Publications by authors named "Shinji Saitoh"

185 Publications

Temporal inversion of the acid-base equilibrium in newborns: an observational study.

PeerJ 2021 14;9:e11240. Epub 2021 Apr 14.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.

Background: A considerable fraction of newborn infants experience hypoxia-ischaemia and metabolic acidosis at birth. However, little is known regarding the biological response of newborn infants to the pH drift from the physiological equilibrium. The aim of this study was to investigate the relationship between the pH drift at birth and postnatal acid-base regulation in newborn infants.

Methods: Clinical information of 200 spontaneously breathing newborn infants hospitalised at a neonatal intensive care centre were reviewed. Clinical variables associated with venous blood pH on days 5-7 were assessed.

Results: The higher blood pH on days 5-7 were explained by lower cord blood pH (-0.131, -0.210 to -0.052; regression coefficient, 95% confidence interval), greater gestational age (0.004, 0.002 to 0.005) and lower partial pressure of carbon dioxide on days 5-7 (-0.005, -0.006 to -0.004) (adjusted for sex, postnatal age and lactate on days 5-7).

Conclusion: In relatively stable newborn infants, blood pH drift from the physiological equilibrium at birth might trigger a system, which reverts and over-corrects blood pH within the first week of life. Given that the infants within the study cohort was spontaneously breathing, the observed phenomenon might be a common reaction of newborn infants to pH changes at birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.11240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052977PMC
April 2021

Airway gas temperature within endotracheal tube can be monitored using rapid response thermometer.

Sci Rep 2021 May 5;11(1):9537. Epub 2021 May 5.

Department of Paediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, Japan.

Inappropriate preparation of respiratory gases is associated with serious complications during mechanical ventilation. To develop a temperature monitoring system of respiratory gases within the endotracheal tube, four newborn piglets were studied using an ultra-rapid-response thermometer attached to the closed endotracheal tube suction system. Respiratory gas temperatures were monitored at the mouth-corner level of the endotracheal tube using three thermocouples (T, inserted into the endotracheal tube via the closed suction system; T and T, embedded within the endotracheal tube 0.5 mm and 1.6 mm from the tube wall, respectively). Univariate analysis showed that inspiratory T and inspiratory T were positively correlated with inspiratory T (both p < 0.001). Multivariate analysis showed the dependence of inspiratory T on inspiratory T and T and deflation of endotracheal tube cuff (p < 0.001, p = 0.001 and p = 0.046, respectively). Inspiratory gas temperature within the endotracheal tube can be monitored using a thermometer attached to the closed endotracheal tube suction system. Our system, with further validation, might help optimise respiratory gas humidification during mechanical ventilation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88787-3DOI Listing
May 2021

SCN8A-related developmental and epileptic encephalopathy with ictal asystole requiring cardiac pacemaker implantation.

Brain Dev 2021 Apr 4. Epub 2021 Apr 4.

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

Introduction: SCN8A-related epilepsy has various phenotypes. In particular, patients with developmental and epileptic encephalopathy (DEE) are resistant to antiepileptic drugs and may present with autonomic symptoms, such as marked bradycardia and apnea during seizures, and thus have an increased risk of sudden death. Herein, we report a case of very severe SCN8A-related epilepsy necessitating cardiac pacemaker implantation because of repetitive ictal asystole.

Case Report: The patient was a 14-month-old girl. Tremor and generalized tonic seizure occurred after birth. During seizures, bradycardia and perioral cyanosis occurred, and then, after developing tachycardia and apnea, marked bradycardia and generalized cyanosis occurred, which sometimes resulted in ictal asystole requiring cardiopulmonary resuscitation. Her seizures were refractory to antiepileptic drugs. As the seizures requiring resuscitation did not decrease, cardiac pacemaker implantation was performed four months after birth. Exome sequencing revealed a heterozygous de novo variant in SCN8A (NM_014191.3:c.4934T>C,p.(Met1645Thr)). Even though phenytoin was effective, seizures with bradycardia remained approximately once a month, and pacemaker activity was observed.

