Publications by authors named "Shin Nabatame"

34 Publications

High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency.

Brain Dev 2021 Jun 3;43(6):680-687. Epub 2021 Apr 3.

Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Objective: We aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs).

Methods: In this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20-30 mg/kg/day) for 1 year, in addition to previous treatment.

Results: All nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient.

Conclusion: One year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings. (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number: UMIN000024185.).
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http://dx.doi.org/10.1016/j.braindev.2021.02.007DOI Listing
June 2021

Phenotypic overlap between pyruvate dehydrogenase complex deficiency and FOXG1 syndrome.

Clin Case Rep 2021 Mar 6;9(3):1711-1715. Epub 2021 Feb 6.

Department of Human Genetics Graduate School of Medicine Yokohama City University Yokohama Japan.

Pyruvate dehydrogenase complex (PDHC) deficiency is a mitochondrial disorder. We report two cases of PDHC deficiency with clinical symptoms and brain imaging findings reminiscent of FOXG1 syndrome, suggesting a phenotypic overlap of these disorders.
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http://dx.doi.org/10.1002/ccr3.3883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981633PMC
March 2021

Early diagnosis of MECP2 duplication syndrome: Insights from a nationwide survey in Japan.

J Neurol Sci 2021 Mar 19;422:117321. Epub 2021 Jan 19.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.jns.2021.117321DOI Listing
March 2021

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study.

J Neuroinflammation 2021 Jan 6;18(1). Epub 2021 Jan 6.

Department of Child Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.

Background: Neuroinflammation is associated with various chronic neurological diseases, including epilepsy; however, neuroimaging approaches for visualizing neuroinflammation have not been used in the clinical routine yet. In this study, we used the translocator protein positron emission tomography (PET) with [C] DPA713 to investigate neuroinflammation in the epileptogenic zone in patients with child-onset focal epilepsy.

Methods: Patients with intractable focal epilepsy were recruited at the Epilepsy Center of Osaka University; those who were taking any immunosuppressants or steroids were excluded. PET images were acquired for 60 min after intravenous administration of [C] DPA713. The PET image of [C] DPA713 was co-registered to individual's magnetic resonance imaging (MRI), and the standardized uptake value ratio (SUVr) in regions of interest, which were created in non-lesions and lesions, was calculated using the cerebellum as a pseudo-reference region. In the case of epilepsy surgery, the correlation between SUVr in lesions and pathological findings was analyzed.

Results: Twenty-seven patients (mean age: 11.3 ± 6.2 years, male/female: 17/10) were included in this study. Of these, 85.1% showed increased uptake of [C] DPA713 in the focal epileptic lesion. Three patients showed epileptic spasms, suggesting partial seizure onset, and all 18 patients with abnormal lesions on MRI were similarly highlighted by significant uptake of [C] DPA713. DPA713-positive patients had a broad range of etiologies, including focal cortical dysplasia, tumors, infarction, and hippocampal sclerosis. Five out of nine MRI-negative patients showed abnormal [C] DPA713 uptake. The SUVr of [C] DPA713 in lesions was significantly higher than that in non-lesions. In seven patients who underwent epilepsy surgery, increased [C] DPA713 uptake was associated with microglial activation.

Conclusions: This study indicates that [C] DPA713 uptake has valuable sensitivity in the identification of epileptic foci in child-onset focal epilepsy, and inflammation is implicated in the pathophysiology in the epileptic foci caused by various etiologies. Further research is required to establish diagnostic tools for identifying focal epileptogenic zones.
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http://dx.doi.org/10.1186/s12974-020-02055-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789379PMC
January 2021

Lenticular nuclei to thalamic ratio on PET is useful for diagnosis of GLUT1 deficiency syndrome.

Brain Dev 2021 Jan 30;43(1):69-77. Epub 2020 Jul 30.

Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: To establish an objective method of [F]-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.
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http://dx.doi.org/10.1016/j.braindev.2020.07.001DOI Listing
January 2021

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan.

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

Endocrinological Features of Hartsfield Syndrome in an Adult Patient With a Novel Mutation of .

J Endocr Soc 2020 May 2;4(5):bvaa041. Epub 2020 Apr 2.

Division of Diabetes and Endocrinology, Department of Internal Medicine, Daini Osaka Police Hospital, Karasugatsuji, Ten-noji, Osaka, Japan.

