Publications by authors named "Kenji Yokochi"

42 Publications

Nusinersen helps restore walking ability in childhood spinal muscular atrophy.

Pediatr Int 2019 Jul 9;61(7):728-729. Epub 2019 Jul 9.

Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

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http://dx.doi.org/10.1111/ped.13867DOI 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

The Persistent Generalized Muscle Contraction in Siblings with Molybdenum Cofactor Deficiency Type A.

Neuropediatrics 2019 04 29;50(2):126-129. Epub 2019 Jan 29.

Departments of Pediatrics, Seirei-Mikatahara General Hospital, Shizuoka, Japan.

Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive metabolic disease with severe neurological symptoms. Most disease-causing mutations are found in the gene, corresponding to MoCD type A (MoCD-A). There have been few reports describing the long-term detailed neurological features with MoCD-A because most patients do not survive childhood. We describe the clinical, radiologic, biochemical, and genetic data of two patients (female siblings aged 26 and 22 years) with MoCD-A. Both patients presented with feeding difficulties, neurological deterioration, and persistent generalized muscle contraction which can be easily confused with status dystonicus. Biochemical tests revealed low serum uric acid, elevated urinary sulfocysteine, and xanthine. Brain magnetic resonance imaging (MRI) revealed distinctive abnormalities in the bilateral caudate nucleus, putamen, globus pallidus, and cerebral white matter adjacent to the cortex. The thalamus was relatively unaffected. Genetic testing identified a novel homozygous variant in the gene (c.949C > T p.Arg317Cys). Biochemical results supported the hypothesis that this genetic variant is a pathological mutation. When there are symptoms of persistent generalized muscle contraction and characteristic MRI findings, MoCD should be considered as a differential diagnosis.
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http://dx.doi.org/10.1055/s-0039-1677869DOI Listing
April 2019

Biallelic COLGALT1 variants are associated with cerebral small vessel disease.

Ann Neurol 2018 12 30;84(6):843-853. Epub 2018 Nov 30.

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

Objective: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders.

Methods: Whole exome sequencing was performed in 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating collagen β (1-O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments.

Results: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding ColGalT1, which was involved in the post-translational modification of type IV collagen in 2 unrelated patients: c.452 T > G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G > C (p.Ala154Pro) and c.1129G > C (p.Gly377Arg) in Patient 2. Three-dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild type.

Interpretation: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2-related disorders. Ann Neurol 2018;84:843-853.
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http://dx.doi.org/10.1002/ana.25367DOI Listing
December 2018

Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities.

Congenit Anom (Kyoto) 2019 Sep 15;59(5):169-173. Epub 2018 Nov 15.

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

Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.
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http://dx.doi.org/10.1111/cga.12318DOI Listing
September 2019

Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic.

J Hum Genet 2018 Dec 27;63(12):1223-1229. Epub 2018 Sep 27.

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

Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated. In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy. In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.
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http://dx.doi.org/10.1038/s10038-018-0516-xDOI Listing
December 2018

De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy.

Hum Mutat 2018 08 25;39(8):1070-1075. Epub 2018 May 25.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan.

By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function.
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http://dx.doi.org/10.1002/humu.23550DOI Listing
August 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

Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter.

Am J Med Genet A 2017 Aug 9;173(8):2201-2209. Epub 2017 Jun 9.

Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.

Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.
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http://dx.doi.org/10.1002/ajmg.a.38313DOI Listing
August 2017

A Video Report of Brain-Lung-Thyroid Syndrome in a Japanese Female With a Novel Frameshift Mutation of the Gene.

Child Neurol Open 2016 Jan-Dec;3:2329048X16665012. Epub 2016 Aug 24.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Benign hereditary chorea is a rare autosomal-dominant disorder that is characterized by childhood-onset nonprogressive chorea and normal cognitive function. Defects in on chromosome 14q13, which encodes thyroid transcription factor 1, produce a concurrent clinical manifestation of chorea, respiratory distress, and hypothyroidism known as "brain-lung-thyroid syndrome." Here, the authors describe a video report of benign hereditary chorea in a Japanese female with a novel frameshift mutation of (c.915_916insC) (p.Ala303ArgfsX132) that was initially misdiagnosed as ataxic cerebral palsy. In early infancy, especially before the appearance of chorea, benign hereditary chorea can be misdiagnosed as ataxic and dyskinetic cerebral palsy due to shared clinical features including motor delay, hypotonia, ataxic gait, and dystonia.
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http://dx.doi.org/10.1177/2329048X16665012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417288PMC
August 2016

A case report of mitochondrial respiratory chain disorder in the neonatal period for which home mechanical ventilation was introduced.