Conclusions: This is, to our knowledge, the first reported case of SCN8A-related DEE in whom pacemaker implantation was performed. Pacemaker implantation should be considered as a treatment option for critical patients with SCN8A-related DEE as in the present case, because the incidence of sudden unexpected death in epilepsy is reported to be approximately 10% in patients with SCN8A-related DEE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2021.03.004DOI Listing
April 2021

Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability.

Neurol Sci 2021 Mar 11. Epub 2021 Mar 11.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Background: Mutations of theADCY5 have been identified in patients with familial dyskinesia, early-onsetautosomal dominant chorea and dystonia, and benign hereditary chorea. Most ofthe ADCY5 mutations are de novo or transmitted in an autosomal dominantfashion. Only two pedigrees are known to show autosomal recessive inheritance.

Objectives: We report twosiblings with severe ID, dystonic movement, and growth failure with unknownetiology.

Methods: We planned a proband-parentapproach using whole exome sequencing.

Results: Homozygous mutationin exon 21 of the ADCY5 (p.R1238W) was identified in the siblings. Althoughtheir parents were heterozygous for the mutation, they were free from clinicalmanifestations.

Conclusions: Our results furtherexpand the phenotype/genotype correlations of the ADCY5-related disorders.Mutations of ADCY5 should be considered in pediatric patients with ID andinvoluntary movement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-021-05152-yDOI Listing
March 2021

Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings.

J Autism Dev Disord 2021 Feb 15. Epub 2021 Feb 15.

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

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10803-021-04910-3DOI Listing
February 2021

Variance in the pathophysiological impact of the hemizygosity of gamma-aminobutyric acid type A receptor subunit genes between Prader-Willi syndrome and Angelman syndrome.

Brain Dev 2021 Apr 5;43(4):521-527. Epub 2021 Jan 5.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Introduction: Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders caused by loss of function of maternally expressed UBE3A and paternally expressed contiguous genes on chromosome 15q11-13, respectively. A majority of these syndromes suffer from a large deletion of the relevant chromosome (AS Del or PWS Del), which includes biallelically expressed gamma-aminobutyric acid type A receptor subunit (GABAaR) genes, while remaining individuals present without the deletion (AS non-Del or PWS non-Del). We previously reported that AS Del, but not AS non-Del individuals, show aberrantly desynchronized somatosensory-evoked magnetic fields (SEFs) and speculated that it might reflect GABAergic dysfunction due to the hemizygosity of GABAaR genes. To verify its pathophysiological impact on PWS and AS, we analyzed the SEFs of PWS individuals.

Method: SEFs were recorded from eight PWS Del and two PWS non-Del individuals. The latency and strength of the first peak (N1m) were compared with those of AS Del/non-Del individuals and controls, most of which were obtained earlier.

Results: In contrast to AS, both PWS Del and PWS non-Del showed normal SEF waveforms. Desynchronized response with delayed N1m peak latency was exclusively indicated in AS Del. N1m strength was statistically higher in AS Del and AS non-Del, but not in PWS Del and PWS non-Del.

Conclusions: Our results indicate that the pathophysiological impact of the hemizygosity of GABAaR genes is lower in PWS than AS. UBE3A deficiency and the hemizygosity of GABAaR genes could synergistically deteriorate neuronal function, resulting in aberrant SEFs in AS Del.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.12.014DOI Listing
April 2021

Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant.

Brain Dev 2021 Apr 2;43(4):590-595. Epub 2021 Jan 2.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan. Electronic address:

Introduction: Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date.

Case Report: The case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant.

Conclusion: Here, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.12.008DOI Listing
April 2021

Promoting sound development of preterm infants in the name of developmental neuroscience: Beyond advanced life support and neuroprotection.

Pediatr Neonatol 2021 Feb 5;62 Suppl 1:S10-S15. Epub 2020 Dec 5.