Hartsfield syndrome (HS: OMIM 615465) is a rare congenital disease associated with a mutation of the gene () with the main features of holoprosencephaly and ectrodactyly. Patients with HS also present with endocrinological deficits, such as isolated hypogonadotropic hypogonadism and central diabetes insipidus. Although there are several studies on infancy/childhood history, there is no study of infant/childhood/adolescent/young adult HS natural history and endocrinological findings. Here, we report a male patient with HS associated with a novel de novo mutation (c. 1868A > C). The endocrinological profile was evaluated at ages 1 and 31 years. This long-term follow-up study highlights functional changes in the posterior pituitary gland and features of bone metabolism disorder. We also describe the anterior pituitary function. To our knowledge this is the first description of the natural history of an HS patient through birth to young adult age. Although the HS infants reported in the literature develop central diabetes insipidus, little is known about the serial changes in pituitary gland function during growth in HS patients. In this study we describe an adult patient with HS who showed improvement of hypernatremia during early adulthood. In addition, we emphasize the importance of prevention and treatment of osteoporosis in HS.
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http://dx.doi.org/10.1210/jendso/bvaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192098PMC
May 2020

Quantitative susceptibility mapping (QSM) evaluation of infantile neuroaxonal dystrophy.

BJR Case Rep 2019 Jun 21;5(2):20180078. Epub 2019 Feb 21.

Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, Suita, Japan.

We present the first case of twins with infantile neuroaxonal dystrophy evaluating brain iron deposition using quantitative susceptibility mapping (QSM). A 6-year-old boy who was normal at birth had psychomotor regression and hypotonia from 2-years-old. Brain MRI showed low intensity areas in globus pallidus (GP) and substantia nigra (SN) on * weighted imaging. QSM values of GP and SN were 0.19 and 0.29 ppm, respectively. His twin brother showed almost the same imaging findings. Follow-up MRI revealed increase of QSM value in GP and SN.
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http://dx.doi.org/10.1259/bjrcr.20180078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726173PMC
June 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

J Med Genet 2019 06 6;56(6):396-407. Epub 2019 Mar 6.

Division of Pediatrics, Tokyo Metropolitan Tobu Medical Center for Persons with Developmental and Multiple Disabilities, Tokyo, Japan.

Background: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (). Our objective to investigate the genetic landscape of -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).

Methods: We performed WES on 77 -negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.

Results: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including ) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H transporting V0 subunit A1 (), ubiquitin-specific peptidase 8 () and microtubule-associated serine/threonine kinase 3 (), as well as biallelic variants in nuclear receptor corepressor 2 ().

Conclusions: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.
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http://dx.doi.org/10.1136/jmedgenet-2018-105775DOI Listing
June 2019

Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.

Brain 2019 03;142(3):560-573

Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.

The leukodystrophies cause severe neurodevelopmental defects from birth and follow an incurable and progressive course that often leads to premature death. It has recently been reported that abnormalities in aminoacyl t-RNA synthetase (ARS) genes are linked to various unique leukodystrophies and leukoencephalopathies. Aminoacyl t-RNA synthetase proteins are fundamentally known as the first enzymes of translation, catalysing the conjugation of amino acids to cognate tRNAs for protein synthesis. It is known that certain aminoacyl t-RNA synthetase have multiple non-canonical roles in both transcription and translation, and their disruption results in varied and complicated phenotypes. We clinically and genetically studied seven patients (six male and one female; aged 2 to 12 years) from five unrelated families who all showed the same phenotypes of severe developmental delay or arrest (7/7), hypotonia (6/7), deafness (7/7) and inability to speak (6/7). The subjects further developed intractable epilepsy (7/7) and nystagmus (6/6) with increasing age. They demonstrated characteristic laboratory data, including increased lactate and/or pyruvate levels (7/7), and imaging findings (7/7), including calcification and abnormal signals in the white matter and pathological involvement (2/2) of the corticospinal tracts. Through whole-exome sequencing, we discovered genetic abnormalities in lysyl-tRNA synthetase (KARS). All patients harboured the variant [c.1786C>T, p.Leu596Phe] KARS isoform 1 ([c.1702C>T, p.Leu568Phe] of KARS isoform 2) either in the homozygous state or compound heterozygous state with the following KARS variants, [c.879+1G>A; c.1786C>T, p.Glu252_Glu293del; p.Leu596Phe] ([c.795+1G>A; c.1702C>T, p.Glu224_Glu255del; p.Leu568Phe]) and [c.650G>A; c.1786C>T, p.Gly217Asp; p.Leu596Phe] ([c.566G>A; c.1702C>T, p.Gly189Asp; p.Leu568Phe]). Moreover, similarly disrupted lysyl-tRNA synthetase (LysRS) proteins showed reduced enzymatic activities and abnormal CNSs in Xenopus embryos. Additionally, LysRS acts as a non-canonical inducer of the immune response and has transcriptional activity. We speculated that the complex functions of the abnormal LysRS proteins led to the severe phenotypes in our patients. These KARS pathological variants are novel, including the variant [c.1786C>T; p.Leu596Phe] (c.1702C>T; p.Leu568Phe) shared by all patients in the homozygous or compound-heterozygous state. This common position may play an important role in the development of severe progressive leukodystrophy. Further research is warranted to further elucidate this relationship and to investigate how specific mutated LysRS proteins function to understand the broad spectrum of KARS-related diseases.
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http://dx.doi.org/10.1093/brain/awz001DOI Listing
March 2019