No To Hattatsu 2017 Jan;49(1):37-41

We report the case of a patient born with extreme muscle hypotonia, respiratory failure, and slightly elevated serum levels of lactic acid. Histochemical examination and mitochondrial respiratory chain enzyme activities of a muscle biopsy specimen revealed reduced activities of complexes Ⅰ, Ⅲ, and Ⅳ, diagnostic of mitochondrial respiratory chain disorder. Hypertrophic cardiomyopathy developed as a complication and additional therapy was administered at 3 months after birth. He was able to be discharged to home on applied home mechanical ventilation with tracheotomy at 1 year old. The patient survived until 4 years and 10 months of age, upon which he died of bronchitis. Early-onset mitochondrial respiratory chain disorder shows very poor prognosis and long-term survival has not been reported. Prompt assessment of mitochondrial respiratory chain enzyme activities is necessary for the diagnosis of congenital nonspecific multiple-organ failure, and early intervention may achieve better prognosis for mitochondrial respiratory chain disorder.
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January 2017

Predominant Corticospinal Tract Involvement in a Late Infant with Krabbe Disease.

Jpn Clin Med 2016 18;7:23-6. Epub 2016 Sep 18.

Department of Pediatrics and Pediatric Neurology, Seirei-Mikatahara General Hospital, Shizuoka, Japan.

A case of late-infantile Krabbe disease in a patient who presented with developmental regression and spastic quadriplegia in late infancy is reported. Brain magnetic resonance imaging (MRI) at 11 months of age showed predominant corticospinal tract involvement, which usually appears in adult Krabbe disease. Galactocerebrosidase activity in lymphocytes and skin fibroblasts was very low. Genetic testing revealed compound heterozygous mutations of the galactocerebrosidase (GALC) gene, c.635_646 delinsCTC and c.1901T>C [p.L618S], both of which are known pathogenic mutations. It has been reported that the c.1901T>C [p.L618S] mutation is associated with the late-onset phenotype and, in a past case, a homozygous mutation at this location showed predominant corticospinal tract involvement on MRI. Although further analysis is needed to identify the pathophysiological mechanism, this combination of mutations is likely to be associated with this unusual MRI finding in late-infantile Krabbe disease. Because these types of mutations are common for Japanese patients, it is possible that there are more undiagnosed and late-diagnosed patients of late-infantile Krabbe disease who display limited lesions on MRI. Pediatricians should be aware that patients with late-infantile Krabbe disease can present with predominant corticospinal tract involvement on MRI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027888PMC
http://dx.doi.org/10.4137/JCM.S40470DOI Listing
September 2016

The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients.

Brain Dev 2016 Jun 13;38(6):571-80. Epub 2016 Jan 13.

Department of Radiology, National Center Hospital of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Electronic address:

Purpose: We retrospectively evaluated the imaging spectrum of Pelizaeus-Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality.

Methods: We collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings.

Results: The clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age "before birth" on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were > 4months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum.

Conclusion: Our multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies.
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http://dx.doi.org/10.1016/j.braindev.2015.12.007DOI Listing
June 2016

Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion.

J Med Genet 2015 Oct 6;52(10):691-8. Epub 2015 Aug 6.

Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.

Background: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid β-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis.

Methods: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways.

Results: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (∼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA.

Conclusions: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and β-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.
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http://dx.doi.org/10.1136/jmedgenet-2015-103231DOI Listing
October 2015

Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state.

Brain Dev 2015 Oct 24;37(9):887-90. Epub 2015 Feb 24.

Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan; Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.