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

Despite the increased survival opportunities for extremely preterm infants, their long-term cognitive outcomes remain poor, with increased incidence of cognitive impairments in childhood and reduced opportunities to attend higher education in young adulthood compared to their term-born peers. Given that a considerable fraction of preterm infants develop cognitive impairments even without apparent sentinel events at birth and cerebral lesions on MRI assessed at term equivalent age, future strategies to improve the outcome may need to address cerebral dysfunction, which cannot be explained by the classical understanding of the injury cascade triggered by hypoxia-ischaemia around birth. Developmental care has been proposed to minimize neurodevelopmental impairments related to preterm birth. However, considerable modes of cares, environmental settings and procedures provided by the developmental care of current style appear to offer little benefit to the sound development of infants. Although it is obvious that advanced life support and neuroprotective treatments fall far short in compensating for the burden of preterm birth, researchers need to make further effort to fill the knowledge gap in the cerebral function of foetuses and newborn infants before establishing evidence-based developmental care. Clinicians need to develop an ability to translate the findings from basic and translational studies incorporating their potential biases and limitations. Care for newborn infants needs to be reassessed, including but not limited to developmental care, in the context that any sensory input and motor reaction of preterm infants may ultimately affect their cognitive functioning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pedneo.2020.11.006DOI Listing
February 2021

Short-latency somatosensory-evoked potentials demonstrate cortical dysfunction in patients with Angelman syndrome.

eNeurologicalSci 2021 Mar 1;22:100298. Epub 2020 Dec 1.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan.

Background: Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed . A majority of patients results from the large deletion of relevant chromosome which includes GABA receptor subunit genes (GABARs) as well as (AS Del) We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS.

Methods: We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times.

Results: The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times.

Conclusion: Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of function and heterozygosity of GABARs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ensci.2020.100298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721653PMC
March 2021

Characteristics and considerations in the medical treatment of COVID-19 in children.

Acute Med Surg 2020 Oct 15. Epub 2020 Oct 15.

Department of Pediatrics and Neonatology Nagoya City University Graduate School of Medical Sciences.

It is rare for children to be in serious condition or die from Coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) except for those with underlying diseases such as chronic lung disease (including asthma), cardiovascular disease, and immunosuppressive disease. Recently, patients with hyperinflammatory shock have been identified among children who are confirmed to have or are suspected of having SARS-CoV-2 infection. The presenting signs and symptoms are characterized by prolonged fever, abdominal pain, and cardiac involvement without any signs of pneumonia on chest computed tomography. However, it is uncertain at this time whether SARS-CoV-2 infection affects this syndrome. Compared to adults, quite a few children are asymptomatic even when infected with SARS-CoV-2, which could make these children serious sources of infection at home or in medical institutions. Considering these characteristics, it is important to take appropriate precautions during medical examinations and perform infection control in emergency departments to save the lives of both the children and adult patients. Most healthy children are suffering huge stress due to restrictions against going outside and school closures as social means to control infection. It is possible that children are socially isolated when they come to the emergency department, and they might require mental or social support even if they are only complaining about their physical condition. Healthcare providers are required to examine the children's circumstances carefully and cooperate with workers in other professions appropriately.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ams2.597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675523PMC
October 2020

Cumulative exposure assessment of neonicotinoids and an investigation into their intake-related factors in young children in Japan.

Sci Total Environ 2021 Jan 15;750:141630. Epub 2020 Aug 15.

