Search

Myosin-binding protein C1 (MYBPC1) encodes myosin-binding protein C, slow type (sMyBP-C), an accessory protein that regulates actomyosin cross-linking, stabilizes thick filaments, and modulates contractility in muscle sarcomeres and has recently been linked to myopathy with tremor. The clinical features of MYBPC1 mutations manifesting in early childhood bear some similarities to those of spinal muscular atrophy (SMA), such as hypotonia, involuntary movement of the tongue and limbs, and delayed motor development. The development of novel therapies for SMA has necessitated the importance of differentiating SMA from other diseases in the early infancy period. We report the characteristic tongue movements of MYBPC1 mutations, along with other clinical findings, such as positive deep tendon reflexes and normal peripheral nerve conduction velocity testing, which could help in considering other diseases as differential diagnoses., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The ketogenic diet (KD), a high-fat and low-carbohydrate diet, is effective for a subset of patients with drug-resistant epilepsy, although the mechanisms of the KD have not been fully elucidated. The aims of this observational study were to investigate comprehensive short-term metabolic changes induced by the KD and to explore candidate metabolites or pathways for potential new therapeutic targets., Methods: Subjects included patients with intractable epilepsy who had undergone the KD therapy (the medium-chain triglyceride [MCT] KD or the modified Atkins diet using MCT oil). Plasma and urine samples were obtained before and at 2-4 weeks after initiation of the KD. Targeted metabolome analyses of these samples were performed using gas chromatography-tandem mass spectrometry (GC/MS/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS)., Results: Samples from 10 and 11 patients were analysed using GC/MS/MS and LC/MS/MS, respectively. The KD increased ketone bodies, various fatty acids, lipids, and their conjugates. In addition, levels of metabolites located upstream of acetyl-CoA and propionyl-CoA, including catabolites of branched-chain amino acids and structural analogues of γ-aminobutyric acid and lactic acid, were elevated., Conclusions: The metabolites that were significantly changed after the initiation of the KD and related metabolites may be candidates for further studies for neuronal actions to develop new anti-seizure medications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mari Akiyama reports financial support was provided by Public Interest Incorporated Foundation Japan Epilepsy Research Foundation. Daisuke Saigusa reports financial support was provided by Government of Japan Ministry of Education, Culture, Sports, Science, and Technology. Daisuke Saigusa reports financial support was provided by Japan Agency for Medical Research and Development. Daisuke Saigusa reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Accurate estimation of the epileptogenic zone (EZ) is essential for favorable outcomes in epilepsy surgery. Conventional ictal electrocorticography (ECoG) onset is generally used to detect the EZ but is insufficient in achieving seizure-free outcomes. By contrast, high-frequency oscillations (HFOs) could be useful markers of the EZ. Hence, we aimed to detect the EZ using interictal spikes and investigated whether the onset area of interictal spike-related HFOs was within the EZ. Methods: The EZ is considered to be included in the resection area among patients with seizure-free outcomes after surgery. Using a complex demodulation technique, we developed a method to determine the onset channels of interictal spike-related ripples (HFOs of 80-200 Hz) and investigated whether they are within the resection area. Results: We retrospectively examined 12 serial patients who achieved seizure-free status after focal resection surgery. Using the method that we developed, we determined the onset channels of interictal spike-related ripples and found that for all 12 patients, they were among the resection channels. The onset frequencies of ripples were in the range of 80-150 Hz. However, the ictal onset channels (evaluated based on ictal ECoG patterns) and ripple onset channels coincided in only 3 of 12 patients. Conclusions: Determining the onset area of interictal spike-related ripples could facilitate EZ estimation. This simple method that utilizes interictal ECoG may aid in preoperative evaluation and improve epilepsy surgery outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Numata-Uematsu, Uematsu, Sakuraba, Iwasaki, Osawa, Jin, Nakasato and Kure.)

Biallelic 4-hydroxyphenylpyruvate dioxygenase-like protein ( HPDL ) variants were recently reported as a cause of progressive and incurable neurodegenerative diseases ranging from neonatal-onset leukoencephalopathy with severe neurodevelopmental delay to spastic paraplegia. Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported. Here, we report a case of HPDL -related neurological disease that was clinically and neuroimaging compatible with Leigh syndrome, previously unreported, and was treated with a ketogenic diet., Competing Interests: None., (© 2021 The Authors.)

Background: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported., Aim: The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment., Method: The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale-2nd edition (SRS-2)., Results: All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score., Conclusion: Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest "TAND impact" on families., Competing Interests: Declaration of competing interest Mitsugu Uematsu declares the following competing interests: This study was funded by The NOVARTIS Foundation (Japan) for the Promotion of Science (Novartis Research Grants 2016 and 2017). The other authors (Yurika Numata-Uematsu, Yu Aihara, Tomoko Kobayashi, Mayu Fujikawa, Noriko Togashi, Takashi Shiihara, Kei Ohashi, Ayako Hattori, Shinji Saitoh, Shigeo Kure) declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA-binding protein 43 kDa (TDP-43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG-ErbB4 pathway may underlie the TDP-43-dependent motor neuron degeneration in ALS., (© 2019 The Authors. Neuropathology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Neuropathology.)