We report a case of nemaline myopathy with KLHL40 mutation, presenting as congenital totally locked-in state. At birth, a male patient developed hydrops fetalis, which was diagnosed based on the generalized edema and pleural effusion and could perform no significant spontaneous movements. His eyes were open, without blinking, and the eyeballs were locked in the midposition. He could not express his intentions by vocalization or moving his trunk, extremities, facial muscles, mouth, eyelids, or eyeballs in response to ambient events or personal interactions. Electrophysiological tests and neuroimaging revealed no evidence of visual or auditory impairment that might indicate a lack of sensory perception, and no evidence of impaired consciousness or intellectual disorder(s) that might prevent him from recognizing ambient events or expressing his intentions. He subsequently died at 4 years of age. Our case highlights the fact that severe congenital neuromuscular disorders can present as congenital totally locked-in state, and that special attention should be provided to these patients.
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http://dx.doi.org/10.1016/j.braindev.2015.02.002DOI Listing
October 2015

[Cervical myelopathy associated with os odontoideum after botulinum toxin treatment in a patient with cerebral palsy].

No To Hattatsu 2014 Jul;46(4):307-10

Os odontoideum is a separate ossicle from the odontoid process from the body of the axis by a variable transverse gap. A boy with cerebral palsy probably due to prematurity and kernicterus, was treated with botulinum toxin for continuous dystonic movements at the age of 3.5 years. Although botulinum toxin appeared to be remarkably effective for relaxing hypertonia, abnormal frequent anterior flexion of the neck remained. Because of feeding difficulty and frequent aspiration episodes, additional botulinum toxin therapy was discontinued. His condition seemed to be stable and he could walk with support at age 7. However, at age 8, he presented with decreased movement of the extremities and bilateral ankle clonus. Radiographic examination of the cervical spine revealed cystic lesion and os odontoideum. With cervical posterior fixation, the patient made a good recovery. Although athetoid cerebral palsy displays an increased risk of cervical myelopathy, os odontoideum is rare in early childhood. The frequent dynamic stress of the neck due to an unbalanced, persistently contracted state and sudden collapse, possibly attributed to botulinum toxin therapy, might have led to atlantoaxial instability and os odontoideum.
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July 2014

Hypoxic ischemic encephalopathy in a case of intranuclear rod myopathy without any prenatal sentinel event.

Brain Dev 2015 Feb 29;37(2):265-9. Epub 2014 Apr 29.

Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan; Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.

Intranuclear rod myopathy (IRM), a variant of nemaline myopathy, is characterized by the presence of nemaline bodies in myonuclei. We report a case of IRM presenting with hypoxic ischemic encephalopathy (HIE). There were no prenatal complications caused by fetal brain injury. Although no nemaline bodies were observed in the cytoplasm, intranuclear rods were observed in some fibers under light and electron microscopy. Molecular analysis identified a heterozygous variant, c.449C>T (p.Thr150Ile), in ACTA1. On magnetic resonance imaging at 9days of age, injuries to the basal ganglia, thalamus, and brainstem consistent with perinatal HIE were seen. Respiratory insufficiency at birth was strongly suspected to be the cause of HIE. Our case highlights that a patient with a congenital neuromuscular disorder who presents with severe respiratory dysfunction requiring substantial resuscitative efforts at birth can be complicated by HIE without any prenatal sentinel event. Prenatal detection of neuromuscular disorders, careful management of delivery, and neonatal resuscitation and adequate respiratory management are important in preventing irreversible brain injury in these patients.
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http://dx.doi.org/10.1016/j.braindev.2014.04.002DOI Listing
February 2015

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.

Am J Med Genet A 2014 Aug 8;164A(8):1899-908. Epub 2014 Apr 8.

Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
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http://dx.doi.org/10.1002/ajmg.a.36551DOI Listing
August 2014

[Clinical profile of persistent generalized muscle contraction following the insult of developing brain].

No To Hattatsu 2014 Jan;46(1):10-5

Objective: Persons with severe motor and intellectual disabilities (SMID) caused by injury to the developing brain sometimes present generalized hypertonia in a specific position with extreme muscle overactivity persisting for most of the time during wakefulness. This "persistent generalized muscle contraction" is often associated with bad humor, sleep disturbance, hyperhidrosis, wasting, elevation of serum creatine kinase levels, regular daytime use of hypnotic or sedative medication, and the necessity to maintain the neck or hip in a flexed position manually. The aim of this study is to elucidate the clinical profile of this condition.

Methods: We retrospectively examined the medical records and brain imaging data of 66 SMID patients in the state of persistent generalized muscle contraction.

