Publications by authors named "Akihiko Ishiyama"

58 Publications

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 Feb 24. Epub 2021 Feb 24.

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

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
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http://dx.doi.org/10.1002/ajmg.a.62138DOI Listing
February 2021

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells.

J Neurol Sci 2021 Feb 15;423:117337. Epub 2021 Feb 15.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. Electronic address:

Exon skipping using short antisense oligonucleotides (AONs) is a promising treatment for Duchenne muscular dystrophy (DMD). Several exon-skipping drugs, including viltolarsen (NS-065/NCNP-01), have been approved worldwide. Immortalized human skeletal muscle cell lines, such as rhabdomyosarcoma cells, are frequently used to screen efficient oligonucleotide sequences. However, rhabdomyosarcoma cells do not recapitulate DMD pathophysiology as they express endogenous dystrophin. To overcome this limitation, we recently established a direct human somatic cell reprogramming technology and successfully developed a cellular skeletal muscle DMD model by using myogenic differentiation 1 (MYOD1)-transduced urine-derived cells (MYOD1-UDCs). Here, we compared in vitro drug screening systems in MYOD1-UDCs and rhabdomyosarcoma cells. We collected UDCs from patients with DMD amenable to exon 51 skipping, and obtained MYOD1-UDCs. We then compared the efficiency of exon 51 skipping induced by various morpholino-based AONs, including eteplirsen in differentiated MYOD1-UDCs (UDC-myotubes) and rhabdomyosarcoma cells. Exon skipping was induced more efficiently in UDC-myotubes than in rhabdomyosarcoma cells even at a low AON concentration (1 μM). Furthermore, exon 51 skipping efficiency was higher in UDC-myotubes with a deletion of exons 49-50 than in those with a deletion of exons 48-50, suggesting that the skipping efficiency may vary depending on the DMD mutation pattern. An essential finding of this study is that the sequence of eteplirsen consistently leads to much lower efficiency than other sequences. These findings underscore the importance of AON sequence optimization by our cellular system, which enables highly sensitive screening of exon skipping drugs that target different types of DMD mutations.
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http://dx.doi.org/10.1016/j.jns.2021.117337DOI Listing
February 2021

Association between lack of functional connectivity of the frontal brain region and poor response inhibition in children with frontal lobe epilepsy.

Epilepsy Behav 2020 12 21;113:107561. Epub 2020 Nov 21.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8553, Japan. Electronic address:

Purpose: We investigated the relationship between electroencephalographic (EEG) functional connectivity and executive function in children with frontal lobe epilepsy (FLE).

Methods: We enrolled 24 children with FLE (mean age, 11.0 years; 13 boys) and 22 sex-, age-, and intelligence-matched typically developing children (TDC) to undergo 19-channel EEG during light sleep. We estimated functional connectivity using the phase lag index (PLI) that captures the synchronization of EEG. We also performed continuous performance tests (CPTs) on the children and obtained questionnaire responses on attention deficit hyperactivity disorder and oppositional defiant disorder (ODD).

Results: The average gamma PLI was lower in the FLE group than in the TDC group, especially between long-distance frontoparietal pairs, between interhemispheric frontal pairs, and between interhemispheric parietotemporal pairs. Gamma PLIs with long-distance frontoparietal and interhemispheric frontal pairs were positively associated with inattention, ODD scores, omission error, and reaction time in the FLE group but not in the TDC group. Conversely, they were negatively associated with age, hyperactivity score, and commission error.

Conclusions: A lack of functional connectivity of the frontal brain regions in children with FLE was associated with poor response inhibition.
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http://dx.doi.org/10.1016/j.yebeh.2020.107561DOI Listing
December 2020

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice.

BMC Med 2020 11 19;18(1):343. Epub 2020 Nov 19.

Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Background: Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca-dependent manner. However, its roles in dystrophic pathology have not yet been clarified.

Methods: To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice).

Results: Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus.

Conclusions: nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.
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http://dx.doi.org/10.1186/s12916-020-01805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677854PMC
November 2020

Hyperglycemic Crisis in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).

