Publications by authors named "Jun Tohyama"

85 Publications

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Kurume Med J 2021 Jul 15;66(2):115-120. Epub 2021 Jun 15.

Department of Pediatrics, Showa University School of Medicine.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.
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http://dx.doi.org/10.2739/kurumemedj.MS662007DOI Listing
July 2021

ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H-ATPases is essential for brain development in humans and mice.

Nat Commun 2021 04 8;12(1):2107. Epub 2021 Apr 8.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Vacuolar H-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1) and A512P (Atp6v0a1) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1 mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.
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http://dx.doi.org/10.1038/s41467-021-22389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032687PMC
April 2021

Positive and negative effects of perampanel treatment on psychiatric and behavioral symptoms in adult patients with epilepsy.

Epilepsy Behav 2021 04 17;117:107515. Epub 2021 Feb 17.

Department of Pediatric Neurology, National Hospital Organization, Nishiniigata Chuo Hospital Epilepsy Center, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan.

Purposes: The purpose of the study was to investigate the positive and negative effects of perampanel (PER) treatment on the psychiatric and behavioral symptoms in patients with epilepsy and to evaluate factors associated with the psychiatric and behavioral changes caused by PER.

Methods: We retrospectively examined medical records of patients with epilepsy treated with PER in the Department of Psychiatry, Epilepsy Center, Nishiniigata Chuo National Hospital. Multiple regression analyses were performed with the psychiatric and behavioral prognoses as dependent variables and clinical characteristics of the patients as independent variables.

Results: Thirty-two of 135 patients (23.7%) had psychiatric and behavioral deterioration after the initiation of PER, whereas 22 patients (16.3%) showed improvement in psychiatric and behavioral symptoms after PER administration. Etiology of structural abnormalities, concomitant use of nitrazepam, and comorbidities of irritability and depression were significantly associated with increasing incidence of psychiatric and behavioral deterioration. Concomitant use of carbamazepine was significantly associated with decreasing incidence of psychiatric and behavioral deterioration. Suppression of awareness-impaired seizures by PER, concomitant use of carbamazepine, and comorbidities of insomnia, anxiety, and amnesia were significantly associated with an increasing incidence of psychiatric and behavioral improvement. Improvements in psychiatric symptoms by PER were associated with a reduction in the use of psychotropic drugs. In particular, about 1/4 of benzodiazepines had been discontinued.

Conclusions: Perampanel therapy may aggravate or even ameliorate psychiatric and behavioral symptoms in patients with epilepsy. The psychiatric and behavioral prognoses after administration of PER vary depending on the type of psychiatric and behavioral comorbidities in patients with epilepsy. Psychiatric and behavioral symptoms may improve in patients with successful suppression of seizures by PER. Additionally, combination therapy consisting of PER and carbamazepine may be associated with good outcomes of psychiatric and behavioral symptoms in patients with epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2020.107515DOI Listing
April 2021

Differences in levetiracetam and perampanel treatment-related irritability in patients with epilepsy.

Epilepsy Behav 2021 03 3;116:107644. Epub 2021 Feb 3.

Department of Pediatric Neurology, National Hospital Organization, Nishiniigata Chuo Hospital Epilepsy Center, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan.

Purpose: The present study evaluated whether patients with epilepsy who received both levetiracetam (LEV) and perampanel (PER) therapy showed side effects of irritability. The study also examined the relationship between patient characteristics and irritability when it occurred as a side effect.

Methods: We retrospectively examined medical records of 98 patients with epilepsy who were treated with both LEV and PER at the Department of Psychiatry in the Epilepsy Center of Nishiniigata Chuo National Hospital in Japan. We performed multiple regression analyses with the presence/absence of irritability due to LEV or PER as the dependent variables and clinical characteristics of the patients as independent variables.

Results: LEV and PER caused irritability in 7 and 17 of 98 patients, respectively. LEV- and PER-related irritability did not occur in the same patients. A logistic multiple regression analysis revealed that EEG findings of temporal focal epileptic discharge were significantly associated with increased incidence of irritability due to LEV. LEV-related irritability decreased significantly with higher dosages of LEV. Another logistic multiple regression analysis revealed that a psychiatric comorbidity of irritability and EEG findings of nontemporal focal epileptic discharge were significantly associated with increased incidence of irritability due to PER.

