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Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.

DOI： 10.1093/hmg/ddt578

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OBJECTIVE: To identify other causative genes for Andersen-Tawil syndrome, which is characterized by a triad of periodic paralysis, cardiac arrhythmia, and dysmorphic features. Andersen-Tawil syndrome is caused in a majority of cases by mutations in KCNJ2, which encodes the Kir2.1 subunit of the inwardly rectifying potassium channel. METHODS: The proband exhibited episodic flaccid weakness and a characteristic TU-wave pattern, both suggestive of Andersen-Tawil syndrome, but did not harbor KCNJ2 mutations. We performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The expression of gene products in heart and skeletal muscle tissues was examined by immunoblotting. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit. RESULTS: We identified a mutation in the KCNJ5 gene, which encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4). Immunoblotting demonstrated significant expression of the Kir3.4 protein in human heart and skeletal muscles. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4. CONCLUSIONS: We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.

DOI： 10.1212/WNL.0000000000000239

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Authorship：Lead author   Language：English   Publishing type：Doctoral thesis  

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is mostly composed of an asymmetric form in which three tetramers of catalytic AChE subunits are linked to a triple helical collagen Q (ColQ). Mutations in COLQ cause endplate AChE deficiency. We report three patients with endplate AChE deficiency with five recessive COLQ mutations. Sedimentation profiles showed that p.Val322Asp and p.Arg227X, but not p.Cys444Tyr, p.Asp447His, or p.Arg452Cys, inhibit formation of triple helical ColQ. In vitro overlay of mutant ColQ-tailed AChE on muscle sections of Colq(-/-) mice revealed that p.Cys444Tyr, p.Asp447His, and p.Arg452Cys in the C-terminal domain (CTD) abrogate anchoring ColQ-tailed AChE to the NMJ. In vitro plate-binding assay similarly demonstrated that the three mutants inhibit binding of ColQ-tailed AChE to MuSK. We also confirmed the pathogenicity of p.Asp447His by treating Colq(-/-) mice with adeno-associated virus serotype 8 carrying mutant COLQ-p.Asp447His. The treated mice showed no improvement in motor functions and no anchoring of ColQ-tailed AChE at the NMJ. Electroporation of mutant COLQ harboring p.Cys444Tyr, p.Asp447His, and p.Arg452Cys into anterior tibial muscles of Colq(-/-) mice similarly failed to anchor ColQ-tailed AChE at the NMJ. We proved that the missense mutations in ColQ-CTD cause endplate AChE deficiency by compromising ColQ-MuSK interaction at the NMJ.

DOI： 10.1002/humu.22325

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OBJECTIVES: Ataxic-rigid gait is a characteristic gait pathology in patients with Rett syndrome (RTT). In the present study, we aimed to quantitatively evaluate gait pathology in patients with RTT using three-dimensional gait analysis (3DGA). METHODS: We performed 3DGA in 11 patients with RTT ranging from 5 to 18 years (median age, 9 years) and in 33 age-matched healthy female controls. We compared the results of 3DGA, including spatiotemporal gait parameters and comprehensive indices of gait kinematics, such as the Gait Deviation Index (GDI) and Gait Profile Score (GPS), between the two groups. The GPS consists of nine sub-indices called Gait Variable Scores (GVSs). Decline in GDI or elevation of GPS and GVS indicated greater abnormal gait pathology. RESULTS: The patients demonstrated significantly slower walking speed, lower step length/length of the lower extremities, lower cadence, wider step width, and higher coefficient of variation of step length than the controls. Moreover, the patients had a lower GDI and higher GPS than the controls. The patients also exhibited higher GVSs for eight out of nine gait kinematics, particularly the sagittal plane in the pelvis, hip, knee, and ankle joint; coronal plane in the pelvis and hip joint; and horizontal plane in the pelvis than the controls. CONCLUSIONS: Quantitative evaluation of gait pathology in patients with RTT is possible using 3DGA. We found that in addition to ataxic-rigid gait, abnormalities in the coronal plane of the pelvis and hip joint and the horizontal plane of the pelvis were prominent.

