Publications by authors named "Takeshi Taketani"

103 Publications

Clinical and molecular features of patients with COL1-related disorders: Implications for the wider spectrum and the risk of vascular complications.

Am J Med Genet A 2022 Sep 13;188(9):2560-2575. Epub 2022 Jul 13.

Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.

Abnormalities in type I procollagen genes (COL1A1 and COL1A2) are responsible for hereditary connective tissue disorders including osteogenesis imperfecta (OI), specific types of Ehlers-Danlos syndrome (EDS), and COL1-related overlapping disorder (C1ROD). C1ROD is a recently proposed disorder characterized by predominant EDS symptoms of joint and skin laxity and mild OI symptoms of bone fragility and blue sclera. Patients with C1ROD do not carry specific variants for COL1-related EDS, including classical, vascular, cardiac-valvular, and arthrochalasia types. We describe clinical and molecular findings of 23 Japanese patients with pathogenic or likely pathogenic variants of COL1A1 or COL1A2, who had either OI-like or EDS-like phenotypes. The final diagnoses were OI in 17 patients, classical EDS in one, and C1ROD in five. The OI group predominantly experienced recurrent bone fractures, and the EDS group primarily showed joint hypermobility and skin hyperextensibility, though various clinical and molecular overlaps between OI, COL1-related EDS, and C1ROD as well as intrafamilial phenotypic variabilities were present. Notably, life-threatening vascular complications (vascular dissections, arterial aneurysms, subarachnoidal hemorrhages) occurred in seven patients (41% of those aged >20 years) with OI or C1ROD. Careful lifelong surveillance and intervention regarding bone and vascular fragility could be required.
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http://dx.doi.org/10.1002/ajmg.a.62887DOI Listing
September 2022

A Simple Flow Injection Analysis-Tandem Mass Spectrometry Method to Reduce False Positives of C5-Acylcarnitines Due to Pivaloylcarnitine Using Reference Ions.

Children (Basel) 2022 May 10;9(5). Epub 2022 May 10.

Laboratories Division, Shimane University Hospital, Izumo 693-8501, Japan.

Flow injection analysis-tandem mass spectrometry (FIA-TMS) has been applied in a first-tier test of newborn screening (NBS). Although isovalerylcarnitine (i-C5), which is a diagnostic indicator of isovaleric acidemia (IVA), is isobaric with pivaloylcarnitine (p-C5), 2-methylbutyrylcarnitine, and n-valerylcarnitine, these isomers cannot be distinguished by the FIA-TMS. There are many reports of false positives derived from p-C5 due to the use of pivalate-conjugated antibiotics. In this study, we developed a new FIA-TMS method to distinguish i-C5 and p-C5. We found that the intensity ratio of product ions for i-C5 and p-C5 was different in a certain range even under the same analytical conditions. The product ions with the most distinct differences in ionic intensity between the isomers and the collision energies that produce them were determined to be 246.2 > 187.1 and -15 V, respectively. In addition to the quantification ion, a reference ion was defined, and the similarity of the i-C5 and p-C5 reference ion ratios (i-C5 score and p-C5 score, respectively) were used to estimate which isomer (i-C5 and p-C5) was responsible for elevated C5 acylcarnitine in dried blood spots (DBSs). As a result of analyses of 11 DBS samples derived from pivalate-conjugated antibiotics and four DBS samples from IVA patients using our method, it was found that our method was able to correctly determine the type of C5-acylcarnitine (i-C5 or p-C5) in the DBS samples. Implementation of this new FIA-TMS method into the current NBS protocol will allow for a reduction in false positives in IVA.
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http://dx.doi.org/10.3390/children9050694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139860PMC
May 2022

The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening.

Mol Genet Metab 2022 05 25;136(1):74-79. Epub 2022 Mar 25.

Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address:

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.
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http://dx.doi.org/10.1016/j.ymgme.2022.03.009DOI Listing
May 2022

Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.

Clin Immunol 2022 04 30;237:108993. Epub 2022 Mar 30.

Deparment of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.
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http://dx.doi.org/10.1016/j.clim.2022.108993DOI Listing
April 2022

Idiopathic pulmonary hemosiderosis: A mimic of severe COVID-19 pneumonia.

Pediatr Int 2022 Jan;64(1):e14991

Department of Pediatrics, Faculty of Medicine, Shimane University, Shimane, Japan.