Conclusions: LEV and PER cause irritability in different patient groups. Additionally, irritability as a side effect was present only at low dosages of LEV, but PER tended to cause irritability even at high dosages.
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http://dx.doi.org/10.1016/j.yebeh.2020.107644DOI Listing
March 2021

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Brain Dev 2021 Apr 9;43(4):505-514. Epub 2021 Jan 9.

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

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.

Results: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.

Conclusion: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
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http://dx.doi.org/10.1016/j.braindev.2020.12.006DOI Listing
April 2021

Polymicrogyria with calcification in Pallister-Killian syndrome detected by microarray analysis.

Brain Dev 2021 Mar 21;43(3):448-453. Epub 2020 Nov 21.

Department of Child Neurology, NHO Nishiniigata Chuo Hospital, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan. Electronic address:

Background: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures.

Results: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses.

Conclusion: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.
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http://dx.doi.org/10.1016/j.braindev.2020.11.003DOI Listing
March 2021

De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.

Hum Mutat 2021 Jan 10;42(1):66-76. Epub 2020 Nov 10.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.
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http://dx.doi.org/10.1002/humu.24130DOI Listing
January 2021

De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy.

Am J Hum Genet 2020 04 12;106(4):549-558. Epub 2020 Mar 12.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10; exome-wide threshold: 2.5 × 10). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118575PMC
April 2020

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy.

Orphanet J Rare Dis 2019 12 2;14(1):277. Epub 2019 Dec 2.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.

Background: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail.

Results: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae.

Conclusions: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.
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http://dx.doi.org/10.1186/s13023-019-1249-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888944PMC
December 2019

Pathogenic variants of , , and associated with hypothalamic hamartoma.

Neurology 2019 07 13;93(3):e237-e251. Epub 2019 Jun 13.

From the Departments of Human Genetics (A.F., S. Mitsuhashi, T.M., A.T., S. Miyatake, N. Miyake, N. Matsumoto) and Neurosurgery (M.S.), Yokohama City University Graduate School of Medicine; Departments of Functional Neurosurgery (T.H., H. Shirozu, H.M., M.F., S.K.) and Child Neurology (J.T.), Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital Niigata, Japan; Department of Pediatrics and Neurology (M.S.), Wayne State University, Children's Hospital of Michigan, Detroit Medical Center; Department of Pediatrics (M.K.), Showa University School of Medicine, Tokyo; Department of Biochemistry (M.N., H. Saitsu), Hamamatsu University School of Medicine; and Clinical Research Institute (Y.T.), Kanagawa Children's Medical Center, Yokohama, Japan.

Objective: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).

Methods: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.

Results: We identified a germline variant of , which encodes a ciliary protein, and 2 somatic variants of , which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included , which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of ). Furthermore, a combination of a germline and a somatic variant was detected in another patient.

Conclusions: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.
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http://dx.doi.org/10.1212/WNL.0000000000007774DOI Listing
July 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

PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia.

Seizure 2019 Oct 20;71:1-5. Epub 2019 May 20.

Institute of Medical Genetics, Tokyo Women's Medical University, Japan.

Purpose: This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations.

Methods: The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire.

Results: PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5.

Conclusion: PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.
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http://dx.doi.org/10.1016/j.seizure.2019.05.017DOI Listing
October 2019

[Development of a New Resilience Scale for Parents of Children with Profound Intellectual and Multiple Disabilities].

Nihon Eiseigaku Zasshi 2019 ;74(0)

Niigata University Graduate School of Health Sciences.

Objetives: As the first step forward building a supporting system for the Parents of Children with Profound Intellectual and Multiple Disabilities (PIMD) at home, we developed a new resilience scale that can be used by multiple professionals to understand the situation of those parents and to provide the necessary support.

Methods: First, we collected scale items on the basis of our previous study as well as related reports in the literature. These items were then screened by the research team with knowledge and experience in supporting those parents, finally, 37 items were generated. Then, we asked the parents of children with PIMD who were of elementary school age and above in the Kanto-Shinetsu area to complete a questionnaire. Out of 477 questionnaires sent, 193 were refused, and the data were statistically analyzed.

Results: Exploratory factor analysis revealed that the scale was made up of the following seven factors. 1) Understanding and awareness of the child, 2) Empowerment by the child, 3) Use of specialists, 4) Interest and concern in something other than the child, 5) Emotional adjustment, 6) Maintenance of lifestyle balance, and 7) Request for assistances. Cronbach's alpha coefficient of each factor was calculated. The validity was also confirmed by determining the relationship of resilience with parents' well-being.