Results: Most patients could be classified into 2 major categories on the basis of clinical presentation and brain imaging: (A) those with premature birth and bilateral lesion of globus pallidus interna (kernicterus) (n = 16), and (B) those with various widespread bilateral basal ganglia/thalamic and/or cerebral lesions such as hypoxia-ischemia, acute encephalopathy, malformation, etc (n = 50). Group A assumed an asymmetrical tonic-neck-reflex-like position, torsion of the trunk, fluctuation of hypertonia, and better mental development. Three of them exhibited extreme hypertonia resembling status dystonicus. Group B often exhibited persistent and fixed retroflexion of the neck and trunk or opisthotonus. Drugs such as oral muscular relaxants were ineffective in both groups. Injection of botulinum toxin into the cervical and paravertebral muscles partially alleviated symptoms.

Conclusions: Persistent generalized muscle contraction in SMID has at least two different types. Group A has characteristics of severe dystonic hypertonia that could lead to status dystonicus. Group B might have peculiar characteristics of muscle overactivity triggered by wakefulness or discomfort, which probably results from inability to achieve spontaneous muscle relaxation.
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January 2014

Genotype-phenotype correlations in alternating hemiplegia of childhood.

Neurology 2014 Feb 15;82(6):482-90. Epub 2014 Jan 15.

From the Department of Child Neurology (M. Sasaki, Y.S.), National Center of Neurology and Psychiatry, Kodaira; Department of Pediatrics and Central Research Institute for the Molecular Pathomechanisms of Epilepsy (A.I., S. Hirose) and Department of Biochemistry (B.Z.), Fukuoka University School of Medicine; Department of Pediatrics (N.M., K.I., S. Takada), Kobe University School of Medicine; Department of Pediatrics (A.A., Y.T.), Kansai Medical University, Osaka; Department of Neurology (H.A.), Chiba Children's Hospital; Division of Neurology (S.Y.), Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (T.O.), Nishi-Niigata Central Hospital, Niigata; Department of Pediatrics (Y. Oda, H.I.), Chigasaki Municipal Hospital; Department of Neurology (S. Hirabayashi), Nagano Children's Hospital, Azumino; Yasuhara Children's Clinic (A.Y.), Osaka; Department of Pediatrics (H.K.), Osaka City General Hospital; Division of Child Neurology (S.K.), Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi; Department of Pediatrics (M. Shimono), University of Occupational and Environmental Health, Kitakyushu; Department of Pediatrics (S.N.), Nagahama Red Cross Hospital; Department of Child Neurology (M. Suzuki), Aichi Prefectural Colony Central Hospital, Kasugai; Department of Pediatrics (T.Y.), Kyoto University School of Medicine; Department of Pediatrics (Y. Oyazato), Kakogawa-Nishi Municipal Hospital, Kakogawa; Department of Pediatrics (S. Tsuneishi), Medical and Welfare Center Kizuna, Kasai; Department of Child Development (S.O.), Faculty of Life Sciences, Kumamoto University Graduate School, Kumamoto; Department of Pediatric Neurology (K.Y.), Seirei-Mikatahara Hospital, Hamamatsu; Department of Pediatrics (S.D.), Kyoto Min-iren Chuo Hospital, Kyoto; Department of Child Neurology (T.A.), Okayama University Graduate School of Medicine; Department of Psychiatry (N.K.), Kyoto Katsura Hospital, Kyoto; Department of Pediatrics, (R.K.) Fukuo

Objective: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC.

Methods: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care.

Results: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations.

Conclusions: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
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http://dx.doi.org/10.1212/WNL.0000000000000102DOI Listing
February 2014

Clinical impacts of genomic copy number gains at Xq28.

Hum Genome Var 2014 24;1:14001. Epub 2014 Jul 24.

Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health , Izumi, Japan .