DOI： 10.1016/j.ejpn.2022.11.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

At the neuromuscular junction (NMJ), DOK7 enhances the phosphorylation of muscle-specific kinase (MuSK) and induces clustering of acetylcholine receptors (AChRs). We identified a patient with congenital myasthenic syndrome (CMS) with two heteroallelic mutations in DOK7, c.653-1G>C in intron 5 and c.190G>A predicting p.G64R in the pleckstrin homology domain. iPS cells established from the patient (CMS-iPSCs) showed that c.653-1G>C caused in-frame skipping of exon 6 (120 bp) and frame-shifting activation of a cryptic splice site deleting seven nucleotides in exon 6. p.G64R reduced the expression of DOK7 to 10% of wild-type DOK7, and markedly compromised AChR clustering in transfected C2C12 myotubes. p.G64R-DOK7 made insoluble aggresomes at the juxtanuclear region in transfected C2C12 myoblasts and COS7 cells, which were co-localized with molecules in the autophagosome system. A protease inhibitor MG132 reduced the soluble fraction of p.G64R-DOK7 and enhance the aggresome formation of p.G64R-DOK7. To match the differentiation levels between patient-derived and control iPSCs, we corrected c.190G>A (p.G64R) by CRISPR/Cas9 to make isogenic iPSCs while retaining c.653-1G>C (CMS-iPSCsCas9). Myogenically differentiated CMS-iPSCs showed juxtanuclear aggregates of DOK7, reduced expression of endogenous DOK7, and reduced phosphorylation of endogenous MuSK. Another mutation, p.T77M, also made aggresome to a less extent compared to p.G64R in transfected COS7 cells. These results suggest that p.G64R-DOK7 makes aggresomes in cultured cells and is likely to compromise MuSK phosphorylation for AChR clustering.

DOI： 10.1093/hmg/ddac306

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BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common type of acute encephalopathy in Japan; the condition is clinically characterized by prolonged seizures as the initial neurological symptom, followed by late seizures 4-6 days later. It is difficult to differentiate AESD from prolonged febrile seizures (PFSs). Here, we explored the use of electroencephalography to differentiate AESD from PFSs. METHODS: We studied the electroencephalograms (EEGs) of children <6 years of age diagnosed with AESD or PFSs; all EEGs were recorded within 48 h of seizure onset (i.e., before the late seizures of AESD). Two pediatric neurologists evaluated all EEGs, focusing on the basic rhythm, slowing during wakefulness/arousal by stimuli, spindles, fast waves, and slowing during sleep. RESULTS: The EEGs of 14 children with AESD and 31 children with PFSs were evaluated. Spindles were more commonly reduced or absent in children with AESD than in those with PFSs (71% vs. 31%, p = 0.021). Fast waves were also more commonly reduced or absent in children with AESD (21% vs. 0%, p = 0.030). The rates of all types of slowing did not differ between children with AESD and those with PFSs, but continuous or frequent slowing during sleep was more common in the former (50% vs. 17%, p = 0.035). CONCLUSIONS: EEG findings may usefully differentiate AESD from PFSs. Reduced or absent spindles/fast waves and continuous or frequent slowing during sleep are suggestive of AESD in children with prolonged seizures associated with fever.