Pediatr Neurol 2021 Jan 30;114:1-4. Epub 2020 Sep 30.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Background: Diabetes mellitus is the most commonly encountered endocrinopathy in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which manifests as multisystemic organ failure. Whether the management of diabetes mellitus in MELAS requires special consideration is not fully clarified.

Methods: In this single-center study, we retrospectively reviewed the medical records of patients with MELAS to elucidate the clinical characteristics of MELAS-associated diabetes mellitus.

Results: Four patients among a total of 25 individuals with MELAS who were treated in the study institution developed diabetes mellitus. One patient had well-controlled diabetes mellitus, whereas the remaining three patients experienced hyperglycemic crisis as the first manifestation of diabetes mellitus. Two of the three patients were children aged four and six years. The hyperglycemic events occurred after surgery, infection, and status epilepticus, respectively. None of the three patients had diabetes mellitus previously based on randomly measured serum glucose levels that were within the normal range before the hyperglycemic crisis. Glycated hemoglobin levels measured during the hyperglycemic crisis indicated prediabetes in two patients and diabetes mellitus in one patient. Two patients recovered, whereas one patient died after developing multiorgan failure.

Conclusions: Fulminant-onset diabetes mellitus occurring in patients with MELAS underscore the importance of routine measurement for glycated hemoglobin and more intense evaluation of glucose intolerance regardless of the patient age and lack of symptoms. Clinicians should be aware of the potential acute onset of hyperglycemic crisis in patients with MELAS, especially in individuals with aggravating factors.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.09.013DOI Listing
January 2021

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

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

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Postoperative improvement of executive function and adaptive behavior in children with intractable epilepsy.

Brain Dev 2021 Feb 29;43(2):280-287. Epub 2020 Aug 29.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: An alteration in postoperative cognitive function varies according to the patients' background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy.

Methodology: We enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively.

Result: ADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain.

Conclusion: Improvement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.
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http://dx.doi.org/10.1016/j.braindev.2020.08.005DOI Listing
February 2021

Prenatal clinical manifestations in individuals with variants.

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

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 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

ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features.

Neurology 2020 09 9;95(11):e1500-e1511. Epub 2020 Jul 9.

From the Department of Neuromuscular Research, National Institute of Neuroscience (Y.S., A.N., S.H., I. Nonaka, S. Noguchi and I. Nishino), Medical Genome Center (Y.S., A. Iida, S.H., S.N., I. Nishino), and Departments of Neurology (M.M.-Y., Y.O.) and Child Neurology (A. Ishiyama and H.K.), National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo; Integrated Graduate School of Medicine, Engineering, and Agricultural Science (Y.S.), University of Yamanashi; Department of Neurology (S. Nakamura), National Hospital Organization, Shizuoka Medical Center; Department of Neurology and Clinical Neuroscience (S.F. and T.K.), Yamaguchi University Graduate School of Medical Science; Department of Neurology (M.Y. and H.S.), Osaka Toneyama Medical Center; and Department of Neurology (H.S.), Osaka University Graduate School of Medicine, Japan.

Objective: To elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathologic features of the disease.

Methods: We searched for variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathologic features of patients with variants.

Results: We identified 63 patients from 59 families with biallelic variants of . Among the 7 distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other 5 were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that myopathy is the most frequent among all genetically diagnosable nemaline myopathies in our center.

Conclusions: ADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.
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http://dx.doi.org/10.1212/WNL.0000000000010237DOI Listing
September 2020

13q13.3 microdeletion associated with apparently balanced translocation of 46,XX,t(7;13) suggests NBEA involvement.

Brain Dev 2020 Sep 4;42(8):581-586. Epub 2020 Jun 4.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.

Background: Deletion of 13q13.3 is an extremely rare event.

