and a cut-off value of 4 points showed a sensitivity of 90.0% and specificity of 80.6%. The score was also correlated with the duration of abdominal pain after admission. A significantly higher score (s) was observed in patients presenting with nephritis, although the predictive value was poor., Conclusion: A scoring system consisting of generally available parameters was of use in predicting severe GI involvement in HSP patients. Although further study is needed, initial therapy in accordance with disease activity may be taken into consideration using this scoring system.