DOI： 10.1016/j.braindev.2021.11.003

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BACKGROUND: We aimed to investigate electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) findings to elucidate the interictal epileptiform discharge (IED)-related functional alterations in deep brain structures as well as the neocortex in childhood epilepsy with centrotemporal spikes (CECTS). METHODS: Ten children with CECTS (median age; 8.2 years) referred to our hospital within a year of onset were eligible for inclusion. They underwent EEG-fMRI recording during sleep. In addition, longitudinal evaluations, including medical examinations, intelligence tests, and questionnaires about developmental disabilities, were performed. The initial evaluation was performed at the same time as the EEG-fMRI, and the second evaluation was performed over 2 years after the initial evaluation. RESULTS: Three children were unable to maintain sleep during the EEG-fMRI recording, and the remaining seven children were eligible for further assessment. All patients showed unilateral-dominant centrotemporal spikes during scans. One patient had only positive hemodynamic responses, while the others had both positive and negative hemodynamic responses. All patients showed IED-related hemodynamic responses in the bilateral neocortex. For deep brain structures, IED-related hemodynamic responses were observed in the cingulate gyrus (n=4), basal ganglia (n=3), thalamus (n=2), and default mode network (n=1). Seizure frequencies at the second evaluation were infrequent or absent, and the longitudinal results of intelligence tests and questionnaires were within normal ranges. CONCLUSIONS: We demonstrated that IEDs affect broad brain areas, including deep brain structures such as cingulate gyrus, basal ganglia, and thalamus. Deep brain structures may play an important role in the pathophysiology of CECTS.

DOI： 10.1111/ped.15001

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BACKGROUND: Brush or delta brush is a well-known characteristic waveform in preterm electroencephalograms. However, the longitudinal trajectory of brushes and its association with neurodevelopment remain uncertain. METHODS: We analyzed the longitudinal incidence of brushes in 36 extremely low birth weight infants without severe brain lesions and its association with neurodevelopment and white matter abnormality. Conventional eight-channel electroencephalograms were recorded at 30, 32, 36, and 40 postmenstrual weeks (PMW). Incidence of brushes was calculated as the sum of brushes from each channel separated by active sleep and quiet sleep. A developmental delay was defined as a developmental quotient of <85 assessed at corrected age of 18 months. White matter abnormalities were evaluated with term-equivalent magnetic resonance imaging. RESULTS: The median incidence of brushes (per minute) in 36 infants at PMW 30, 32, 36, and 40 was 16.4, 20.4, 22.5, and 1.8 during active sleep and 7.5, 10.3, 11.5, and 1.7 during quiet sleep, respectively. Among the 36 infants, 14 infants were diagnosed with developmental delay. Longitudinal trajectories of the incidence of brushes were different between the normal and the delayed development groups. Brushes were observed most frequently at 36 PMW in the delayed development group. The incidence of brushes at 36 PMW was significantly correlated with the severity of white matter abnormalities and negatively correlated with the developmental quotient. CONCLUSION: The incidence of brushes at 36 PMW can be a unique predictor of early neurodevelopment in extremely low birth weight infants without severe brain lesions.

DOI： 10.1016/j.braindev.2021.07.003

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OBJECTIVE: Repetitive sleep starts (RSS) are clusters of nonepileptic, spasm-like movements occurring during sleep onset. However, their characteristics have yet to be defined. We conducted a clinicoelectroencephalographic study of children with RSS to clarify their detailed characteristics. METHODS: To differentiate starts from epileptic spasms, we recruited children with brief "crescendo-decrescendo" muscle contractions that simultaneously involved the limbs and trunk without electroencephalogram changes, and that fulfilled the following criteria: (1) repeated occurrence (five or more) and (2) manifestation during sleep stage N1-N2. A total of nine children met these criteria. Their clinical information and video-electroencephalogram data were analyzed retrospectively. RESULTS: The background conditions observed at onset of RSS were perinatal hypoxic-ischemic encephalopathy (n = 4), West syndrome of unknown etiology (n = 1), and traumatic brain injury (n = 1). The age at onset of RSS, the number of starts in a given RSS cluster, the interval between starts, and the duration of surface electromyogram activity were between 3 and 46 months, 5 and 547, <1 and 60 s, and 0.3 and 5.4 s, respectively. None of the median value of these parameters differed between children with and without corticospinal tract injury. During the median follow-up period of 33 months, RSS disappeared spontaneously in five. CONCLUSION: This is the largest case series of RSS clarifying their clinicoelectroencephalographic characteristics reported to date. To avoid unnecessary antiepileptic therapies, clinicians should be aware of RSS and distinguish it from other disorders involving involuntary movements or seizures, especially epileptic spasms.