Case: We report on a 25-month-old girl with neurodevelopmental disorder and intellectual disability. She had dysmorphic facies characterized by synophrys, long and narrow palpebral fissures; and a large, round face with small organs such as the eyes and mouth positioned near the center. She was hypotonic and had autism-like behaviors. Blood tests and brain MRI revealed no specific findings. However, G-banding chromosome analysis showed an apparently balanced translocation: 46,XX,t(7,13)(q11.23;q12.3). Both parents had normal karyotypes. Furthermore, her abnormal phenotype and chromosomal breakpoint lesion were suspected to be associated. Hence, we conducted array comparative genomic hybridization, which revealed a 3.2 Mb novel pathological microdeletion at 13q13.3 involving 17 genes including neurobeachin (NBEA), a neurodevelopment disorder gene. Furthermore, fluorescence in situ hybridization using probes adjacent to the microdeletion suggested a concomitant occurrence of the deletion and translocation as the structural basis of this rare genomic variant.

Conclusion: NBEA may have roles in her neurodevelopmental phenotypes, whereas other genes within the 13q13.3 microdeletion may contribute to her dysmorphic features.
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http://dx.doi.org/10.1016/j.braindev.2020.05.006DOI Listing
September 2020

Serial MRI alterations of pediatric patients with beta-propeller protein associated neurodegeneration (BPAN).

J Neuroradiol 2020 Apr 23. Epub 2020 Apr 23.

Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background And Purpose: Beta-propeller protein-associated neurodegeneration (BPAN) is one subtype of neurodegeneration with brain iron accumulation. It is difficult to diagnose BPAN due to the non-specificity of their clinical findings and neuroimaging in early childhood. We experienced four pediatric patients with serial brain MRI and evaluated the alteration of the findings through their course.

Methods: We retrospectively reviewed the clinical findings and 21 MRI findings of the four patients with genetically confirmed pediatric BPAN. We also performed a quantitative MR assessment using the quantitative susceptibility mapping (QSM) values of the globus pallidus (GP), substantia nigra (SN), and deep cerebellar nuclei (DCN) compared to 10 age-matched disease controls.

Results: Only one patient was suspected of BPAN based on imaging findings before the genetic diagnosis was made. The other three patients could not be suspected until their Whole-exome sequencings (WES) done. In all four cases, no abnormal signals were noted in the GP and SN at the initial brain MRI, but hypointensities were observed after the ages of 4-7 years on T2-weighted images and after the ages of 2-7 years on susceptibility-weighted images. In three patients, T2 hyperintensity in the bilateral DCN was persistently observed throughout the observational period. Three patients showed transient T2 hyperintensity and swelling in the GP, SN and/or DCN during the episodes of pyrexia and seizures. The other findings included cerebral and cerebellar atrophy, thinning of the corpus callosum, and delayed myelination. The QSM values of the GP and SN were significantly higher in the patients compared to the controls (P=0.005, respectively), but that of the DCN did not differ significantly (P=0.16).

Conclusion: Brain MRI is a useful method to establish the early diagnosis of BPAN.
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http://dx.doi.org/10.1016/j.neurad.2020.04.002DOI Listing
April 2020

Adaptive behavior and its related factors in children with focal epilepsy.

Epilepsy Behav 2020 07 19;108:107092. Epub 2020 Apr 19.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: We aimed to clarify the strengths and weaknesses in adaptive behavior in children with focal epilepsy and show children-associated factors related to adaptive behavior.

Materials And Methods: Sixty-three children with focal epilepsy aged 5-18 years with intellectual quotient (IQ) ranging from 67 to 135 were enrolled in this study. Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). The children performed continuous performance test and tests of reading, writing, and IQ; parents answered questionnaires regarding attention-deficit hyperactivity disorder and autism spectrum disorder (ASD). Participants were categorized into four groups based on IQ and adaptive behavior scores for statistical comparisons.

Results And Discussion: Children with low adaptive behavior were more likely to show a reduction in daily living skills, and those with both low adaptive behavior and IQ were more likely to show a reduction in daily living skills and communication. Lower adaptive behavior was related to more severe autistic symptoms, lower academic achievement in children with IQ > 85, and lower executive function in children with IQ ≤ 85. There was a qualitative difference of cognitive dysfunction in adaptive behavior between both groups.