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

Exposure levels of neonicotinoids (NEO) in young children remain unknown, despite their widespread use and the plausible vulnerability of toddlers to environmental toxicants. Herein we aimed to clarify the exposure levels and sources of NEOs in young Japanese children. Disposable diapers were collected from 1036 children (16-23 months old) participating in an adjunct study of the Japan Environment and Children's Study between 2015 and 2016. Six NEOs and one metabolite in urine extracted from a diaper from each child were analyzed using high-performance liquid chromatography-tandem mass spectrometry. A relative potency factor approach was used to assess the cumulative exposure to NEOs equivalent to dinotefuran levels (DIN). The 95th percentile urinary concentration of DIN was 157 μg/L and 380 μg/g creatinine (Cr). Receiver operating characteristic curve analyses for the propensity scores of the possible exposure-related factors revealed that the discriminatory powers determining whether Cr-adjusted and Cr-unadjusted DIN concentrations exceeding the 95th percentile values were higher for the amount of each foodstuff ingested on the survey day (areas under the curve were 0.62 and 0.75, respectively) than for the exposure-related behaviors (0.60 and 0.71, respectively) or for mothers' attitudes toward food selection and preparation (0.54 and 0.57, respectively). Use of a mosquito coil, insect repellent, and mothproof net for a screen door, and playing on a lawn were associated with increased urinary NEO levels (odds ratio [OR]: 2.0-2.9), while care about the child's nutritional balance by mothers reduced urinary NEO levels (OR: 0.23-0.41). To the best of our knowledge, this is the first study that dealt with urinary concentrations and possible exposure sources of NEOs in a large number of young children. Attention to the children's behavior and diet might result in the reduction of a high exposure to NEOs in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2020.141630DOI Listing
January 2021

A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders.

J Hum Genet 2021 May 31;66(5):491-498. Epub 2020 Oct 31.

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

CUL3 forms Cullin-Ring ubiquitin ligases (CRL) with Ring-box protein and BTB-adaptor proteins. A variety of BTB-adaptor proteins have been reported to interact with the N-terminus of CUL3, which makes it possible to recognize various substrates for degradation. Regarding the association of CUL3 with neurodevelopmental disorders, a recent study reported three patients with global developmental delay, who carried de novo variants in CUL3. Here, we describe a novel de novo CUL3 variant (c.158G > A, p.Ser53Asn) identified in a patient with global developmental delay, who presented some novel dysmorphic features, including macrocephaly, characteristic facial features, and cutis marmorata. Immunoprecipitation and immunoblot analyses identified significantly weaker binding ability to some BTB proteins in CUL3-S53N compared to wild-type. Interestingly, label-free quantification proteomics analysis of samples immunoprecipitated by CUL3-S53N showed a significantly decreased interaction with some BTB proteins, while almost equal interaction or significantly increased interaction was observed with other BTB proteins. The binding between CUL3 and BTB proteins is essential for CRL substrate recognition, and alteration of their interaction is thought to result in the quantitative alteration in substrate proteins. It is possible that the difference of dysmorphic features between the present case and previously reported cases is caused by the distinctive effect of each CUL3 variant on substrate proteins. The clinical information of the present case will expand the picture of CUL3-related global developmental disorders, and subsequent cell biological analysis of the novel mutation will provide insight into the underlying molecular mechanism of how CUL3 pathogenic variants cause neurological disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-00868-9DOI Listing
May 2021

Frequent epileptic apnoea in a patient with Pitt-Hopkins syndrome.

Epileptic Disord 2020 Oct;22(5):673-677

Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.

Pitt-Hopkins syndrome is a rare genetic disease, characterised by severe intellectual disability, distinctive dysmorphic features, epilepsy and distinctive breathing abnormalities during wakefulness. Here, we describe the case of a 22-year-old woman with Pitt-Hopkins syndrome who presented with intractable generalised tonic seizures from the age of 11 years, which increased in frequency with age and onset of menstruation despite usage of some anticonvulsant drugs. From the age of 16 years, polysomnography and video-EEG led to the detection of frequent epileptic apnoea during sleep. Although the frequency of generalised tonic seizure clusters was reduced by treatment with phenobarbital and potassium bromide, epileptic apnoea persisted. Furthermore, frequent epileptic apnoea observed in our patient was regarded as a factor for aspiration and deterioration of respiratory function. This study indicates that patients with Pitt-Hopkins syndrome require close monitoring for epileptic apnoea. Moreover, long-term EEG and respiratory monitoring are necessary to distinguish epileptic apnoea from other respiratory disorders in patients with Pitt-Hopkins syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1212DOI Listing
October 2020

Genome-wide methylation analysis in Silver-Russell syndrome, Temple syndrome, and Prader-Willi syndrome.

Clin Epigenetics 2020 10 22;12(1):159. Epub 2020 Oct 22.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA).

Results: GWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients.