Conclusions: The results suggest that the new resilience scale for parents of children with PIMD developed in this study can be a reliable instrument for assessing resilience in Japanese parents of a child with such disabilities.
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http://dx.doi.org/10.1265/jjh.18025DOI Listing
April 2019

Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures.

J Hum Genet 2019 Apr 17;64(4):313-322. Epub 2019 Jan 17.

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

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.
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http://dx.doi.org/10.1038/s10038-018-0559-zDOI Listing
April 2019

Neuropsychiatric Disorder Associated with Group G Infection.

Case Rep Pediatr 2018 23;2018:6047318. Epub 2018 Sep 23.

Department of Pediatrics, Niigata University, Niigata, Japan.

Immune-mediated central nervous system manifestations of group A -hemolytic (GABHS) infection include Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)-which includes tic and obsessive compulsive disorders-and a variety of neurobehavioral disorders. We report a case of subspecies (group G ) (GGS) infection associated with involuntary movements, complex tics, and emotional lability in an 11-year-old Japanese girl. Serum IgM and IgG antibodies to lysoganglioside were positive, and she responded rapidly to intravenous immunoglobulin treatment. Neuropsychiatric disorder associated with GGS infection was ultimately diagnosed. The present findings suggest that neuropsychiatric disorders can result from GGS infection and that the pathogenic mechanism is similar to that of GABHS infection. Future large-scale studies should examine the relation between GGS infection and onset of neuropsychiatric disorder.
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http://dx.doi.org/10.1155/2018/6047318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174767PMC
September 2018

The association of epileptic focus estimated by magnetoencephalography with cognitive function in non-lesional epilepsy with continuous spikes and waves during slow wave sleep (ECSWS) children.

Brain Dev 2019 Feb 17;41(2):163-172. Epub 2018 Oct 17.

Division of Child Neurology, Nishi-Niigata Chuo National Hospital, Japan.

Objective: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome.

Methods: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis.

Results: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110 months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156 months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (β = 14.7, p = 0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (β = 17.48, p = 0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis.

Conclusion: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences.
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http://dx.doi.org/10.1016/j.braindev.2018.09.005DOI Listing
February 2019

GRIN2D variants in three cases of developmental and epileptic encephalopathy.

Clin Genet 2018 12;94(6):538-547

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

N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.
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http://dx.doi.org/10.1111/cge.13454DOI Listing
December 2018

Characteristics of PPT1 and TPP1 enzymes in neuronal ceroid lipofuscinosis (NCL) 1 and 2 by dried blood spots (DBS) and leukocytes and their application to newborn screening.

Mol Genet Metab 2018 05 19;124(1):64-70. Epub 2018 Mar 19.

Advanced Clinical Research Center, Institute of Neurological Disorder, Kanagawa, Japan; Jikei University School of Medicine, Tokyo, Japan. Electronic address:

We first characterized PPT1 and TPP1 enzymes in dried blood spots (DBS), plasma/serum, and leukocytes/lymphocytes using neuronal ceroid lipofuscinosis (NCL) 1 and 2 patients and control subjects. PPT1 enzyme had only one acid form in control DBS, plasma/serum, and leukocytes/lymphocytes and showed deficient activities in these samples from NCL 1 patients. Conversely, TPP1 enzymes in control DBS and leukocytes/lymphocytes consisted of two forms, an acidic form and a neutral form, whereas serum TPP1 enzyme had only a neutral form. In control subjects, the optimal pH of PPT1 enzyme in DBS, plasma/serum, and leukocytes/lymphocytes was 4.5 to 5.0 in the acidic form, whereas TPP1 enzyme in control DBS and leukocytes/lymphocytes was pH 4.5 and 6.5, respectively. In NCL 1 and 2, both PPT1 and TPP1 enzyme activities in DBS, plasma, and leukocytes/lymphocytes were markedly reduced in acidic pH, whereas heterozygotes of NCL 1 and 2 in the acidic form showed intermediate activities between patients and control subjects. In neutral conditions, pH 6.0, the PPT1 enzyme activities in NCL 1 patients showed rather higher residual activities and intermediate activities in heterozygotes in NCL 1, which was probably caused by mutated proteins in three cases with NCL 1 patients. TPP1 enzyme activities at neutral pH 6.5 to 7.0 in DBS and leukocytes/lymphocytes showed higher enzyme activities in NCL 2 patients and heterozygotes. The reason for the increases of neutral TPP1 enzyme activities at pH 6.5 to 7.0 in NCL 2 DBS and leukocytes/lymphocytes, is obscure, but possibly caused by secondary activation of neutral TPP1 enzyme due to the absence of the acidic form. Interestingly, TPP1 activity in serum only consisted of a neutral form, no acidic form, and was not deficient in any NCL 2 patient. Therefore, we can diagnose NCL 1 patients by plasma/serum enzyme assay of PPT1, but not diagnose NCL 2 by serum TPP1 enzyme assay. A pilot study of newborn screening of NCL 1 and 2 has been established by more than 1000 newborn DBS assays. Using this assay system, we will be able to perform newborn screening of NCL 1 and 2 by DBS.
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http://dx.doi.org/10.1016/j.ymgme.2018.03.007DOI Listing
May 2018