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http://dx.doi.org/10.1111/ped.14991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115395PMC
January 2022

NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine.

Drug Metab Pharmacokinet 2022 Apr 4;43:100436. Epub 2021 Dec 4.

Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand. Electronic address:

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT153 and NUDT152 genotypes were at a 10-15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT153 and NUDT152, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.
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http://dx.doi.org/10.1016/j.dmpk.2021.100436DOI Listing
April 2022

Prevalence of common aneuploidy in twin pregnancies.

J Hum Genet 2022 May 1;67(5):261-265. Epub 2022 Jan 1.

Department of Obstetrics & Gynecology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.
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http://dx.doi.org/10.1038/s10038-021-01001-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035385PMC
May 2022

Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency.

Nat Commun 2021 11 24;12(1):6819. Epub 2021 Nov 24.

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.
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http://dx.doi.org/10.1038/s41467-021-27085-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613290PMC
November 2021

Diagnosis of Mucopolysaccharidoses and Mucolipidosis by Assaying Multiplex Enzymes and Glycosaminoglycans.

Diagnostics (Basel) 2021 Jul 27;11(8). Epub 2021 Jul 27.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

Mucopolysaccharidoses (MPS) and mucolipidosis (ML II/III) are a group of lysosomal storage disorders (LSDs) that occur due to a dysfunction of the lysosomal hydrolases responsible for the catabolism of glycosaminoglycans (GAGs). However, ML is caused by a deficiency of the enzyme uridine-diphosphate N-acetylglucosamine:lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. A timely diagnosis of MPS and ML can lead to appropriate therapeutic options for patients. To improve the accuracy of diagnosis for MPS and ML in a high-risk population, we propose a combination method based on known biomarkers, enzyme activities, and specific GAGs. We measured five lysosomal enzymes (α-L-iduronidase (MPS I), iduronate-2-sulfatase (MPS II), α-N-acetylglucosaminidase (MPS IIIB), N-acetylglucosamine-6-sulfatase (MPS IVA), and N-acetylglucosamine-4-sulfatase (MPS VI)) and five GAGs (two kinds of heparan sulfate (HS), dermatan sulfate (DS), and two kinds of keratan sulfate (KS)) in dried blood samples (DBS) to diagnose suspected MPS patients by five-plex enzyme and simultaneous five GAGs assays. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) for both assays. These combined assays were tested for 43 patients with suspected MPS and 103 normal control subjects. We diagnosed two MPS I, thirteen MPS II, one MPS IIIB, three MPS IVA, two MPS VI, and six ML patients with this combined method, where enzymes, GAGs, and clinical manifestations were compatible. The remaining 16 patients were not diagnosed with MPS or ML. The five-plex enzyme assay successfully identified MPS patients from controls. Patients with MPS I, MPS II, and MPS IIIB had significantly elevated HS and DS levels in DBS. Compared to age-matched controls, patients with ML and MPS had significantly elevated mono-sulfated KS and di-sulfated KS levels. The results indicated that the combination method could distinguish these affected patients with MPS or ML from healthy controls. Overall, this study has shown that this combined method is effective and can be implemented in larger populations, including newborn screening.
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http://dx.doi.org/10.3390/diagnostics11081347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394749PMC
July 2021

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

J Obstet Gynaecol Res 2021 Oct 5;47(10):3437-3446. Epub 2021 Aug 5.

Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.

Aim: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women.

Methods: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated.

Results: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively.

Conclusion: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.
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http://dx.doi.org/10.1111/jog.14954DOI Listing
October 2021

The feasibility of Gazefinder under 12 months of age infants.

Sci Rep 2021 05 11;11(1):10009. Epub 2021 May 11.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, 693-8501, Japan.