Duplications of the Xq28 region are the most frequent chromosomal aberrations observed in patients with intellectual disability (ID), especially in males. These duplications occur by variable mechanisms, including interstitial duplications mediated by segmental duplications in this region and terminal duplications (functional disomy) derived from translocation with other chromosomes. The most commonly duplicated region includes methyl CpG-binding protein 2 gene (MECP2), which has a minimal duplicated size of 0.2 Mb. Patients with MECP2 duplications show severe ID, intractable seizures and recurrent infections. Duplications in the telomeric neighboring regions, which include GDP dissociation inhibitor 1 gene (GDI1) and ras-associated protein RAB39B gene (RAB39B), are independently associated with ID, and many segmental duplications located in this region could mediate these frequently observed interstitial duplications. In addition, large duplications, including MECP2 and GDI1, induce hypoplasia of the corpus callosum. Abnormalities observed in the white matter, revealed by brain magnetic resonance imaging, are a common finding in patients with MECP2 duplications. As primary sequence analysis cannot be used to determine the region responsible for chromosomal duplication syndrome, finding this region relies on the collection of genotype-phenotype data from patients.
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http://dx.doi.org/10.1038/hgv.2014.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785515PMC
April 2016

Spontaneous movements in the supine position of preterm infants with intellectual disability.

Brain Dev 2014 Aug 19;36(7):572-7. Epub 2013 Sep 19.

Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.

Objective: Spontaneous movements at 2 months of corrected age in preterm infants with intellectual disability (ID) were investigated by assessing individual motor elements separated from movements involving the entire body.

Methods: Video recordings of 20 preterm infants with ID (16 males, 4 females; median gestational age 26 weeks; median birth weight 810 g) were analyzed and were compared with those of 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216 g).

Results: In the preterm infants with ID at 2 months corrected age, startle response, lateral decumbent position, predominant shoulder rotation, and maintaining hip adduction were more frequently observed and hand sucking, maintaining shoulder abduction, to-and-fro shoulder abduction, to-and-fro elbow flexion, isolated hip adduction, to-and-fro hip abduction, and leg lift were less frequently seen than in the normal preterm infants (Fisher's exact test, p<0.05).

Conclusion: Abnormal spontaneous movements at 2 months of age in preterm infants with ID result from persistent immature movements and non-emergence of mature movements.
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http://dx.doi.org/10.1016/j.braindev.2013.08.003DOI Listing
August 2014

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

Ann Neurol 2013 Jan 7;73(1):48-57. Epub 2012 Dec 7.

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

Objective: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations.

Methods: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult.

Results: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations.

Interpretation: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.
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http://dx.doi.org/10.1002/ana.23736DOI Listing
January 2013

Spontaneous movements in the supine position of healthy term infants and preterm infants with or without periventricular leukomalacia.

Brain Dev 2013 Apr 31;35(4):340-8. Epub 2012 May 31.

Department of Neonatal Medical Center, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan.

Aim: The individual motor elements presumed to be essential for motor development were determined from spontaneous movements involving the entire body of normal term and preterm infants. Then, diagnostic items for motor abnormality in infants with periventricular leukomalacia (PVL) were investigated.

Methods: Video recordings of 24 healthy term infants, 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216g) and 14 preterm infants with PVL (6 males, 8 females; median gestational age 30 weeks; median birth weight 1360g) were analyzed.

Results: In healthy term infants, predominant shoulder rotation was noticed until 1 month of age. After 2 months of age, isolated movements of the shoulder, elbow, hip, knee, and ankle frequently emerged. In preterm infants with PVL at the corrected age of 2 months, startle response and predominant shoulder rotation were more frequently seen and isolated neck, shoulder, elbow, hip, knee, and ankle movements were less frequently seen than in the normal preterm infants (Fisher's exact test, p<0.025).

Interpretation: At 2 months of age, isolated movements evolve, and their failure to occur is suggested to be a useful sign for the diagnosis of cerebral motor disorders.
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http://dx.doi.org/10.1016/j.braindev.2012.05.005DOI Listing
April 2013

Magnetic resonance imaging in neonates with total asphyxia.

Brain Dev 2013 Jan 12;35(1):53-60. Epub 2012 May 12.

Department of Neonatology, Seirei-Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.

Magnetic resonance (MR) findings in cases of total asphyxia, whose lesions are mainly in the brainstem and deep nuclei, have not been clarified. In this study, we investigated MR images in neonates with total asphyxia. MR images of six infants (three males and three females; gestational age, 35-39 weeks; birth weights, 1880-3572 g) with total asphyxia were examined. In all subjects, neonatal cortical MR lesions were limited to the hippocampus with highlighting on T1-weighted imaging (T1-WI). The neonatal MR lesions of the cerebral white matter were limited to the white matter between the insula and putamen in four infants, and were diffusely involved in two infants. The ventral lateral nucleus of the thalamus was hyperintense on T1-WI in all of the subjects. Other nuclei in the thalamus, the globus pallidus and the putamen were involved in neonatal MR images of all subjects. High intensity areas on T2- weighted imaging were observed at the dorsal areas in the midbrain, pons and medulla oblongata in all or most of the subjects at the neonatal period. Also, high intensity areas on T1-WI were observed in the tegmentum of the pons and the midbrain in five cases. Neonates with total asphyxia had lesions mainly in the tegmentem of the brainstem, thalamus, putamen and globus palludus. Some of the infants had extensive lesions of the white matter.
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http://dx.doi.org/10.1016/j.braindev.2012.04.002DOI Listing
January 2013