Conclusions: GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00949-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583213PMC
October 2020

Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect.

Int J Cardiol 2021 Mar 17;326:81-87. Epub 2020 Oct 17.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. Electronic address:

Background: A gain-of-function mutation in germline ABL1 causes a syndrome including congenital heart defects. However, the molecular mechanisms of this syndrome remain unknown. In this study, we found a novel ABL1 mutation in a Japanese family with ventricular septal defect, finger contracture, skin abnormalities and failure to thrive, and the molecular mechanisms of these phenotypes were investigated.

Methods And Results: Whole-exome sequencing on several family members revealed a novel mutation (c.1522A > C, p.I508L) in the tyrosine kinase domain of ABL1, and complete co-segregation with clinical presentations was confirmed in all members. Wild-type and mutant ABL1 were transfected into human embryonic kidney 293 cells for functional analysis. Western blotting confirmed that tyrosine phosphorylation in STAT5, a substrate of ABL1, was enhanced, and the novel mutation was proved to be a gain-of-function mutation. Since this novel mutation in ABL1 enhances tyrosine kinase activity, phosphorylated proteome analysis was used to elucidate the molecular pathology. The proteome analysis showed that phosphorylation in proteins such as UFD1, AXIN1, ATRX, which may be involved in the phenotypes, was enhanced in the mutant group.

Conclusions: The onset of congenital heart defects associated with this syndrome appears to involve a mechanism caused by UFD1 common to 22q.11.2 deletion syndrome. On the other hand, AXIN1 and ATRX may be important in elucidating the mechanisms of other phenotypes, such as finger contracture and failure to thrive. Verification of these hypotheses would lead to further understanding of the pathophysiology and the development of treatment methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.10.032DOI Listing
March 2021

The identification of two pathogenic variants in a family with mild and severe forms of developmental delay.

J Hum Genet 2021 Apr 9;66(4):445-448. Epub 2020 Oct 9.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box, 14115-331, Tehran, Iran.

Intellectual disability (ID) accounts for 1% of the general population, and it is caused by the interplay between the genetic and/or environmental factors. The genetic components responsible for the development of ID are highly heterogeneous, and the phenotype and severity of the disease vary in patients even if they have an identical pathological variant and/or belong to the same family. Herein, we reported two male siblings with ID in an Iranian family. By means of the whole-exome sequencing method, elder brother affected by a moderate form of ID exhibited a de novo missense variant in the KCNQ3 gene, while another sibling afflicted with a severe form of the disease exhibited a de novo in-frame deletion in the UBE3A gene. Both variants have been previously ascribed to similar clinical phenotypes. In addition, a genetic variant in the KCNQ3 gene was transmitted to his son, who had a mild form of ID. To our knowledge, all individuals with KCNQ3-related developmental delay show de novo variants in the KCNQ3 gene. Thus, this familial case exhibit milder phenotype that might extend the clinical spectrum of KCNQ3 pathogenic variants. In addition, the current report highlights the significance of the clinical evaluation and non-biased assessment of the genetic analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-0809-8DOI Listing
April 2021

A case of tricuspid atresia with Prader-Willi syndrome.

Pediatr Int 2020 Sep 24;62(9):1105-1106. Epub 2020 Aug 24.

Department of Pediatrics, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ped.14240DOI Listing
September 2020

Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes.

PLoS One 2020 17;15(8):e0237814. Epub 2020 Aug 17.