Eye-tracking to evaluate gaze patterns has developed as an assessment tool for children with autism spectrum disorder (ASD). Gazefinder is one of Eye-tracking devices and few studies have investigated whether it can measure the gaze data of infants under 12 months of age. We conducted a prospective cross-sectional study from April 2019 to March 2020 in a periodic health checkup in Ohchi County, Shimane, Japan. Participants included infants between 4 and 11 months of age who were not suspected the presence of developmental problems. Ninety-three participants' datapoints were analyzed. The mean age was 6.5 months and mean developmental quotient was 88%. The mean fixation time percentage of all sequences was 81.0% (standard deviation; 4.4), and there was no significant difference in each age group. Infants in all groups showed a significantly higher predilection for eyes than for mouths. There was a positive association of age with human gaze and a negative association with geometric gaze. Moreover, we confirmed that joint attention skills were enhanced in accordance with their growth process. The eye-tracking data were almost corresponding to previous studies' data of infant with typical development and Gazefinder could be applied to infants starting at 4 months of age.
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http://dx.doi.org/10.1038/s41598-021-89585-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113266PMC
May 2021

Long-Term Neurological Outcomes of Adult Patients with Phenylketonuria before and after Newborn Screening in Japan.

Int J Neonatal Screen 2021 Apr 14;7(2). Epub 2021 Apr 14.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.

Japanese newborn screening (NBS) for phenylketonuria (PKU) was initiated in 1977. We surveyed the neurological outcomes of Japanese adult patients with PKU to investigate the long-term effects and of and issues with NBS. Eighty-five patients with PKU aged over 19 years who continued to be treated with a phenylalanine-free amino acid formula were investigated by administering questionnaires regarding clinical characteristics, such as mental ability, education status, and therapeutic condition. Of the 85 subjects, 68 patients were detected by NBS (NBS group), while the other 17 were clinically diagnosed before the initiation of NBS (pre-NBS group). Further, 10 of the 68 NBS patients presented intellectual and/or psychiatric disabilities, 5 of whom had a history of treatment discontinuation; in contrast, 12 of the 17 pre-NBS patients presented with neuropsychiatric symptoms. Regarding social outcomes, almost all patients in the NBS group could live an independent life, while over half of the patients in the pre-NBS group were not employed or lived in nursing-care facilities. Neurological outcomes are obviously improved by NBS in Japan. However, some patients, even those detected by NBS, developed neuropsychiatric symptoms due to treatment disruption. Lifelong and strict management is essential to maintain good neurological and social prognoses for patients with PKU.
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http://dx.doi.org/10.3390/ijns7020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167766PMC
April 2021

Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor.

J Allergy Clin Immunol 2021 08 13;148(2):639-644. Epub 2021 Mar 13.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways.

Objective: This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified.

Methods: We performed the whole-exome sequencing of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene.

Results: Whole-exome sequencing identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence.

Conclusions: We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.
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http://dx.doi.org/10.1016/j.jaci.2021.03.010DOI Listing
August 2021

A pediatric case of food-dependent exercise-induced anaphylaxis due to rice bran.

Asia Pac Allergy 2021 Jan 21;11(1):e4. Epub 2021 Jan 21.

Department of Pediatrics, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan.

Food-dependent exercise-induced anaphylaxis (FDEIA) caused by fruits and vegetables is increasing in recent years, but rice-induced FDEIA is rarely reported. The mechanism of FDEIA is unclear, although percutaneous sensitization occurs in some cases. A 14-year-old adolescent came our hospital who had 6 episodes of unknown FDEIA occurring from age 13. He affected atopic dermatitis in infancy, and he had been polishing rice daily to help with housework, and also had occasionally begun to observe urticaria while bathing after eating rice from 5 years old. Antigen-specific immunoglobulin E antibody titers (ImmunoCAP) were 1.35 UAmL for rice, 23.6 UAmL for orchard grass. Oral food challenge and exercise provocation test with polished rice were negative. An oral food challenge with rice bran was also negative, but exercise provocation test induced severe anaphylaxis. IgE immunoblotting with rice bran detected patient-specific bands, as 25-, 35-, 50-, and 60 kDa, and the 25- and 60-kDa bands were heat-resistant. In a suppression test using rice bran, these bands disappeared or diminished. In an inhibition test against orchard grass pollen with rice bran, inhibition was not observed. Conversely, an inhibition test against rice bran with orchard grass pollen, inhibition was observed in a concentration-dependent manner. This is extremely rare case of FDEIA in children, caused by rice bran. Furthermore, it might be induced by percutaneous sensitization. In FDEIA, it is necessary to scrutinize the possibility that rice bran may be the cause even in children.
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http://dx.doi.org/10.5415/apallergy.2021.11.e4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870376PMC
January 2021

Long-Term Outcomes of Adult Patients with Homocystinuria before and after Newborn Screening.