DOI： 10.1016/j.yebeh.2021.108075

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OBJECTIVE: Bacille de Calmette et Guérin (BCG) is a live vaccine for tuberculosis that is administered to all infants in Japan. Adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS) causes immunosuppression and may result in BCG infection after BCG vaccination. We evaluated the safety of ACTH therapy initiated shortly after BCG vaccination. METHODS: We analyzed patients with WS who received ACTH therapy between 2005 and 2018. We evaluated the interval between BCG and ACTH therapy, and the rate of BCG infection during and after ACTH therapy, by retrospective chart review. RESULTS: Seventy-nine patients were included in the analysis. Twenty-three patients received ACTH therapy prior to BCG vaccination. For the remaining 56 patients, the median interval between BCG vaccination and the start of ACTH therapy (BCG-ACTH interval) was 91.5 (range 14-280) days. The BCG-ACTH interval was shorter in patients with unknown than in those with known etiologies. It was <8 weeks in 13 patients (10 with unknown and 3 with known etiologies). The minimum BCG-ACTH interval was 14 days. Six patients with epileptic spasms received BCG vaccinations because physicians did not recognize their seizures. None of the patients developed BCG infection. CONCLUSION: No patients who received ACTH therapy after BCG, even at an interval of 8 weeks, developed BCG infection. The timing of ACTH therapy initiation should be based on the risk of BCG-related adverse events and the adverse effects of any delay.

DOI： 10.1016/j.yebeh.2021.107924

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BACKGROUND: MICPCH is manifested as microcephaly associated with pontocerebellar hypoplasia and global developmental delay but developmental regression has never been reported. We describe the detailed clinical history of a woman with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) with a CASK mutation who exhibited gross motor regression after adolescence. CASE: The patient experienced severe motor and intellectual developmental delay with microcephaly from infancy. The initial diagnosis was Rett syndrome based on her clinical features, including hand stereotypes and the absence of structural abnormality on magnetic resonance imaging (MRI) performed at the age of 5 years. Although gross motor abilities developed slowly and she could walk independently, she never acquired speech or understanding of languages. After adolescence, her motor ability gradually regressed so that she was unable to stand without support and moved with a wheelchair. At the age of 31 years, because of her atypical clinical course for Rett syndrome, whole exome sequencing was performed, which revealed a de novo heterozygous c.2068 + 1G > A mutation in the CASK gene (NM_001126055). Brain MRI revealed mild pontocerebellar hypoplasia compatible with the clinical phenotype of MICPCH. DISCUSSION: This case suggests that MICPCH with a CASK mutation might cause developmental regression after adolescence and might be regarded as a neurodegenerative disorder.

DOI： 10.1016/j.braindev.2020.11.007

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PURPOSE: To establish an objective method of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) that can assist in the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1-DS). METHODS: FDG-PET was performed in 8 patients with a mean age of 12.5 years (range, 2-22 years) with GLUT1-DS. Their PET findings were compared with those of 45 controls with a mean age of 11.2 years (range, 2-21 years) by statistical parametric mapping (SPM12, Welcome Neurological Institute). The controls had epilepsy of unknown etiology and normal MRI findings. The age-adjusted ratios of mean radioactivities in regions of interest (ROIs) of bilateral lenticular nuclei, thalami, and the whole cerebral cortex were also measured. The sensitivities and specificities of the ratios for the differential diagnosis of GLUT1-DS were also determined. RESULTS: SPM showed significantly decreased uptake in bilateral thalami and increased uptake in bilateral lenticular nuclei in patients with GLUT1-DS. There were no areas in the cerebral cortex with significant differences between patients and controls. On ROI analysis, by setting the cut-off value of the age-adjusted lenticular nuclei/thalami radioactivity ratio to 1.54, patients with GLUT1-DS were differentiated from controls with sensitivity of 1.00 and specificity of 0.98. CONCLUSION: The age-adjusted lenticular nuclei/thalami radioactivity ratio on PET can distinguish patients with GLUT1-DS from patients with epilepsy of unknown etiology with high sensitivity and specificity. It is important to pay attention to the metabolism of the lenticular nuclei and thalami on PET for the diagnosis of GLUT1-DS.