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

Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternal allele of MAGEL2, located in the Prader-Willi critical region, 15q11-q13. Although the phenotypes of SYS overlap those of Prader-Willi syndrome (PWS), including neonatal hypotonia, feeding problems, and developmental delay/intellectual disability, SYS patients show autism spectrum disorder and joint contractures, which are atypical phenotypes for PWS. Therefore, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects. To test the hypothesis, we generated two engineered mouse models; one, an overexpression model that expressed the N-terminal region of Magel2 that was FLAG tagged with a strong ubiquitous promoter, and another, a genome-edited model that carried a truncating variant in Magel2 generated using the CRISPR/Cas9 system. In the overexpression model, all transgenic mice died in the fetal or neonatal period indicating embryonic or neonatal lethality of the transgene. Therefore, overexpression of the truncated Magel2 could show toxic effects. In the genome-edited model, we generated a mouse model carrying a frameshift variant (c.1690_1924del; p(Glu564Serfs*130)) in Magel2. Model mice carrying the frameshift variant in the paternal or maternal allele of Magel2 were termed Magel2P:fs and Magel2M:fs, respectively. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal Magel2P:fs mice were lighter than wildtype littermates, Magel2P:fs males and females weighed the same as their wildtype littermates by eight and four weeks of age, respectively. Collectively, the overexpression mouse model may recapitulate fetal or neonatal death, which are the severest phenotypes for SYS. In contrast, the genome-edited mouse model maintains genomic imprinting and distribution of truncated Magel2 transcripts in the brain, but only partially recapitulates SYS phenotypes. Therefore, our results imply that simple gain-of-function toxic effects may not explain the patho-mechanism of SYS, but rather suggest a range of effects due to Magel2 variants as in human SYS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237814PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430741PMC
October 2020

Prenatal clinical manifestations in individuals with variants.

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

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

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

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

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

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

Behavioral problems and family distress in tuberous sclerosis complex.

Epilepsy Behav 2020 10 19;111:107321. Epub 2020 Jul 19.

Department of Pediatrics, Tohoku University School of Medicine, 980-8574, Japan.

Background: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported.

Aim: The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment.

Method: The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale-2nd edition (SRS-2).

Results: All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score.

Conclusion: Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest "TAND impact" on families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107321DOI Listing
October 2020

Association between Prenatal Exposure to Household Pesticides and Neonatal Weight and Length Growth in the Japan Environment and Children's Study.

Int J Environ Res Public Health 2020 06 26;17(12). Epub 2020 Jun 26.

Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Aichi 4678601, Japan.

The effects of prenatal exposure to household pesticides on fetal and neonatal growth have not been fully clarified. The present study aims to determine the effects of prenatal exposure to pesticides on neonates' body size and growth during the first month. This study included 93,718 pairs of pregnant women and their children from the Japan Environment and Children's Study. Participants completed self-reporting questionnaires during their second or third trimesters on their demographic characteristics and frequency of pesticide use during pregnancy. Child weight, length, and sex were obtained from medical record transcripts. Birth weight and length, as well as weight and length changes over the first month, were estimated using an analysis of covariance. Frequency of exposure to almost all pesticides had no effects on birth weight and length. However, we found small but significant associations (i) between the use of fumigation insecticides and decreased birth weight, and (ii) between frequencies of exposure to pyrethroid pesticides, especially mosquito coils/mats, and suppression of neonatal length growth. Prenatal exposure to household pesticides, especially those containing pyrethroids, might adversely influence fetal and postnatal growth trajectories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17124608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344403PMC
June 2020

De novo 2q36.3q37.1 deletion encompassing and yields distinct phenotypes.

Hum Genome Var 2020 1;7:19. Epub 2020 Jun 1.

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

We report a patient with developmental delay, extremely short stature, small hands, dysmorphic facial features, hearing loss, and epilepsy carrying a de novo 2.76-Mb deletion of 2q36.3q37.1, including and . haploinsufficiency causes developmental delay with isolated dysmorphic facial features, whereas haploinsufficiency causes short stature and small hands. This is the first report of a unique phenotype, which is secondary to a microdeletion encompassing and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41439-020-0107-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261772PMC
June 2020

Transient cortical diffusion restriction in children immediately after prolonged febrile seizures.

Eur J Paediatr Neurol 2020 Jul 19;27:30-36. Epub 2020 May 19.

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

Aim: Little is known about acute febrile status epilepticus-induced injury of extrahippocampal structures. To clarify the presence and clinical significance of acute extrahippocampal injuries, we performed diffusion-weighted imaging (DWI) in children immediately after prolonged febrile seizure (PFS).