Conclusions: There were differences in VABS-II domain and subdomain characteristics between children with focal epilepsy and those with ASD; however, it was more difficult for children with more severe ASD and coexisting focal epilepsy to show age-equivalent adaptive behavior.
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http://dx.doi.org/10.1016/j.yebeh.2020.107092DOI Listing
July 2020

A case of CLCN2-related leukoencephalopathy with bright tree appearance during aseptic meningitis.

Brain Dev 2020 Jun 12;42(6):462-467. Epub 2020 Mar 12.

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

CLCN2-related leukoencephalopathy (CC2L) is a rare autosomal recessive disorder caused by variants in CLCN2. We report a boy whose brain MRI during an episode of aseptic meningitis at the age of 6 years revealed wide areas of restriction on diffusion-weighted images (DWI) in the cerebral subcortical white matter called bright tree appearance (BTA). In addition to the BTA, high intensity signals were also observed bilaterally in the posterior limbs of the internal capsules, cerebral peduncles, middle cerebellar peduncles, cerebellar white matter, and brain stem (longitudinal pontine bundle) along with low apparent diffusion coefficient values in the same areas. The BTA was transient, seen only during the acute phase of the aseptic meningitis. With the resolution of the infection, his meningitis symptoms completely resolved, but abnormal brain MRI findings remained, other than BTA, which disappeared. At age 13 years, whole exome sequencing revealed a homozygous variant (c.61dupC, p.(Leu21Profs*27)) of CLCN2. He had no intellectual disability or neurological abnormalities. The transient DWI high-intensity signals in the subcortical white matter and the T2 high-intensity signals in the white matter could reflect varying degrees of water imbalance in the extracellular space in myelin sheaths in CC2L.
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http://dx.doi.org/10.1016/j.braindev.2020.02.008DOI Listing
June 2020

Publisher Correction: Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride.

Sci Rep 2020 Feb 7;10(1):2462. Epub 2020 Feb 7.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59351-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005800PMC
February 2020

Alteration of the anatomical covariance network after corpus callosotomy in pediatric intractable epilepsy.

PLoS One 2019 5;14(12):e0222876. Epub 2019 Dec 5.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Purpose: This study aimed to use graph theoretical analysis of anatomical covariance derived from structural MRI to reveal how the gray matter connectivity pattern is altered after corpus callosotomy (CC).

Materials And Methods: We recruited 21 patients with epilepsy who had undergone CC. Enrollment criteria were applied: (1) no lesion identified on brain MRI; (2) no history of other brain surgery; and (3) age not younger than 3 years and not older than 18 years at preoperative MRI evaluation. The most common epilepsy syndrome was Lennox-Gastaut syndrome (11 patients). For voxel-based morphometry, the normalized gray matter images of pre-CC and post-CC patients were analyzed with SPM12 (voxel-level threshold of p<0.05 [familywise error-corrected]). Secondly, the images of both groups were subjected to graph theoretical analysis using the Graph Analysis Toolbox with SPM8. Each group was also compared with 32 age- and sex-matched control patients without brain diseases.

Results: Comparisons between the pre- and post-CC groups revealed a significant reduction in seizure frequency with no change in mean intelligence quotient/developmental quotient levels. There was no relationship among the three groups in global network metrics or in targeted attack. A regional comparison of betweenness centrality revealed decreased connectivity to and from the right middle cingulate gyri and medial side of the right superior frontal gyrus and a partial shift in the distribution of betweenness centrality hubs to the normal location. Significantly lower resilience to random failure was found after versus before CC and versus controls (p = 0.0450 and p = 0.0200, respectively).

Conclusion: Graph theoretical analysis of anatomical covariance derived from structural imaging revealed two neural network effects of resection associated with seizure reduction: the reappearance of a structural network comparable to that in healthy children and reduced connectivity along the median line, including the middle cingulate gyrus.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894802PMC
March 2020

Renal dysfunction can occur in advanced-stage Duchenne muscular dystrophy.