Int J Neonatal Screen 2020 Jul 30;6(3). Epub 2020 Jul 30.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1, En-ya-cho, Izumo, Shimane 693-8501, Japan.

Background: Homocystinuria (HCU) is a rare inherited metabolic disease. In Japan, newborn screening (NBS) for HCU (cystathionine β-synthase deficiency) was initiated in 1977. We compared the outcomes between patients detected by NBS (NBS group) and clinically detected patients (non-NBS group).

Methods: We administered questionnaires about clinical symptoms and social conditions to 16 attending physicians of 19 adult HCU patients treated with methionine-free formula.

Results: Eighteen patients (nine patients each in the NBS and non-NBS groups) participated. The frequency of patients with ocular, vascular, central nervous system, and skeletal symptoms in the NBS group was lower than that in the non-NBS group. Intellectual disability was observed in one and eight patients in the NBS and non-NBS groups, respectively. Concerning their social conditions, all patients in the NBS group were employed or still attending school, while only two patients in the non-NBS group were employed. Three of the four patients who discontinued treatment presented some symptoms, even in the NBS group.

Conclusion: The social and intellectual outcomes of adult Japanese patients with HCU detected by NBS were favorable. However, even in the patients in the NBS group, some symptoms might not be preventable without continuous treatment.
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http://dx.doi.org/10.3390/ijns6030060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569964PMC
July 2020

Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening.

Mol Genet Metab Rep 2020 Sep 27;24:100611. Epub 2020 May 27.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

In Japan, carnitine palmitoyltransferase II (CPTII) deficiency has been included as one of the primary target diseases in the expanded newborn mass screening program since 2018. However, many cases of the severe infantile hepatocardiomuscular form of CPTII deficiency showed severe neurodevelopmental delay or sudden death, which indicated that management of CPTII deficiency in the acute phase remains to be studied in detail. Herein, we discuss two cases diagnosed by newborn mass screening. Patient 1 was under strict clinical management from the neonatal period, with >20 admissions in 14 months, while Patient 2 was managed using a relatively relaxed approach, with only 2 admissions in the same period. Patient 1 showed normal development; however, Patient 2 expired at the age of 1 year 2 months. To develop strategies for preventing sudden deaths in patients with CPTII deficiency, this retrospective study focused on detailed clinical management practices and biochemical findings during the acute phase. We also investigated the correlation between conventional biomarkers (such as creatine kinase) and long-chain acylcarnitines. We propose that strict monitoring and immediate medical attention, even in case of slight fever or minor abdominal symptoms, can help prevent sudden death in patients with CPTII deficiency. Considering the higher morbidity rate of such patients, strict and acute management of CPTII deficiency cannot be overemphasized.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260588PMC
September 2020

Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

Pediatr Blood Cancer 2020 07 23;67(7):e28341. Epub 2020 Apr 23.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Background: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood.

Procedure: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL.

Results: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease.

Conclusions: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.
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http://dx.doi.org/10.1002/pbc.28341DOI Listing
July 2020

Validation of Liquid Chromatography-Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses.

Int J Mol Sci 2020 Mar 16;21(6). Epub 2020 Mar 16.

Department of Pediatrics, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls were as follows: α-iduronidase (IDUA), 4.19 ± 1.53 µM/h; iduronate-2-sulfatase (I2S), 8.39 ± 2.82 µM/h; -acetyl-α-glucosaminidase (NAGLU), 1.96 ± 0.57 µM/h; -acetylgalactosamine-6-sulfatase (GALNS), 0.50 ± 0.20 µM/h; and -acetylgalactosamine-4-sulfatase (ARSB), 2.64 ± 1.01 µM/h. All patients displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly separated from controls, whereas there was some overlap between the control and patient groups in MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing simultaneous pretreatment and measurement of five enzymes relevant to MPSs.
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http://dx.doi.org/10.3390/ijms21062025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139616PMC
March 2020

Newborn screening for mucopolysaccharidoses: Measurement of glycosaminoglycans by LC-MS/MS.

Mol Genet Metab Rep 2020 Mar 10;22:100563. Epub 2020 Jan 10.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States of America.

Mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders which can lead to degenerative and irreversible skeletal, cardiovascular, pulmonary, and neurological damage. Current treatments, including hematopoietic stem cell transplantation and enzyme replacement therapy, have been found most effective if administered before clinical symptoms are present, highlighting the urgent need for the development of newborn screening. This study analyzed 18,222 dried blood spot samples from newborns for both enzyme activity and glycosaminoglycan (GAG) concentration levels. GAG levels were measured using liquid chromatography tandem mass spectrometry. Results were compared to our previously established cutoff values for three subtypes of GAGs: dermatan sulfate (DS) and heparan sulfate (HS0S and HSNS). Samples that were high for two of the three GAGs were identified and screened a second time. Samples were also measured for iduronate-2-sulfatase and alfa-L-iduronidase activity. A total of 300 samples were above the established cutoff values for at least two of the three GAGs after the first screening. One sample was determined through clinical and genetic testing to be a true positive for MPS II. The false positive rate after the first GAG screening was 1.64%. A Cochran's formula test showed that the samples available for the second screening were representative samples (p = .0000601). False positive rate after second GAG screening, extrapolated from the representative sample was 0.4%. False positive rate after enzyme activity assay by fluorimetry for IDUA and IDS enzymes was 0.21% and 0.18%. A combination of GAG and enzyme assays provided no false positive and false negative samples. Two-tier screening involving a combination of enzyme activity and multiple GAGs should be considered the gold standard for the diagnosis of MPS patients.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957835PMC
March 2020

Serum C14:1/C12:1 ratio is a useful marker for differentiating affected patients with very long-chain acyl-CoA dehydrogenase deficiency from heterozygous carriers.

Mol Genet Metab Rep 2019 Dec 5;21:100535. Epub 2019 Nov 5.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan.

Introduction: Various markers, such as C14:1 and the C14:1/C2 ratio, are used as diagnostic markers of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, the levels of these markers in patients with VLCADD overlap with those in heterozygous carriers and even healthy subjects.

Materials And Methods: In twenty-three affected patients and 15 heterozygous carriers with VLCADD, the accuracies of C14:1, C14:1/C12:1, C14:1/C2, and C14:1/C16 in dried blood spots (DBS) and serum were statistically estimated.

Results: Among the serum markers, the sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and validity of C14:1/C12:1 were superior to those of C14:1, C14:1/C2, and C14:1/C16, but C14:1/C2 demonstrated a statistical advantage compared with only C14:1 and C14:1/C16. Elevation in serum C14:1/C12:1 was observed in only one heterozygous carrier, whereas almost half of the carriers displayed false positive results for the other markers. Among the DBS markers, although the accuracy of C14:1/C2 was ostensibly the best, no statistical significance was observed.

Discussion: Serum C14:1/C12:1 might be useful for differentiating patients with VLCADD from heterozygous carriers. Although serum C14:1/C2 was significantly useful for the detection of VLCADD, this marker could not distinguish the affected patients from carriers. C14:1/C12:1 might be optimal compared with the other markers.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895747PMC
December 2019

Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.

PLoS One 2019 10;14(10):e0222931. Epub 2019 Oct 10.

Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, Osaka, Japan.

Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed "non-odonto") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL "c.1559delT" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786601PMC
March 2020

Clinical course in a patient with myopathic VLCAD deficiency during pregnancy with an affected baby.

JIMD Rep 2019 Sep 17;49(1):17-20. Epub 2019 Jul 17.

Department of Pediatrics Shimane University Faculty of Medicine Izumo Shimane Japan.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive mitochondrial fatty acid oxidation disorder that manifests in three clinical forms: (a) severe, (b) milder, and (c) myopathic. Patients with the myopathic form present intermittent muscular symptoms such as myalgia, muscle weakness, and rhabdomyolysis during adolescence or adulthood. Here, the clinical symptoms and serum creatine kinase (CK) levels of a pregnant 31-year-old woman with the myopathic form of VLCAD deficiency were reduced during pregnancy. Clinical symptoms rarely appeared during pregnancy, although she had sometimes suffered from muscular symptoms before pregnancy. When ritodrine was administered for threatened premature labor at 35 weeks of gestation, her CK level was elevated to over 3900 IU/L. She delivered a full-term baby via cesarean section but suffered from muscle weakness with elevated CK levels soon after delivery. It has been reported that an unaffected placenta and fetus can improve maternal β-oxidation during pregnancy. However, in our case, the baby was also affected by VLCAD deficiency. These suggest that the clinical symptoms of a woman with VLCAD deficiency might be reduced during pregnancy even if the fetus is affected with VLCAD deficiency.
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http://dx.doi.org/10.1002/jmd2.12061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718132PMC
September 2019

High incidence of status epilepticus and ongoing seizures on arrival to the hospital due to high prevalence of febrile seizures in Izumo, Japan: A questionnaire-based study.