Atypical auditory language processing in adolescents with autism spectrum disorder.

Clin Neurophysiol 2018 09 8;129(9):2029-2037. Epub 2018 Jun 8.

Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address:

Objective: Individuals with autism spectrum disorder (ASD) often show characteristic differences in auditory processing. To clarify the mechanisms underlying communication impairment in ASD, we examined auditory language processing with both anatomical and functional methods.

Methods: We assessed the language abilities of adolescents with ASD and typically developing (TD) adolescents, and analyzed the surface-based morphometric structure between the groups using magnetic resonance imaging. Furthermore, we measured cortical responses to an auditory word comprehension task with magnetoencephalography and performed network-based statistics using the phase locking values.

Results: We observed no structural differences between the groups. However, the volume of the left ventral central sulcus (vCS) showed a significant correlation with linguistic scores in ASD. Moreover, adolescents with ASD showed weaker cortical activation in the left vCS and superior temporal sulcus. Furthermore, these regions showed differential correlations with linguistic scores between the groups. Moreover, the ASD group had an atypical gamma band (25-40 Hz) network centered on the left vCS.

Conclusions: Adolescents with ASD showed atypical responses on the auditory word comprehension task and functional brain differences.

Significance: Our results suggest that phonological processing and gamma band cortical activity play a critical role in auditory language processing-related pathophysiology in adolescents with ASD.
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http://dx.doi.org/10.1016/j.clinph.2018.05.014DOI Listing
September 2018

Ketogenic diet using a Japanese ketogenic milk for patients with epilepsy: A multi-institutional study.

Brain Dev 2018 Mar 26;40(3):188-195. Epub 2017 Nov 26.

Department of Pediatrics, Tokyo Women's Medical University, Japan.

Background: In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s.

Methods: We retrospectively evaluated the efficacy, tolerability, and side effects of the ketogenic diet using M817-B as the main source of daily food intake for patients with epilepsy by sending questionnaires to the members of a subcommittee of the Japan Epilepsy Society that focuses on the proper use of M817-B.

Results: A total of 42 patients were enrolled. Age at the initiation of the diet therapy ranged from 3 to 244 months (median, 32.5 months). Thirty-four patients were fed via tube, and the remaining 8 were fed orally. About 93% of patients were able to continue the diet for 1 month, 74% for 3 months, and 64% for 6 months. The median period of continuation was 16 months. One patient was able to continue as long as 7 years. The ketogenic ratio was maintained at about 3.0. The seizure-free rate and responder (>50% seizure reduction) rate were about 10% and 30-40%, respectively during the 12 months on the diet. Mean serum beta-hydroxybutyrate increased to almost 4 mM at 1 month and was maintained during the diet period. Side effects, which required discontinuation of the diet therapy, occurred in 11 of 42 patients and included hypertonia, weight loss, vomiting, hypoglycemia, metabolic acidosis, and hypokalemia.