Muscle Nerve 2020 02 28;61(2):192-197. Epub 2019 Nov 28.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Introduction: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed.

Methods: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups.

Results: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014).

Discussion: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.
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http://dx.doi.org/10.1002/mus.26757DOI Listing
February 2020

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

Brain Behav 2019 10 30;9(10):e01392. Epub 2019 Aug 30.

Department of Child Neurology, National Center Hospital for Neurology and Psychiatry, NCNP, Tokyo, Japan.

Objective: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population.

Materials And Methods: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients.

Results: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan.

Conclusions: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.
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http://dx.doi.org/10.1002/brb3.1392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790319PMC
October 2019

Static Leukoencephalopathy Associated with 17p13.3 Microdeletion Syndrome: A Case Report.

Neuropediatrics 2019 12 1;50(6):387-390. Epub 2019 Aug 1.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Background: Leukoencephalopathy associated with dysmorphic features may be attributed to chromosomal abnormalities such as 17p13.3 microdeletion syndrome.

Case: A 19-year-old female patient was referred to our hospital for diagnostic evaluation of her leukoencephalopathy. She demonstrated moderate intellectual disability, minor dysmorphic features, and short stature. Serial brain magnetic resonance images obtained within a 16-year interval revealed prolonged T2 signals in the deep cerebral white matter with enlarged Virchow-Robin spaces. A nonsymptomatic atlas anomaly was also noted. Using microarray-based comparative genomic hybridization, we identified a 2.2-Mb terminal deletion at 17p13.3, encompassing , , and but not .

Conclusion: Except for atlas anomaly, the patient's clinical and imaging findings were compatible with the diagnosis of 17p13.3 microdeletion syndrome. The white matter abnormality was static and nonprogressive. The association between the atlas abnormality and this deletion remains elusive. We note the importance of exploring submicroscopic chromosomal imbalance when patients show prominent but static white matter abnormalities with discrepantly mild and stable neurological signs.
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http://dx.doi.org/10.1055/s-0039-1693972DOI Listing
December 2019

Automatic calculation of Mercuri grades from CT and MR muscle images.

Brain Dev 2019 Nov 12;41(10):870-877. Epub 2019 Jul 12.

Department of Neurology, NHO Suzuka National Hospital, Japan.

Background: Mercuri grading of muscle images is a useful method to evaluate the progression of muscular dystrophies. However, because Mercuri grading is skill-based, few competent experts are available. We therefore developed an automated method for Mercuri grade calculations.

Methods: We used computed tomography (CT) and magnetic resonance (MR) images of the thigh and lower leg muscles taken from a Japanese limb-girdle muscular dystrophy patient database. We calculated muscle impairment ratios based on the CT images, and then converted the ratios to revised Mercuri grades. This method was also applied to T1-weighted MR images. Additionally, radiation absorption doses in muscle and chest CT images from a separate patient group were also analyzed.

Results: We observed a close correlation between our automatically calculated Mercuri grades and skill-based visually determined Mercuri grades in both CT and MR images. The radiation absorption, measured by total dose length product, was lower in muscle CT (121.8 mGy-cm) than in chest CT (524.1 mGy-cm).

Conclusions: We developed a new automatic Mercuri grading method using values obtained from CT images. This method was also applied to calculate the Mercuri grade of T1-weighted MR images. In addition, the radiation doses from muscle CT were observed to be lower than those from chest CT.
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http://dx.doi.org/10.1016/j.braindev.2019.06.008DOI Listing
November 2019

Single-fiber electromyography-based diagnosis of CACNA1A mutation in children: A potential role of the electrodiagnosis in the era of whole exome sequencing.

Brain Dev 2019 Nov 6;41(10):905-909. Epub 2019 Jul 6.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.

Introduction: A loss-of-function mutation in CACNA1A, which encodes P/Q-type Ca channels, causes various diseases. As most of the Ca channels at neuromuscular junctions are of the P/Q type, patients with loss-of-function CACNA1A mutations exhibit disturbed neuromuscular transmission. The associated jitters and blocking in such patients can be detected by single-fiber electromyography (SFEMG).