Brain Dev 2019 Nov 12;41(10):848-853. Epub 2019 Aug 12.

Division of Health Administration and Promotion, Department of Social Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.

Objectives: To determine the incidence of prolonged febrile seizures and status epilepticus in the first three years of life.

Methods: A questionnaire was sent to 1560 families between April 2016 and March 2017 before their child attended a routine health check at three years of age in Izumo, Shimane prefecture, Japan. The questionnaire included an overview of febrile seizures, including the age at which febrile seizures occurred, the duration, and how the condition was managed.

Results: We received 1089 (69.8%) responses and these showed that 134 (12.3%) children had a history of febrile seizures. Fourteen children with febrile seizures (10.4%) had prolonged seizures lasting 10-30 min and six children (4.5%) had status epilepticus. Ongoing febrile seizures that did not terminate on arrival to the hospital were observed in 11 children (8.2%) with febrile seizures. The incidence rates of status epilepticus, prolonged febrile seizures including status epilepticus and ongoing febrile seizures were 184, 612 and 337 per 100,000 children aged 36 months or less, respectively.

Conclusions: There was a greater incidence of status epilepticus than previously thought, possibly due to the high prevalence of febrile seizures in Japan. Eight percent of children with febrile seizures were seizing on arrival to the hospital. These ongoing seizures requiring emergency interventions were almost twice more than status epilepticus. Thus, it is necessary to develop an early intervention for the termination of prolonged febrile seizures.
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http://dx.doi.org/10.1016/j.braindev.2019.07.009DOI Listing
November 2019

Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report.

Brain Dev 2019 Aug 11;41(7):638-642. Epub 2019 Apr 11.

Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia type II, is classically caused by a congenital defect in electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH). Flavin adenine dinucleotide synthase (FADS) deficiency caused by mutations in FLAD1 was recently reported as a novel riboflavin metabolism disorder resembling MADD. Here, we describe a Japanese boy with FADS deficiency due to a novel mutation (p.R249*) in FLAD1. In the asymptomatic male infant born at full term, newborn screening showed positive results with elevated C5 and C14:1 acylcarnitine levels and an increased C14:1/C2 ratio. Biochemical studies were unremarkable except for lactic acidosis (pH 7.197, lactate 61 mg/dL). A diagnosis of MADD was suspected because of mild abnormalities of the acylcarnitine profile and apparent abnormalities of urinary organic acids, although mutations in the ETFA, ETFB, ETFDH, and riboflavin transporter genes (SLC52A1, SLC52A2, and SLC52A3) were not detected. Administration of riboflavin and L-carnitine was initiated at one month of age based on the diagnosis of "biochemical MADD" despite a lack of symptoms. Nevertheless, the acylcarnitine profile was not normalized. Symptoms resembling bulbar palsy, such as vocal cord paralysis and dyspnea with stridor, were present from 3 months of age. At 4 months of age, he became bedridden because of hypoxic-ischemic encephalopathy due to fulminant respiratory failure with aspiration pneumonia. At 2 years and 5 months of age, a homozygous c.745C > T (p.R249*) mutation in the FLAD1 gene was identified, confirming the diagnosis of FADS deficiency. His severe clinical course may be caused by this nonsense mutation associated with poor responsiveness to riboflavin. Persistent lactic acidosis and neuropathy, such as bulbar palsy, may be important for diagnosing FADS deficiency. Although the biochemical findings in FADS deficiency are similar to those in MADD, their clinical symptoms and severity may not be identical.
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http://dx.doi.org/10.1016/j.braindev.2019.04.002DOI Listing
August 2019

Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency.

J Hum Genet 2019 Feb 6;64(2):73-85. Epub 2018 Nov 6.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1, Ennya, Izumo, Shimane, 693-8501, Japan.

Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in β-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.
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http://dx.doi.org/10.1038/s10038-018-0527-7DOI Listing
February 2019

[Clinical application of mesenchymal stem cells for hematological diseases].

Authors:
Takeshi Taketani

Rinsho Ketsueki 2018;59(10):2362-2372

Department of Pediatrics, Shimane University Faculty of Medicine.