Method: We performed a retrospective cohort study in children younger than 6 years old who visited one of two hospitals due to PFSs between January 2013 and October 2018. PFS was defined as a febrile seizure that persisted for 15 min or longer. We collected brain DWI data within 6 h of the end of PFS. When the initial DWI detected an abnormality, a follow-up DWI was performed a few days later.

Results: The study population consisted of 101 patients with PFSs. DWI was performed within 6 h in 51 patients, while the remaining 50 patients did not undergo imaging because of good recovery of consciousness. Restricted cortical diffusion was evident in 9 (18%) patients on initial DWI. All of them underwent DWI within 100 min after PFS. Restricted cortical diffusion was associated with male sex, asymmetrical PFS symptoms, and a shorter duration between the end of the seizure and DWI, but was not associated with seizure duration. All cortical abnormalities had resolved on follow-up DWI of these patients within 72 h after the initial imaging, but ipsilateral hippocampal hyperintensity appeared in one patient. All 9 patients with restricted cortical diffusion were finally diagnosed with PFS and discharged without sequelae.

Conclusions: Some children with PFSs exhibit transient restricted diffusion in the regional cortex on DWI performed immediately after the end of PFS. These transient diffusion changes were not associated with unfavorable epileptic sequelae or neuroimaging in the short-term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.05.004DOI Listing
July 2020

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism.

J Pediatr Endocrinol Metab 2020 May 29;33(6):691-701. Epub 2020 May 29.

Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Objectives Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations. Methods We enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH. Results We identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants. Conclusions The prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2019-0433DOI Listing
May 2020

Splenial Lesions in Benign Convulsions With Gastroenteritis Associated With Rotavirus Infection.

Pediatr Neurol 2020 08 9;109:79-84. Epub 2019 May 9.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; Brain and Mind Research Center, Nagoya University, Nagoya, Japan; Department of Developmental Disability Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Objective: To investigate clinical risk factors for acute magnetic resonance imaging (MRI) abnormalities in patients with benign convulsions with mild gastroenteritis or benign infantile epilepsy.

Study Design: We investigated clinical and diffusion-weighted imaging findings in 32 patients with benign convulsions with mild gastroenteritis and 22 patients with benign infantile epilepsy who underwent MRI within seven days of seizure onset between 2010 and 2015.

Results: Diffusion-weighted imaging showed signal hyperintensity in the splenium of the corpus callosum in seven patients with benign convulsions with mild gastroenteritis, but no abnormalities in patients with benign infantile epilepsy. Patients with benign convulsions with mild gastroenteritis with splenial lesions showed a higher rate of rotavirus detection from feces (P = 0.006), higher serum level of C-reactive protein (P = 0.04), and shorter interval between seizure onset and MRI (P = 0.002) than patients with benign convulsions with mild gastroenteritis without splenial lesions. Multivariate analysis revealed rotavirus infection as a significant risk factor for splenial lesions on diffusion-weighted imaging in patients with benign convulsions with mild gastroenteritis (P = 0.02).

Conclusions: Splenial lesions are often seen during acute period in patients with benign convulsions with mild gastroenteritis. Rotavirus infection is a risk factor for splenial lesions in patients with benign convulsions with mild gastroenteritis, suggesting the role of rotavirus to cause edema in the corpus callosum. From our observations, benign convulsions with mild gastroenteritis with a splenial lesion on diffusion-weighted imaging suggests good outcomes, and extensive evaluation of these patients may be unnecessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2019.05.002DOI Listing
August 2020

A Novel α-Spectrin Pathogenic Variant in Trans to α-Spectrin LELY Causing Neonatal Jaundice With Hemolytic Anemia From Hereditary Pyropoikilocytosis Coexisting With Gilbert Syndrome.

J Pediatr Hematol Oncol 2021 03;43(2):e250-e254

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya.