DOI： 10.1016/j.braindev.2020.07.001

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OBJECTIVE: Clinical identification of neonatal seizures (NS) remains challenging. The International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures has proposed a new classification of NS, based on the 2017 ILAE seizure classification. One of the key points of this proposed NS classification is that seizure types should be determined by the "predominant" clinical feature. However, when the definition of "predominant" is uncertain, interobserver variability may arise. METHODS: We asked 49 health professionals to classify 21 NS video-electroencephalogram (EEG) recordings using the proposed 9 seizure types. RESULTS: The degree of agreement among participants was low, and agreement was weak among experts in neonatal neurology. Among experts, the rate of agreement was <50% for 2 NS. This disagreement was related to differences in the interpretation of "predominant features." Although interobserver variability was present among users of the new NS classification, the reproducibility of the NS classification was satisfactory. CONCLUSION: Education designed to foster consistent application of the standards for NS will be important for reducing interobserver variability and expanding the use of the new NS classification.

DOI： 10.1016/j.yebeh.2020.107292

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BACKGROUND: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed. METHODS: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared. RESULTS: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and a higher mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation. CONCLUSIONS: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation.

DOI： 10.1016/j.pediatrneurol.2020.06.008

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OBJECTIVE: The early diagnosis of beta-propeller protein-associated neurodegeneration (BPAN) before distinct brain magnetic resonance imaging (MRI) findings of iron deposition occur remains challenging. This study examined whether children with BPAN have characteristic high-amplitude (>50 μV) fast activity (HAFA) on electroencephalography (EEG). METHODS: We conducted a retrospective analysis of EEG performed during childhood in five patients with BPAN. We also examined 143 EEGs from 59 patients with different etiologies, including epilepsy (n = 33), acute encephalopathy (n = 6), neurodevelopmental disorders (n = 5), non-epileptic events (n = 4), and others (n = 11). Trained electroencephalographers reviewed all of the EEGs. When excessive fast activity was observed, the amplitude, frequency, and locality were assessed. RESULTS: All five patients with BPAN underwent initial EEGs at 12-21 months old, and diffuse continuous HAFA (range 20-50 Hz) was observed on both awake and sleep EEGs. In the awake records, there was no clear posterior dominant rhythm in 4 of the 5 patients. Although 28% of the 143 EEGs had continuous excessive fast activity, mainly in the sleep records, only two (1.4%) exhibited HAFA when asleep, and their awake EEGs had clear posterior dominant rhythm. CONCLUSIONS: The EEGs of children with BPAN showed diffuse HAFA continuously when both awake and asleep, which is uncommon in children with other etiologies. SIGNIFICANCE: This study provides an important clue for the early diagnosis of BPAN.

DOI： 10.1016/j.clinph.2020.06.006

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AIM: Little is known about acute febrile status epilepticus-induced injury of extrahippocampal structures. To clarify the presence and clinical significance of acute extrahippocampal injuries, we performed diffusion-weighted imaging (DWI) in children immediately after prolonged febrile seizure (PFS). METHOD: We performed a retrospective cohort study in children younger than 6 years old who visited one of two hospitals due to PFSs between January 2013 and October 2018. PFS was defined as a febrile seizure that persisted for 15 min or longer. We collected brain DWI data within 6 h of the end of PFS. When the initial DWI detected an abnormality, a follow-up DWI was performed a few days later. RESULTS: The study population consisted of 101 patients with PFSs. DWI was performed within 6 h in 51 patients, while the remaining 50 patients did not undergo imaging because of good recovery of consciousness. Restricted cortical diffusion was evident in 9 (18%) patients on initial DWI. All of them underwent DWI within 100 min after PFS. Restricted cortical diffusion was associated with male sex, asymmetrical PFS symptoms, and a shorter duration between the end of the seizure and DWI, but was not associated with seizure duration. All cortical abnormalities had resolved on follow-up DWI of these patients within 72 h after the initial imaging, but ipsilateral hippocampal hyperintensity appeared in one patient. All 9 patients with restricted cortical diffusion were finally diagnosed with PFS and discharged without sequelae. CONCLUSIONS: Some children with PFSs exhibit transient restricted diffusion in the regional cortex on DWI performed immediately after the end of PFS. These transient diffusion changes were not associated with unfavorable epileptic sequelae or neuroimaging in the short-term.