Conclusion: M817-B could be used long-term with demonstrated efficacy in seizure reduction, although there are some side effects that may require cessation of the diet therapy.
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http://dx.doi.org/10.1016/j.braindev.2017.11.003DOI Listing
March 2018

An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination.

J Hum Genet 2017 Nov 20;62(11):997-1000. Epub 2017 Jul 20.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging. As a rare clinical feature, delayed myelination has previously been reported in only two patients with CYP2U1 mutations. Here, we report a patient with SPG56 with novel compound heterozygous mutations in CYP2U1 which were identified by whole exome sequencing. Our patient exhibited complex features together with delayed myelination, broadening the phenotypic spectrum of SPG56, and implying that CYP2U1 should be screened in HSP with delayed myelination.
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http://dx.doi.org/10.1038/jhg.2017.77DOI Listing
November 2017

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties.

Hum Mutat 2017 07 20;38(7):805-815. Epub 2017 Apr 20.

Department of Immunoregulation, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan.

Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.
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http://dx.doi.org/10.1002/humu.23219DOI Listing
July 2017

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

Magn Reson Med Sci 2017 Jul 31;16(3):209-216. Epub 2016 Oct 31.

Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine.

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 T- (TW) and T-weighted (TW) 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 TW and TW 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 TW and TW). Inter-method comparison indicated overall good to excellent agreement (TW and TW images, κ = 0.76 and 0.80, respectively); however, agreement was poor for cerebellar myelination on TW images (κ = 0.14). The percent contrast of silent and conventional MRI sequences had a strong correlation (TW, correlation coefficient [CC] = 0.76; TW excluding the middle cerebellar peduncle, CC = 0.82; TW, 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 TW sequences.
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http://dx.doi.org/10.2463/mrms.mp.2016-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600027PMC
July 2017

Marked elevation of urinary β2-microglobulin in patients with reversible splenial lesions: A small case series.

J Neurol Sci 2016 Sep 1;368:109-12. Epub 2016 Jul 1.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.

The magnetic resonance imaging findings of reversible isolated lesions with transiently reduced diffusion in the splenium of corpus callosum of patients with a wide spectrum of pathological conditions are referred to as reversible splenial lesion syndrome (RESLES). Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is probably included within the spectrum of RESLES; however, its exact pathophysiology is not known. Here, we describe three patients with MERS and one patient with RESLES, all of whom showed elevated urinary β2-microglobulin regardless of diagnosis and presence of pathogens. Elevated urinary β2-microglobulin suggested that an excessive immune response might play a role in the pathophysiology of reversible splenial lesions.
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http://dx.doi.org/10.1016/j.jns.2016.06.066DOI Listing
September 2016

[Introductory remarks].

No To Hattatsu 2016 May;48(3):174-6

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May 2016

Multidisciplinary treatment for prepubertal juvenile myasthenia gravis with crisis.

Pediatr Int 2016 Aug 21;58(8):772-4. Epub 2016 Jun 21.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

The management of juvenile myasthenia gravis (MG) remains controversial. We report herein the case of a 12-year-old girl with prepubertal juvenile MG with respiratory crisis who underwent thymectomy following methylprednisolone pulse therapy. The patient initially developed progressively worsening fatigability, eyelid ptosis, and diplopia, followed by worsening generalized weakness, dysphagia, and dyspnea. Even after i.v. immunoglobulin, the patient presented with rapid onset of severe dyspnea requiring respiratory support with mechanical ventilation and was graded as Myasthenia Gravis Foundation of America class V. After a course of i.v. methylprednisolone pulse therapy, successful control of respiratory crisis was achieved, and trans-sternal thymectomy was performed. Partial remission was achieved postoperatively with oral pyridostigmine without immunosuppressive agents such as steroids or calcineurin inhibitors for 18 months after thymectomy. Early thymectomy following induction methylprednisolone pulse therapy might be a treatment option for prepubertal juvenile MG with severe respiratory crisis.
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http://dx.doi.org/10.1111/ped.12957DOI Listing
August 2016

De novo KCNT1 mutations in early-onset epileptic encephalopathy.

Epilepsia 2015 Sep 3;56(9):e121-8. Epub 2015 Jul 3.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.
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http://dx.doi.org/10.1111/epi.13072DOI Listing
September 2015

SPTAN1 encephalopathy: distinct phenotypes and genotypes.