Cases: We report two cases with different phenotypes, which were predicted to harbor loss-of-function mutations of CACNA1A, by using axonal stimulation SFEMG. One case involved a 2-year-old boy with episodic ataxia type 2. The other case involved a 7-year-old girl diagnosed with epileptic encephalopathy. SFEMG results revealed jitters and blocking in both cases. Moreover, whole exome sequencing (WES) revealed a heterozygous CACNA1A mutation, c.5251C>T, p.Arg1751Trp, in the former case and a novel de novo CACNA1A mutation, c.2122G>A, p.Val708Met, in the latter.

Conclusions: Our cases indicate that SFEMG is a potentially useful diagnostic tool for patients with CACNA1A mutation, especially in pediatric cases where trio analysis is difficult or novel mutations are present.
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http://dx.doi.org/10.1016/j.braindev.2019.06.006DOI Listing
November 2019

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders.

Brain Dev 2019 Oct 4;41(9):776-782. Epub 2019 Jun 4.

Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.

Background: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders.

Methods: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM).

Results: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1.

Conclusion: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.
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http://dx.doi.org/10.1016/j.braindev.2019.05.007DOI Listing
October 2019

Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride.

Sci Rep 2019 03 7;9(1):3807. Epub 2019 Mar 7.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Duchenne muscular dystrophy (DMD) is a severe muscle disorder characterised by mutations in the DMD gene. Recently, we have completed a phase I study in Japan based on systemic administration of the morpholino antisense that is amenable to exon-53 skipping, successfully. However, to achieve the effective treatment of DMD, in vitro assays on patient muscle cells to screen drugs and patient eligibility before clinical trials are indispensable. Here, we report a novel MYOD1-converted, urine-derived cells (UDCs) as a novel DMD muscle cell model. We discovered that 3-deazaneplanocin A hydrochloride, a histone methyltransferase inhibitor, could significantly promote MYOGENIN expression and myotube differentiation. We also demonstrated that our system, based on UDCs from DMD patients, could be used successfully to evaluate exon-skipping drugs targeting DMD exons including 44, 50, 51, and 55. This new autologous UDC-based disease modelling could lead to the application of precision medicine for various muscle diseases.
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http://dx.doi.org/10.1038/s41598-019-40421-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405839PMC
March 2019

A phase I study of TAS-205 in patients with Duchenne muscular dystrophy.

Ann Clin Transl Neurol 2018 Nov 10;5(11):1338-1349. Epub 2018 Oct 10.

National Institute of Neuroscience National Center of Neurology and Psychiatry Tokyo Japan.

Objective: Currently, the only approved standard Duchenne muscular dystrophy (DMD) treatment in Japan is oral steroids, which have various disadvantages. Previous work has suggested that hematopoietic-type prostaglandin D synthase (HPGDS), involved in production of the inflammatory mediator prostaglandin D (PGD), might have a role in DMD pathology. We therefore investigated the safety, pharmacokinetics (PK), and pharmacodynamics of a highly selective HPGDS inhibitor (TAS-205) in Japanese patients with genetically confirmed DMD.

Methods: This was a double-blind, randomized, placebo-controlled phase I study to evaluate the use of single or 7-day repeated doses of TAS-205 administered orally. The urinary excretion of PGD metabolites was also assessed.

Results: The PK analysis set included 15 and 14 patients in the single- and repeated-dose periods, respectively; the pharmacodynamics set and the safety set included 21 and 19 patients in each period, respectively. The PK of TAS-205 were linear in the dose range studied (1.67-13.33 mg/kg/dose) and the plasma concentration of TAS-205 reached steady state by Day 4. TAS-205 dose-dependently decreased the urinary excretion of tetranor-prostaglandin D metabolite at each measurement time point and did not affect the urinary excretion of tetranor-prostaglandin E metabolite. No clinically significant adverse events were reported after TAS-205 single or repeated administration.