Hereditary pyropoikilocytosis is a subtype of hereditary elliptocytosis because of biallelic mutations of SPTA1, SPTB, and EPB41. The authors present a proband with neonatal jaundice and hemolytic anemia, with poikilocytosis in the blood film. Targeted next-generation sequencing identified Q267del trans to the αLELY allele in SPTA1. In addition, the proband presented coexisting Gilbert syndrome as determined by homozygous mutation of UGT1A1. Investigation of 13 relatives and his sibling revealed that only his sibling showed the same phenotype and genotype as the proband. This is the first report of molecular confirmation of coexisting hereditary pyropoikilocytosis and Gilbert syndrome and a novel mutation in SPTA1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000001796DOI Listing
March 2021

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy.

Ann Clin Transl Neurol 2020 02 20;7(2):181-190. Epub 2020 Jan 20.

National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D (PGD ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years.

Methods: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24.

Results: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed.

Interpretation: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034509PMC
February 2020

Influence of Percutaneous Occlusion of Atrial Septal Defect on Left Atrial Function Evaluated Using 2D Speckle Tracking Echocardiography.

Int Heart J 2020 Jan 17;61(1):83-88. Epub 2020 Jan 17.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences.

Percutaneous occlusion of atrial septal defect (ASD) has recently become a standard therapeutic strategy, but little is known about left atrial (LA) function thereafter. The present study aimed to determine LA function in 43 children with ASD and 13 controls based on LA strain measured by two-dimensional echocardiographic speckle tracking (2DE-ST). Among these children, 12 underwent surgery (ASD-S), 31 had device closure (ASD-D), and 13 were included as controls. LA strain was significantly decreased after ASD-D but was not significantly altered after ASD-S, indicating that percutaneous occlusion of an ASD might decrease LA function. Furthermore, the size of the ASD device negatively correlated with LA strain. These results imply that ASD occlusion devices negatively influence LA function and might be important when decided therapeutic strategies for ASD. LA strain measured by 2DE-ST should become a good indicator of LA function after ASD treatment in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1536/ihj.19-173DOI Listing
January 2020

Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum.

Brain Dev 2020 Mar 31;42(3):298-301. Epub 2019 Dec 31.

Department of Neonatology and Pediatrics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address:

Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits. Brain magnetic resonance imaging showed signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing was performed on the proband and her parents, and novel compound heterozygous mutations at c.936_938del (p.Phe313del) and c.1503dupC (p.Ile502Hisfs*106) in MCOLN1 (NM_020533.2) were identified in the proband. Additional biochemical examinations revealed elevated serum gastrin level and iron deficiency anemia, leading to the diagnosis of MLIV. More reports of such pathogenic mutations are expected to broaden the understanding of the channel function of mucolipin-1 and genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2019.12.003DOI Listing
March 2020

Successful treatment of adult-onset type II citrullinemia with a low-carbohydrate diet and L-arginine after DNA analysis produced a definitive diagnosis.

Clin J Gastroenterol 2020 Oct 2;13(5):823-833. Epub 2020 Jan 2.

Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

A 60-year-old male, who exhibited finger tremors, obnubilation, and hyperammonemia (409 μg/dL), was admitted to our hospital. Initially, we suspected that a portosystemic shunt had caused his hyperammonemia. However, his symptoms did not improve after balloon-occluded retrograde transvenous obliteration. He was subsequently found to have some peculiar eating habits, including a fondness for bean curd and peanuts, and an aversion to alcohol and sweets. Furthermore, marked citrullinemia (454.2 nmol/mL) was revealed, which led us to suspect adult-onset type II citrullinemia (CTLN2). DNA analysis of the patient and his mother, son, and daughter confirmed that he was homozygous for the c.852_855del mutation in the SLC25A13 gene, and his relatives were heterozygous for the c.852_855del mutation, which led to a definitive diagnosis. A low-carbohydrate diet and the administration of L-arginine ameliorated his symptoms. It is important to be aware that CTLN2 can occur in elderly patients. Thus, patients who exhibit symptoms of CTLN2 should be interviewed about their dietary habits and subjected to plasma amino acid analysis.In this report, we consider the metabolic disorders seen in citrin deficiency and the associated compensatory mechanisms in relation to the clinical features and treatment of CTLN2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-019-01083-6DOI Listing
October 2020