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu 2+ /Zn 2+ superoxide dismutase 1 (SOD1) accounts for 15-20% of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called "dying back", in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2 ki/ki ) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2 ki/ki /SOD1 G93A mice showed delay in the progression of the motor phenotype compared to their SOD1 G93 -Tg littermates. Histological analysis revealed that the CRMP2 ki/ki /SOD1 G93A mice retained more intact axons and NMJs than their SOD1 G93A -Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full-term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders., Methods: A total of 107 patients-all full-term births-without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole-exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines., Results: Pathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1 , CYP2U1 , SPAST , GNAO1 , CACNA1A , AMPD2 , STXBP1 , and SCN2A . Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice-site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments., Interpretation: The high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full-term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here 2 siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNaseP into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the phenotypic spectrum of PNPT1 mutations that can cause delayed myelination., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Many studies have reported many adverse effects of children's use of media. These effects include reduced cognitive development and hyperactivity and attention disorders. Although it has been recommended that child be kept away from the media during the early developmental period, many modern parents use the media as a way to calm their children. Consequently, these children lack the opportunity to form selective attachments by reduced social engagement. These children's symptoms occasionally mimic autism spectrum disorder (ASD). However, few studies have examined the symptoms children develop with early media exposure. Here, we present a boy exposed to the media during his early development who was diagnosed with attachment disorder. He was unable to make eye contact and was hyperactive and had delayed language development, like children with ASD. His symptoms improved dramatically after he was prevented from using all media and encouraged to play in other ways. After this treatment, he would make eye contact, and talked about playing with their parents. Simply avoiding the media and playing with others can change the behavior of a child with ASD-like symptoms. It is important to understand the symptoms caused by attachment disorder and early media exposure. J. Med. Invest. 65:280-282, August, 2018.

Glutaric aciduria type 1 (GA1) is a rare metabolic disorder caused by a deficiency of glutaryl-CoA dehydrogenase. The typical clinical onset features an acute encephalopathic crisis developed in early childhood, causing irreversible striatal injury. Recently, tandem mass spectrometry of spots of dried blood has allowed pre-symptomatic detection of GA1 in newborns. Early treatment can prevent irreversible neurological injury. We report the case of a girl with GA1 who exhibited a characteristic reversible change upon brain magnetic resonance imaging (MRI). She was diagnosed with GA1 as a newborn. She commenced dietary carnitine and her intake of lysine and tryptophan were reduced at the age of 4weeks. After treatment commenced, her mean glutarylcarnitine level was lower than that in the previous reports. The plasma lysine and tryptophan levels were maintained below the normal ranges. At 4months, brain MRI revealed a widened operculum with dilatation of the subarachnoid spaces surrounding the atrophic bilateral frontotemporal lobes; this is typical of GA1 patients. However, at 17months, MRI revealed that the atrophic lesion had disappeared and she subsequently underwent normal maturation. She has never suffered a metabolic decompensation episode. At 26months, her development and brain MRI were normal. The present reversible brain atrophy in a patient with GA1 indicates that early dietary modifications with a lower level of glutarylcarnitine and administration of carnitine can lead to normal development., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We describe the case of a 10-year-old boy who developed reversible cerebral vasoconstriction syndrome (RCVS) after cerebellitis. He received intravenous immunoglobulin and methylprednisolone to treat the cerebellitis. However, he then presented with a sudden severe headache, vomiting, and generalized tonic-clonic seizure. Brain magnetic resonance angiography (MRA) initially revealed diffuse cerebral vasodilatations, and diffuse multifocal segmental vasoconstrictions developed several days later. His clinical symptoms gradually resolved after several days, in the absence of any specific therapy. MRA performed 46days after symptom onset showed that the multifocal segmental vasoconstrictions had resolved, suggesting a diagnosis of RCVS. The imaging features of RCVS include multifocal segmental vasoconstriction. However, our case suggests that diffuse cerebral vasodilatation may in fact be evident during the early stage of disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our “low dosage and limited period” protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by prolonged severe seizures and a high-grade fever. We experienced a boy with severe AERRPS with frequent partial seizures that exhibited right-side predominance. The patient required the continuous intravenous administration of many antiepileptic drugs and respirator management for several months. Methylprednisolone pulse therapy and intravenous immunoglobulin administration were only temporarily effective. The MRI and EEG showed the abnormality in the left occipital lobe. Although occipital lobectomy was performed, his seizures continued. His cerebrospinal fluid exhibited elevated protein and proinflammatory cytokine levels, and was positive for anti-glutamate receptor ε2 antibodies. Pathological examination showed infiltration of many neutrophilic leukocytes, T cells, and microglia in the area exhibiting severe spongiosis. We thought that the exaggerated microglia and T-cell responses were related to the pathogenesis of the patient's seizures, and we therefore initiated treatment with tacrolimus. As a result, many of the daily seizure clusters were ameliorated, and the patient was discharged. We attempted to discontinue the tacrolimus twice, but the patient's seizure clusters recurred each time. This is the first case report of the pathological findings of AERRPS and showing an effective therapeutic approach using tacrolimus. Tacrolimus may be an effective immunosuppressant, especially for patients with severe AERRPS., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)