Interpretation: We confirmed the safety and tolerability of TAS-205 in this study. TAS-205 decreased the total urinary excretion of PGD metabolites in a dose-dependent manner, suggesting that TAS-205 might be a therapeutic option to treat DMD patients.
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http://dx.doi.org/10.1002/acn3.651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243382PMC
November 2018

A novel mutation identified in a Japanese patient with LMNA-associated congenital muscular dystrophy.

Hum Genome Var 2018 20;5:19. Epub 2018 Jul 20.

2Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

LMNA-associated congenital muscular dystrophy (L-CMD) is a severe form of muscle laminopathy. encodes lamin A, which an intermediate filament protein that attaches to the inner membrane of the nuclear envelope. We performed sequence analysis based on our original targeted gene panel system for muscle diseases to obtain a molecular diagnosis in a Japanese girl with L-CMD. A novel heterozygous missense mutation, c.115A>C (p.Asn39His), in is reported.
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http://dx.doi.org/10.1038/s41439-018-0018-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054619PMC
July 2018

Quantitative Analysis of Surface Electromyography for Pediatric Neuromuscular Disorders.

Muscle Nerve 2018 12 17;58(6):824-827. Epub 2018 Oct 17.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children.

Methods: SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values.

Results: Forty-five children (29 with myopathy, 16 with neurogenic disorders; age 9 ± 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 ± 0.88 (-0.48-2.30), whereas that of the myopathic group was -0.55 ± 0.70 (-2.38-0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified.

Discussion: The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve 58:824-827, 2018.
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http://dx.doi.org/10.1002/mus.26299DOI Listing
December 2018

Urinary prostaglandin metabolites as Duchenne muscular dystrophy progression markers.

Brain Dev 2018 Nov 10;40(10):918-925. Epub 2018 Jul 10.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Background: Patients with Duchenne muscular dystrophy (DMD) exhibit increased prostaglandin D (PGD) expression in necrotic muscle and increased PGD metabolites in their urine. In mouse models, inhibiting PGD production suppresses muscle necrosis, suggesting a possible intervention through PGD-mediated activities.

Objective: We investigated the involvement of PGD and its potential use as a marker of pathological progression in DMD.

Methods: Sixty-one male children with DMD and thirty-five age-matched controls were enrolled in the study. DMD patients were divided into "ambulant" and "non-ambulant" groups, which were further subdivided into "steroid" and "non-steroid" therapy groups. Levels of the PGD metabolite tetranor-PGDM (t-PGDM) and creatinine were measured in both spot and 24-hour urine samples, with comparisons between groups made according to geometric mean values.

Results: DMD patients had significantly higher levels of creatinine-corrected t-PGDM in spot urine samples as compared with the control group. Additionally, both ambulant and non-ambulant DMD groups had significantly higher levels of t-PGDM as compared with controls, with no significant difference in t-PGDM levels observed between steroid and non-steroid groups. Moreover, total creatinine excretion in 24-hour urine samples was significantly lower in DMD patients as compared with controls, and although DMD patients had lower muscle mass than controls, their overall levels of t-PGDM did not differ significantly from those in the non-ambulant and control groups.

Conclusion: PGD might help explain the progression and symptomatic presentations (e.g., ambulatory difficulty) associated with DMD, suggesting it as a useful pathological marker and use of a selective PGD inhibitor as a potential treatment modality.
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http://dx.doi.org/10.1016/j.braindev.2018.06.012DOI Listing
November 2018

Seizure imitators monitored using video-EEG in children with intellectual disabilities.