variants in and cause neurodevelopmental disorders.

Ann Clin Transl Neurol 2018 03 29;5(3):280-296. Epub 2018 Jan 29.

Department of Biochemistry Hamamatsu University School of Medicine 1-20-1 Handayama, Higashi-ku Hamamatsu 431-3192 Japan.

Objective: () and () isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of - and -CaMKII variants in neurodevelopmental disorders.

Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of and variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis.

Results: We identified a total of five de novo and variants in three and two individuals, respectively. Seizures were common to three individuals with variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII . By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII mutant in primary hippocampal neurons significantly increased A-type K currents, which facilitated spike repolarization of single action potentials.

Interpretation: Our data highlight the importance of CaMKII and CaMKII and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K currents as a possible pathophysiological basis.
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http://dx.doi.org/10.1002/acn3.528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846454PMC
March 2018

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.

Cell Rep 2018 01;22(3):734-747

Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan.

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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http://dx.doi.org/10.1016/j.celrep.2017.12.074DOI Listing
January 2018

Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy.

J Hum Genet 2018 Mar 16;63(3):263-270. Epub 2018 Jan 16.

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

Misato 1, mitochondrial distribution and morphology regulator (encoded by the MSTO1 gene), is involved in mitochondrial distribution and morphology. Recently, MSTO1 mutations have been shown to cause clinical manifestations suggestive of mitochondrial dysfunction, such as muscle weakness, short stature, motor developmental delay, and cerebellar atrophy. Both autosomal dominant and recessive modes of inheritance have been suggested. We performed whole-exome sequencing in two unrelated patients showing cerebellar atrophy, intellectual disability, and pigmentary retinopathy. Three novel mutations were identified: c.836 G > A (p.Arg279His), c.1099-1 G > A (p.Val367Trpfs*2), and c.79 C > T (p.Gln27*). Both patients had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation, the latter shared by them both. This survey of two patients with recessive and novel MSTO1 mutations provides additional clinical and genetic information on the pathogenicity of MSTO1 in humans.
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http://dx.doi.org/10.1038/s10038-017-0405-8DOI Listing
March 2018

Waardenburg syndrome type IIE in a Japanese patient caused by a novel non-frame-shift duplication mutation in the SOX10 gene.

J Dermatol 2018 May 23;45(5):e110-e111. Epub 2017 Nov 23.

Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.

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http://dx.doi.org/10.1111/1346-8138.14151DOI Listing
May 2018

Corrigendum to "Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child".

Case Rep Pediatr 2017 20;2017:4120361. Epub 2017 Sep 20.

Sanin Rosai Hospital, 1-8-1 Kaike Shinden, Yonago, Tottori 683-8605, Japan.

[This corrects the article DOI: 10.1155/2015/807591.].
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http://dx.doi.org/10.1155/2017/4120361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632490PMC
September 2017

Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

Brain 2017 Sep;140(9):2322-2336

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.
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http://dx.doi.org/10.1093/brain/awx195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248409PMC
September 2017

Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement.

Sci Rep 2017 06 14;7(1):3552. Epub 2017 Jun 14.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.
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http://dx.doi.org/10.1038/s41598-017-02840-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471274PMC
June 2017

A 7q31.33q32.1 microdeletion including and is associated with severe intellectual disability and characteristics of autism.

Hum Genome Var 2017 9;4:17001. Epub 2017 Feb 9.