J Hum Genet 2015 Apr 29;60(4):167-73. Epub 2015 Jan 29.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.
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http://dx.doi.org/10.1038/jhg.2015.5DOI Listing
April 2015

Expression of astrocyte-related receptors in cortical dysplasia with intractable epilepsy.

J Neuropathol Exp Neurol 2014 Aug;73(8):798-806

From the Epilepsy Center (SS, TO, SH, RH, TS, EN, TK, NS, YK, AT, KS, YS, MS, YG, MI), Departments of Mental Retardation and Birth Defect Research (SS, HD, SN, SH, YG, MI), Neurosurgery (TO, TK, YK, AT), Child Neurology (RH, TS, EN, KS, MS), Radiology (NS), and Laboratory Medicine (YS), National Center of Neurology and Psychiatry, Kodaira, Tokyo; and Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi (SS, SH, SK), Japan.

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.
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http://dx.doi.org/10.1097/NEN.0000000000000099DOI Listing
August 2014

Prognostic factors for acute encephalopathy with bright tree appearance.

Brain Dev 2015 Feb 28;37(2):191-9. Epub 2014 Apr 28.

Department of Pediatrics, Osaka University Graduate School of Medicine, Japan; Epilepsy Center, Osaka University Hospital, Japan.

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.
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http://dx.doi.org/10.1016/j.braindev.2014.04.001DOI Listing
February 2015

De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain.

J Hum Genet 2014 May 13;59(5):292-5. Epub 2014 Mar 13.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by MECP2 mutations. We identified a de novo WDR45 mutation, which caused a subtype of neurodegeneration with brain iron accumulation, in a patient showing clinically typical RTT. The mutation (c.830+1G>A) led to aberrant splicing in lymphoblastoid cells. Sequential brain magnetic resonance imaging demonstrated that iron deposition in the globus pallidus and the substantia nigra was observed as early as at 11 years of age. Because the patient showed four of the main RTT diagnostic criteria, WDR45 should be investigated in patients with RTT without MECP2 mutations.
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http://dx.doi.org/10.1038/jhg.2014.18DOI Listing
May 2014

A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia.

Am J Med Genet A 2013 Jan 13;161A(1):203-7. Epub 2012 Dec 13.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

We reported on a male patient with rare leukoencephalopathy and skeletal abnormalities. The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age. At 4 years of age, he was diagnosed as hypomyelination with skeletal abnormalities from clinical features, brain magnetic resonance imaging (MRI) and skeletal X-rays. His brain MRI revealed diffuse hypomyelination. These findings suggested the classical type of Pelizaeus-Merzbacher disease (PMD) caused by proteolipid protein (PLP)-1 gene or Pelizaeus-Merzbacher-like disease (PMLD). However, we found neither mutation nor duplication of PLP-1. The patient had severe growth retardation and general skeletal dysplasia compatible with spondylo-epi-metaphyseal dysplasia; however the mutation of discoidin domain receptor (DDR) 2 gene was absent. The co-morbidity of hypomyelination with skeletal abnormalities is rare. We performed array CGH and no causal copy number variation was recognized. Alternatively, this condition may have been caused by a mutation of the gene encoding a molecule that functions in both cerebral myelination and skeletal development.
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http://dx.doi.org/10.1002/ajmg.a.35686DOI Listing
January 2013

Abnormal maturation and differentiation of neocortical neurons in epileptogenic cortical malformation: unique distribution of layer-specific marker cells of focal cortical dysplasia and hemimegalencephaly.

Brain Res 2012 Aug 1;1470:89-97. Epub 2012 Jul 1.