Lateral medullary syndrome in a boy with hereditary dysfibrinogenemia.

Brain Dev 2012 Nov 24;34(10):857-60. Epub 2012 Mar 24.

Department of Pediatrics and Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.

A 9-year-old boy presented with sudden onset of nausea, vomiting and unsteady gait after a bread-eating game, which possibly caused neck hyperextension. Neurological examination revealed hemisensory loss of pain and temperature sensation in the right trunk and limbs along with left Horner's syndrome, suggesting lateral medullary syndrome (LMS). Magnetic resonance (MR) imaging of the brain revealed infarction at the left lateral medulla. MR angiography showed no sign of arterial dissection and no occlusion or stenosis of the intracranial, basilar or vertebral arteries or their branches. No evidence of cardioemboli or systemic inflammation was apparent. Repeated blood examination revealed low activity of fibrinogen. Genetic testing confirmed the presence of hereditary dysfibrinogenemia with a mutation in the FGB gene (BβGly15Cys). This fibrinogen variant has previously been found in Japanese patients with atherosclerosis obliterans or no symptoms. Under conservative treatment without anticoagulation and aspirin, the patient made a good recovery within a few months. We presume that microthrombosis may have been deposited within the vertebral system as a result of extension and rotation of the neck during sports activity, with a contribution from hereditary dysfibrinogenemia.
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http://dx.doi.org/10.1016/j.braindev.2012.02.010DOI Listing
November 2012

De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly.

Am J Hum Genet 2012 Jan 29;90(1):86-90. Epub 2011 Dec 29.

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

Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia. It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages. De novo or inherited heterozygous mutations in COL4A1, which encodes the type IV α1 collagen chain that is essential for structural integrity for vascular basement membranes, have been reported in individuals with porencephaly. Most mutations occurred at conserved Gly residues in the Gly-Xaa-Yaa repeats of the triple-helical domain, leading to alterations of the α1α1α2 heterotrimers. Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain. Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers. The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo. Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1.
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http://dx.doi.org/10.1016/j.ajhg.2011.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257897PMC
January 2012

Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia.

Brain Dev 2012 Mar 19;34(3):230-3. Epub 2011 May 19.

Tokyo Women's Medical University Institute for Integrated Medical Sciences, Shinjuku-ward, Tokyo, Japan.

Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD.
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http://dx.doi.org/10.1016/j.braindev.2011.04.014DOI Listing
March 2012

Two concurrent chromosomal aberrations involving interstitial deletion in 1q24.2q25.2 and inverted duplication and deletion in 10q26 in a patient with stroke associated with antithrombin deficiency and a patent foramen ovale.

Am J Med Genet A 2011 Jan;155A(1):215-20

Department of Pediatrics, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.

Advanced high-throughput molecular cytogenetic analysis has enabled the identification of small chromosomal rearrangements, and two or more concurrently occurring chromosomal rearrangements have been identified using this technique. A girl with severe psychomotor developmental delay associated with an uncertain abnormality (detected by conventional karyotyping) in chromosome 10q had a sudden stroke at the age of 35 months. Laboratory and radiographic examinations revealed antithrombin (AT) deficiency and a patent foramen ovale (PFO). Two concurrent chromosomal aberrations, inverted duplication and deletion in the 10q26 region and a microdeletion in the 1q24.2q25.2 region including the AT gene (SERPINC1), were identified by microarray-based comparative genomic hybridization analysis. Both chromosomal aberrations were found to be of paternal origin. This study described the concurrence of chromosomal rearrangements involving two chromosomes, and estimated the frequency of two or more chromosomal aberrations as 2-4%.
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http://dx.doi.org/10.1002/ajmg.a.33786DOI Listing
January 2011