Institute of Medical Genetics, Tokyo Women's Medical University , Tokyo, Japan.

A 4-year-old boy with severe intellectual disability (ID) and characteristics of autism was found to have a 1.9-Mb microdeletion in 7q31.33q32.1, in which , , and 11 other genes were included. is associated with attention deficit hyperactivity disorder. is related to synaptic cell adhesion molecules, some of which are associated with autism. The deletion of may be responsible for the severe ID and characteristics of autism observed in the present patient.
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http://dx.doi.org/10.1038/hgv.2017.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298938PMC
February 2017

Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.

BMC Pulm Med 2017 02 17;17(1):40. Epub 2017 Feb 17.

Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.

Background: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP.

Case Presentation: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high.

Conclusions: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.
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http://dx.doi.org/10.1186/s12890-017-0382-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316164PMC
February 2017

Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency.

Brain Dev 2017 Mar 12;39(3):266-270. Epub 2016 Oct 12.

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

Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable.
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http://dx.doi.org/10.1016/j.braindev.2016.09.011DOI Listing
March 2017

Hypocretin-1 levels in the cerebrospinal fluid of patients with Percheron artery infarction with or without midbrain involvement: A case series.

Medicine (Baltimore) 2016 Jul;95(29):e4281

Department of Neurology, Dokkyo Medical University, Tochigi, Japan Department of Neurology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan Department of Clinical Medicine for Nursing, Dokkyo Medical University School of Nursing, Tochigi, Japan Department of Nephrology, Shimonoseki City Hospital, Yamaguchi, Japan Department of Neurology, Fujita Health University School of Medicine, Aichi, Japan Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.

Background: Bilateral paramedian thalamic infarctions (BPTIs) due to artery of Percheron occlusion are known to cause hypersomnia. However, the role of hypocretin-1, a wake-promoting peptide that is located at the lateral hypothalamus, in hypersomnia in these patients remains unclear.

Methods: To clarify the role of hypocretin-1 in hypersomnia in patients with BPTIs, hypocretin-1 levels in the cerebrospinal fluid (CSF) were measured in 6 patients with BPTIs: 2 with rostral midbrain involvement (BPT+RMI) and 4 without midbrain involvement (BPT-MI).

Results: CSF hypocretin-1 levels were decreased in 2 patients with BPT+RMI and were within normal ranges in 4 patients with BPT-MI. Hypersomnia was noted in all the patients. In one BPT+RMI patient, hypersomnia was improved within 2 weeks and decreased CSF hypocretin-1 levels were reversed (acute phase (on day 9), 109.2 pg/mL; chronic phase (at 3 months), 323 pg/mL), whereas another BPT+RMI patient who displayed coma in the acute phase had decreased CSF orexin levels (107 pg/mL) at day 49 and exhibited severe disability.

Conclusion: Hypocretin deficiency was not involved in hypersomnia observed in BPT-MI patients; however, CSF hypocretin-1 levels were reduced in BPT+RMI patients. Reduced CSF hypocretin-1 levels in the chronic phase may possibly predict a poor clinical outcome in patients with Percheron artery infarction.
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http://dx.doi.org/10.1097/MD.0000000000004281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265783PMC
July 2016

Megalencephaly, polymicrogyria and ribbon-like band heterotopia: A new cortical malformation.

Brain Dev 2016 Nov 2;38(10):950-953. Epub 2016 Jul 2.

Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Japan; Niigata University Medical and Dental Hospital, Japan.

Megalencephalic polymicrogyria syndromes include megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. Recent genetic studies have identified that genes in the PI3K-AKT pathway are involved in the pathogenesis of these disorders. Herein, we report a patient who presented with developmental delay, epilepsy and peculiar neuroimaging findings of megalencephaly, polymicrogyria, and symmetrical band heterotopia in the periventricular region. The heterotopias exhibited inhomogeneous signals with undulatory mixtures of gray and white matter, resembling ribbon-like heterotopia, with a predominance in the temporal to occipital regions. These neuroradiological findings were not consistent with those in known megalencephalic polymicrogyria syndromes. No genetic abnormality was identified through whole-exome sequencing. The neuroimaging findings of this patient may represent a novel cortical malformation involving megalencephaly with polymicrogyria and ribbon-like band heterotopia.
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http://dx.doi.org/10.1016/j.braindev.2016.06.004DOI Listing
November 2016
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