Epilepsy Behav 2018 07 20;84:122-126. Epub 2018 May 20.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Diagnosis of seizure imitators in children is often challenging, and individuals with intellectual disability (ID) could be at additional risk of seizure imitator misdiagnosis. We aimed to elucidate distinct features of clinical semiology among children of different intellectual levels, which may help in distinguishing seizure imitators from epilepsy in such individuals. We retrospectively compared semiological features of seizure imitators in children with and without ID captured using video-electroencephalography (video-EEG). Seizure imitators were classified based on the definition of the International League Against Epilepsy (ILAE). A total of 67 individuals (mean age: 8.4 years, SD: 4.2 years) with seizure imitators documented using long-term video-EEG were identified, in which 27 patients had normal IQ/DQ, 20 had moderate ID, and 20 had severe ID. There was no statistically significant difference in the semiological features of seizure imitators between individuals with ID and those without ID; similarly, no difference was found between those with moderate ID and severe ID compared with individuals with normal IQ/DQ. Among all the patients, altered responsiveness mimicking cognitive or absence seizures was most frequently observed (36%), followed by jerks mimicking myoclonic seizures (22%). The most common seizure imitators among all the patients were unclassifiable nonepileptic seizures per the ILAE definition (28 cases, 42%), followed by day dreaming (24 cases, 36%) and physiological myoclonus (14 cases, 21%). In summary, the present study found no marked difference in semiological features of seizure imitators between patients with ID and those without ID regardless of ID severity, suggesting the necessity of early video-EEG for correct diagnosis.
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http://dx.doi.org/10.1016/j.yebeh.2018.05.006DOI Listing
July 2018

Interpretation of acid α-glucosidase activity in creatine kinase elevation: A case of Becker muscular dystrophy.

Brain Dev 2018 Oct 16;40(9):837-840. Epub 2018 May 16.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Background: Diagnosis of Pompe disease is sometimes challenging because it exhibits clinical similarities to muscular dystrophy.

Case: We describe a case of Becker muscular dystrophy (BMD) with a remarkable reduction in activity of the acid α-glucosidase (GAA) enzyme, caused by a combination of pathogenic mutation and polymorphism variants resulting in pseudodeficiency in GAA. The three-year-old boy demonstrated asymptomatic creatine kinase elevation. Neither exon deletion nor duplication was detected on multiplex ligation-dependent probe amplification (MLPA) of DMD. GAA enzyme activity in both dried blood spots and lymphocytes was low, at 11.7% and 7.7% of normal, respectively. However, genetic analysis of GAA detected only heterozygosity for a nonsense mutation (c.118C > T, p.Arg40). Muscle pathology showed no glycogen deposits and no high acid phosphatase activity. Hematoxylin-eosin staining detected scattered regenerating fibers; the fibers were faint and patchy on immunochemistry staining of dystrophin. The amount of dystrophin protein was reduced to 11.8% of normal, on Western blotting analysis. Direct sequencing analysis of DMD revealed hemizygosity for a nonsense mutation (c.72G > A, p.Trp24). The boy was diagnosed with BMD, despite remarkable reduction in GAA activity; further, he demonstrated heterozygosity for [p.Gly576Ser; p.Glu689Lys] polymorphism variants that indicated pseudodeficiency on another allele in GAA.

Conclusions: Pseudodeficiency alleles are detected in approximately 4% of the Asian population; these demonstrate low activity of acid α-glucosidase (GAA), similar to levels found in Pompe disease. Clinicians should be careful in their interpretations of pseudodeficiency alleles that complicate diagnosis in cases of elevated creatine kinase.
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http://dx.doi.org/10.1016/j.braindev.2018.05.001DOI Listing
October 2018

Transient swelling in the globus pallidus and substantia nigra in childhood suggests SENDA/BPAN.

Neurology 2018 05 25;90(21):974-976. Epub 2018 Apr 25.

From the National Center Hospital (A. Ishiyama, Y.K., Y.S., N.S., M.S.); National Institute of Neuroscience (A. Ishiyama, I.N.); Medical Genome Center (A. Iida, I.N.), National Center of Neurology and Psychiatry, Tokyo; Kawasaki Municipal Tama Hospital (Y.M.), St. Marianna University School of Medicine, Kanagawa; and Japanese Red Cross Musashino Hospital (M.O.), Tokyo, Japan.

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http://dx.doi.org/10.1212/WNL.0000000000005564DOI Listing
May 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