DOI： 10.1016/j.ejpn.2020.05.004

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OBJECTIVE: The objective of this study was to describe a novel amplitude-integrated electroencephalography (aEEG) pattern in infants with hypoxic-ischemic encephalopathy (HIE) and to assess the clinical significance. METHODS: The aEEG traces of infants with HIE who were treated with therapeutic hypothermia (TH) from 2012 to 2017 were analyzed. A pseudo-sawtooth (PST) pattern was defined as a periodic increase of the upper and/or lower margin of the trace on aEEG without showing seizure activities on conventional EEG (CEEG). RESULTS: Of the 46 infants, 6 (13%) had the PST pattern. The PST pattern appeared following a flat trace or a continuous low-voltage pattern and was followed by a burst-suppression pattern. On CEEG, the PST pattern consists of alternating cycles of low-voltage irregular activities and almost flat tracing. The PST pattern was associated with neuroimaging abnormalities and with various degrees of neurodevelopmental outcomes. Positive predictive values of the PST or worse pattern for adverse outcomes were high at 12 h after birth. CONCLUSION: A novel aEEG background pattern in infants with HIE was reported. The PST pattern likely indicates a suppressed background pattern and may be linked to unfavorable outcomes. Further multicenter validation study is needed to clarify its clinical significance.

DOI： 10.1038/s41390-019-0567-5

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FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%-80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder.

DOI： 10.1016/j.braindev.2019.11.006

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Language：English   Publisher：WILEY  

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OBJECTIVE: To assess hippocampal signal changes on diffusion-weighted imaging (DWI) during the acute period after febrile status epilepticus (FSE) and to examine the relationship between DWI and subsequent epilepsy. METHODS: A prospective, multicenter study of children with a first episode of FSE was performed. The patients underwent magnetic resonance imaging (MRI) within 3 days of FSE, and signal intensity was evaluated on DWI. Electroencephalography studies within 3 days of FSE were also assessed. Nine to 13 years after FSE, information on subsequent epilepsy was obtained. RESULTS: Twenty-two children with FSE were evaluated. DWI showed unilateral hippocampal hyperintensity in six patients (27%). Three of six patients with hippocampal hyperintensity had ipsilateral thalamic hyperintensity. On EEG within 3 days of FSE, five of six patients with hippocampal hyperintensity had ipsilateral focal slowing, spikes, or attenuation. Nine to 13 years later, the outcomes could be determined in five patients with hippocampal hyperintensity and in 10 without. All 5 patients with hippocampal hyperintensity had hippocampal atrophy and developed focal epilepsy, whereas only 1 of 10 patients without hippocampal hyperintensity developed epilepsy (P = 0.002). Ictal semiology was concordant with temporal lobe seizures in all patients. Ipsilateral temporal epileptiform abnormalities were seen on EEG in four of five at last follow-up. SIGNIFICANCE: Acute DWI hippocampal hyperintensity was seen in 27% of patients with FSE. Acute DWI hyperintensity suggests cytotoxic edema caused by prolonged seizure activity. Hippocampal DWI hyperintensity is related to mesial temporal lobe epilepsy and can be a target of neuroprotective treatments to prevent the onset of epilepsy.