Epilepsy Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are major causes of intractable epilepsy in children. The probable pathogenesis of FCD and HMG is the abnormal migration and differentiation of neurons. The aim of the present study was to clarify the abnormal cytoarchitecture, based on neuronal immaturation. Tissue samples were obtained from 16 FCD and seven HME patients, aged between 2 months and 12 years, who had been diagnosed as typical FCD and HME, following surgical treatment for intractable epilepsy. Paraffin-embedded sections were stained with the antibodies of three layer-markers that are usually present only during the fetal period, namely SATB2 (expressed in the upper layer of the normal fetal neocortex), FOXP1 (expressed in the 5th layer), and TBR1 (expressed in the 6th layer). In FCD, SATB2-positive (+) cells located in the middle and deep regions of FCD Ia and Ib, but only in the superficial region of FCD IIa and IIb. FOXP1+ cells diffusely located in the neocortex, especially the upper layer of FCD IIa and IIb. TBR1+ cells mainly located in the middle and deep regions, and also white matter. In FCD IIb, TBR1+ cells were in the superficial region. In HME, SATB2+ and FOXP1+ cells were found diffusely. TBR1+ cells were in the middle and deep regions. On the basis of continued expression of fetal cortical layer-specific markers in FCD and HME brains, the abnormal neocortical formation in both is likely to be the result of disrupted neuronal migration and dysmaturation. The expression pattern is different between FCD and HME.
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http://dx.doi.org/10.1016/j.brainres.2012.06.009DOI Listing
August 2012

8p deletion and 9p duplication in two children with electrical status epilepticus in sleep syndrome.

Seizure 2012 May 1;21(4):295-9. Epub 2012 Feb 1.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan.

We describe two individuals with the same chromosomal aberrations derived from an unbalanced translocation between chromosomes 8p and 9p, who presented with intellectual disabilities, dysmorphic features, and localization-related epilepsy. Several years after the onset of epilepsy, aggravation of widespread epileptic discharges during sleep resulted in the emergence of absence and/or atonic seizures in both patients; one patient additionally presented with psychomotor deterioration. These symptoms completely disappeared after treatment with ethosuximide and benzodiazepines, and marked improvement was observed in electroencephalographic findings. We review the clinical features of der(8)t(8;9) with particular focus on epileptic complications. We conclude that particular types of chromosomal aberrations may have a propensity to develop the condition categorized as electrical status epilepticus in sleep.
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http://dx.doi.org/10.1016/j.seizure.2012.01.002DOI Listing
May 2012

SLC2A1 gene analysis of Japanese patients with glucose transporter 1 deficiency syndrome.

J Hum Genet 2011 Dec 20;56(12):846-51. Epub 2011 Oct 20.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Glucose transporter 1 deficiency syndrome (Glut1-DS) is a congenital metabolic disorder characterized by refractory seizures with early infantile onset, developmental delay, movement disorders and acquired microcephaly. Glut1-DS is caused by heterozygous abnormalities of the SLC2A1 (Glut1) gene, whose product acts to transport glucose into the brain across the blood-brain barrier. We analyzed the SLC2A1 gene in 12 Japanese Glut1-DS patients who were diagnosed by characteristic clinical symptoms and hypoglycorrhachia as follows: all patients had infantile-onset seizures and mild to severe developmental delay, and ataxia was detected in 11 patients. For the 12 patients, we identified seven different mutations (three missense, one nonsense, two frameshift and one splice-site) in exons and exon-intron boundaries of the SLC2A1 gene by direct sequencing, of which six were novel mutations. Of the remaining five patients who had no point mutations and underwent investigation by multiplex ligation-dependent probe amplification, a complex abnormality with deletion and duplication was identified in one patient: this is the first case of such recombination of the SLC2A1 gene. Changes in regulatory sequences in the promoter region or genes other than SLC2A1 might be responsible for onset of Glut1-DS in the other four patients (33%) without SLC2A1 mutation.
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http://dx.doi.org/10.1038/jhg.2011.115DOI Listing
December 2011

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.

J Hum Genet 2011 Oct 18;56(10):707-15. Epub 2011 Aug 18.

Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.
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http://dx.doi.org/10.1038/jhg.2011.85DOI Listing
October 2011

Effects of acetazolamide on epileptic apnea in migrating partial seizures in infancy.

Epilepsy Res 2011 Sep 1;96(1-2):185-9. Epub 2011 Jun 1.

Department of Child Neurology, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaita, Tokyo 187-8551, Japan.

We report two cases of migrating partial seizures in infancy complicated with intractable epileptic apnea with severe desaturation. Ictal electroencephalography revealed migrating foci of epileptiform discharges, which spread to bilateral temporal areas resulting in the onset of apnea. Magnetoencephalography detected dipole sources at bilateral perisylvian areas. Single photon emission tomography revealed a significant ictal change in perfusion at bilateral anterior temporal lobes in one patient. Addition of acetazolamide to the regimen resulted in complete disappearance of epileptic seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2011.05.007DOI Listing
September 2011