Mesenchymal stem cells (MSCs) perform multiple functions, such as immunomodulation and tissue repair, and they are also capable of differentiation into bone, cartilage, and fat cells. Furthermore, an MSC culture method has been established, and clinical safety is guaranteed; therefore, MSCs can be clinically applied for the treatment of many diseases. MSC treatment for hematological diseases is expected to be effective against refractory acute graft-versus-host disease (GVHD). It is presently used for treating chronic GVHD, preventing GVHD, promoting the engraftment of hematopoietic stem cells, and treating refractory aplastic anemia. However, owing to the cellular properties of MSCs, there are some concerns including increases in relapse, the deterioration of infectious diseases, and tumor formation or malignant transformation of MSCs. In the present review, I describe the present situation, problems, and prospects of the clinical application of MSCs for treating hematological diseases, including recent topics such as placental-derived decidual stromal cells and highly purified MSCs.
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http://dx.doi.org/10.11406/rinketsu.59.2362DOI Listing
July 2019

Simultaneous transcatheter aortic valve implantation and endovascular aneurysm repair in a patient with very severe aortic stenosis with abdominal aortic aneurysm.

J Cardiol Cases 2018 Apr 10;17(4):123-125. Epub 2018 Jan 10.

Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan.

The safety of non-cardiac surgery is uncertain for asymptomatic patients with very severe aortic stenosis (AS). Herein, we describe a case involving an elderly and frail patient with asymptomatic, very severe AS. The patient was considered a high-risk candidate for aortic valve replacement (AVR); thus, transcatheter aortic valve implantation (TAVI) was planned. On perioperative examination, an abdominal aortic aneurysm (AAA) was observed, which required endovascular aneurysm repair (EVAR). To reduce the risks involved with sequential procedures, TAVI and EVAR were performed simultaneously. In patients with severe AS who are high-risk candidates for AVR, TAVI can be considered as an alternative therapy before non-cardiac surgery. In addition, the combined TAVI and EVAR procedure can reduce the risks associated with the perioperative period. < For patients with severe aortic stenosis who are high-risk candidates for aortic valve replacement (e.g. elderly patients with comorbidities), transcatheter aortic valve implantation (TAVI) can be considered as an alternative therapy before non-cardiac surgery. In addition, combining TAVI and endovascular aneurysm repair can reduce the perioperative risks compared with those for sequential procedures. However, additional research is needed.>.
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http://dx.doi.org/10.1016/j.jccase.2017.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149652PMC
April 2018

Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.

Mol Genet Metab Rep 2018 Sep 21;16:5-10. Epub 2018 May 21.

Department of Pediatrics, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan.

Background: Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records.

Materials And Methods: Selective screening for IMDs using gas chromatography-mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared.

Results: Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias.

Conclusion: The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.
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http://dx.doi.org/10.1016/j.ymgmr.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014585PMC
September 2018

Parental questionnaire study showed that annular ligament displacement was common in three-year-old children and almost a half had reoccurring episodes.

Acta Paediatr 2018 11 14;107(11):1983-1985. Epub 2018 Jun 14.

Faculty of Medicine, Division of Health Administration and Promotion, Department of Social Medicine, Tottori University, Yonago, Japan.

Aim: This study sought to determine the incidence of annular ligament displacement (ALD), also known as nursemaid's elbow, in the first 3 years of life.

Methods: A questionnaire was sent to 1098 families between August 2014 and July 2015 before their child attended a routine health check at 3 years of age in Izumo, Shimane prefecture, Japan. The questionnaire included a brief description about ALD, the age when ALD occurred and how the condition was managed.

Results: We received 784 (71.4%) responses and these showed that 61 (7.8%) children had a history of ALD and 31 (51%) were girls. The incidence was 2.6%, calculated by multiplying the number of children by the 3-year observation period. The mean and median ages of the first ALD occurrence were both 25 months. In addition, 28 (46%) children with ALD had a recurrence and the mean number of ALD episodes was 1.8 (range 1-5). The total number of ALD episodes was 108, and of these, 33 (30%) were seen at the hospital emergency department and 17 (16%) spontaneously resolved.

Conclusion: This study confirmed that ALD was a common occurrence in 3-year-old children and that there was a high rate of recurrence.
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http://dx.doi.org/10.1111/apa.14422DOI Listing
November 2018
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