DOI： 10.1111/epi.16059

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OBJECTIVE: To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. METHODS: Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). RESULTS: TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). SIGNIFICANCE: These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

DOI： 10.1111/epi.13988

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OBJECTIVE: The aim of this study was to clarify the characteristics of paroxysmal nonepileptic events (PNEs) suspected as being epileptic seizures by families of children with epilepsy. METHODS: The video-EEG (vEEG) recordings of habitual paroxysmal events in children with epilepsy at Nagoya University Hospital between October 2006 and January 2016 were reviewed. Based on the doctor's suspicion before the vEEG, the PNEs were divided into two groups that included PNEs suspected as epileptic seizures and PNEs suspected as PNEs. PNEs in the former group were classified based on the suspected seizure type. RESULTS: Of 886 habitual paroxysmal events, vEEG confirmed that 83 events (68 children) were PNEs. The median age of the 68 children was 3.2 years. Concurrent epilepsies included focal epilepsies (n=33), infantile spasms (n=16), and other types (n=19). The most common types of PNEs were sleep myoclonus (n=11), followed by stereotypies (n=9), awake myoclonus (n=8), paroxysmal ocular deviations (PODs, n=8), and tonic posturing (n=8). Even after direct observation or video viewing, the doctors suspected epileptic seizures in all three of the PODs and two of the tonic posturing children. Before the vEEG, however, the accurate visual information led to the speculation that the four psychogenic and two sleep myoclonus events were all PNEs. Myoclonus, stereotypies, and head drops were often misdiagnosed as epileptic spasms, while PODs and tonic posturing were often misdiagnosed as focal seizures with motor components. Additionally, staring and motion arrest during a drowsy state were often misdiagnosed as focal dyscognitive seizures. Seven of eight patients with PODs had epileptic spasms that were concurrent with epileptic seizures. A diffuse cerebral lesion or reduced visual acuity was seen in seven patients with PODs. CONCLUSION: We re-emphasize that vEEG is essential for accurate diagnosis and provides evidence for listing POD in the differential diagnosis of oculomotor paroxysmal events.

DOI： 10.1016/j.eplepsyres.2017.02.009

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We report an immunocompromised child who experienced two episodes of bacteremia due to Streptococcus pyogenes. Random amplification of polymorphic DNA profiles, emm genotypes, superantigen profiles, antimicrobial susceptibility, and resistance-related genes were investigated, and the results showed different profiles between the two isolates. This is the first report describing recurrent bacteremia caused by different strains of S. pyogenes.

DOI： 10.1016/j.jiac.2015.12.014

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Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space.

DOI： 10.1016/j.nmd.2015.05.002

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PubMed

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Mutations in the pore-forming subunit of the skeletal muscle sodium channel (SCN4A) are responsible for hyperkalemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are classified based on their cardinal symptoms, myotonia and/or paralysis. We report the case of a Japanese boy with a novel mutation of SCN4A, p.I693L, who exhibited severe episodic myotonia from infancy and later onset mild paralytic attack. He started to have apneic episodes with generalized hypertonia at age of 11 months, then developed severe episodic myotonia since 2 years of age. He presented characteristic generalized features which resembled Schwarz-Jampel syndrome. After 7 years old, paralytic episodes occurred several times a year. The compound muscle action potential did not change during short and long exercise tests. Functional analysis of the mutant channel expressed in cultured cell revealed enhancement of the activation and disruption of the slow inactivation, which were consistent with myotonia and paralytic attack. The severe clinical features in his infancy may correspond to myotonia permanence, however, he subsequently experienced paralytic attacks. This case provides an example of the complexity and overlap of the clinical features of sodium channel myotonic disorders.

DOI： 10.1016/j.jns.2011.12.015

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PubMed

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We retrospectively reviewed electroencephalography and magnetic resonance imaging findings for 21 children exhibiting delirious behavior during febrile illness. Among these, five patients had transient callosal lesions with or without white matter lesions on diffusion-weighted images. We compared the clinical characteristics, duration, and components of delirious behavior, the duration and severity of reduced consciousness, and EEG findings among patients with or without callosal lesions. No significant differences were detected in these items according to the presence or absence of callosal lesions. Adding insight into the pathogenesis of this condition, our study revealed that callosal lesions are not uncommon in patients exhibiting delirious behavior during febrile illness.

DOI： 10.1016/j.braindev.2008.06.002

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