Haruo Shintaku

Osaka Metropoliran University Graduate School of Medicine · Donated Course “Disability medicine and Regenerative medicine"

Purpose: To clarify staff awareness and the current status of facilities regarding end-of-life care and the planning for severely disabled children and adults. Methods: A questionnaire survey on ACP was conducted on all 466 staff members of a residential facility for children with medical disabilities. Results: The response rate was 77.0%; 20.2% of...

Menkes disease (MD) is an X-linked recessive disorder caused by mutations in ATP7A. Patients with MD exhibit severe neurological and connective tissue disorders due to copper deficiency and typically die before 3 years of age. Early treatment with copper injections during the neonatal period, before the occurrence of neurological symptoms, can alle...

Glucose metabolism has been the focus of research in order to understand pathological conditions associated with diseases such as neonatal hypoxic-ischemic-encephalopathy (HIE), cerebral palsy (CP) and cerebral infarction. [Objective] To evaluate the use of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy...

Mitochondrial disease presents a variety of clinical manifestations such as encephalopathy, diabetes, and cardiomyopathy. Mitochondrial encephalopathy includes mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome (LS), and MELAS/Leigh overlap syndrome. Mitochondrial encephalopathy has been modele...

Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging treatments, such as splicing modulation of SMN2 and SMN gene replacement therapy, have impro...

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs—nusinersen and onas...

Introduction: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the fac...

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder caused by a mutation in the autoimmune regulator gene. Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy typically exhibit hypoparathyroidism, adrenocortical failure, and chronic mucocutaneous candidiasis. The...

Objective Neonatal hypoxic–ischemic encephalopathy (HIE) causes permanent motor deficit “cerebral palsy (CP),” and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number...

Perinatal asphyxia is a well-known medical condition that can lead to cerebral palsy. Several etiologies are involved in this process, but the primary cause is hypoxic-ischemic encephalopathy (HIE) that is characterized by reduced blood flow and oxygen supply to the baby’s brain. Cerebral palsy is one of the possible consequences of this neurologic...

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carryi...

This open-label, phase 1/2 study (JMACCT CTR JMA-IIA00350) evaluated the efficacy and safety of intracerebroventricular idursulfase beta in patients with MPS II. Here, we report the 100-week results. Six patients with severe MPS II aged 23–65 months were enrolled. Idursulfase beta (increasing from 1 to 30 mg between weeks 0 and 24, followed by a 30...

Importance Sapropterin hydrochloride, a natural coenzyme (6R‐tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin‐responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. G...

Ischemic brain injury provokes complex, time-dependent downstream pathways that ultimately lead to cell death. We aimed to demonstrate the levels of a wide range of metabolites in brain lysates and their on-tissue distribution following neonatal stroke and cell therapies. Postnatal day 12 mice underwent middle cerebral artery occlusion (MCAO) and w...

Objective Baloxavir marboxil is a novel anti-influenza drug reported to have an early antiviral effect, although it also causes the appearance of variant viruses with a reduced susceptibility to baloxavir. In Japan, four neuraminidase inhibitors (NAIs) have been commonly used to treat patients with influenza. In clinical practice, the differences i...

Autologous UCBSCs for newborn HIE are safe and feasible, and warrant a larger and controlled phase II study. Good results in the number and stability of UCBCs were obtained with the effects of land transportation. Hypoxic-ischemic encephalopathy (HIE) occurs in 0.5-1.0 per one thousand newborns and leads to cerebral palsy (CP).Therapeutic hypotherm...

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to exa...

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 sym...

Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symp...

Sepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH 4 ) synthesis. ¹ Unlike other forms of BH 4 -deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening...

Neuronal ceroid lipofuscinosis (NCL) is lysosomal storage disease caused by accumulation of ceroid/lipofuscin in various tissues, which leads to devastating brain disorders. The NCL consisted of 14 different genetic types and among these, we focused on NCL 1 and 2. NCL 1 is caused by the deficiency of palmitoyl protein thioesterase (PPT1), whereas...

Background Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. Methods We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4–17 years who visited the periodical...

Introduction Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood–brain barrier in...

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-d...

Cell-based therapy is attracting attention not only for its regenerative property but also for its long therapeutic time window. A growing number of studies in animal models with brain injuries have shown that cell therapies are beneficial. Among the variety of cell types to be used for cell therapies, autologous umbilical cord blood cells (UCBCs)...

CD34 surface antigen has been extensively used as a marker for hematopoietic stem cells in adult bone marrow. Cord blood contains high number of hematopoietic and non-hematopoietic stem/progenitor cells. This chapter focuses on recent progresses in stem cell biology on cord blood cells. During embryonic development, expression of CD34 is tightly re...

In Japan, we started autologous cord blood therapy for newborns with HIE in 2014 (described in Chap. 1). Another research group started autologous cord blood therapy for patients with cerebral palsy in 2017. However, cerebral palsy is induced in nearly twice as many premature babies with IVH and PVL as that by term newborns with HIE (Touyama et al....

We first characterized PPT1 and TPP1 enzymes in dried blood spots (DBS), plasma/serum, and leukocytes/lymphocytes using neuronal ceroid lipofuscinosis (NCL) 1 and 2 patients and control subjects. PPT1 enzyme had only one acid form in control DBS, plasma/serum, and leukocytes/lymphocytes and showed deficient activities in these samples from NCL 1 pa...

Purpose: For a diagnosis of Rasmussen syndrome (RS), clinical course together with electroencephalography (EEG) and magnetic resonance imaging (MRI) findings are considered important, but there are few reports on functional neuroimaging. This study investigated cerebral blood flow (CBF)-single photon emission computed tomography (SPECT), central b...

This book provides a wealth of insights, advances and new perspectives on cell therapy for different types of neonatal ischemic disease, such as Hypoxic-Ischemic Encephalopathy (HIE), Periventricular Leukomalacia (PVL) and neonatal infarction. These diseases pose serious challenges for neonatologists and neurologists, because the severe sequelae le...

Neonatal ischemic brain injury causes permanent motor-deficit cerebral palsy. Hypoxic-ischemic encephalopathy (HIE) is a very serious condition that can result in death and disability. In 1997, we reported that irreversible neuronal cell damage is induced by the elevation of intracellular Ca ion concentration that has occurred in sequence after exc...

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease that results in the accumulation of very long chain fatty acids (VLCFA) in plasma and all tissues. Recent studies regarding cerebral X-ALD (CALD) treatment emphasize the importance of its early diagnosis. 26:0 lysophosphatidylcholine (LysoPC) is a sensitive biomarker for ne...

Objective To evaluate current attitudes and barriers to advance care planning for adolescent patients with life-threatening conditions among paediatric neurologists. Design Cross-sectional study. A self-reported questionnaire was administered to assess the practice of advance care planning, advance directives and barriers to advance care planning...

The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders; a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD)....

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for Mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiological findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were colle...

Background: A patency capsule (PC) can help predict capsule endoscope (CE) retention; however, PC tolerability is unknown in children. We retrospectively evaluated PC tolerability in school-aged children. Methods: Sixty-one patients (median age, 12.9 years; range 7.4-17.3 years) who underwent PC examination were analyzed for occurrence and deter...

Background After the A/H1N1 influenza pandemic in 2009, two new drugs against the influenza virus, laninamivir and peramivir, were released in 2010 in Japan. We investigated the current usage and effectiveness of influenza medications and factors related to the time taken to alleviate fever. Methods Patients diagnosed with influenza during the 201...

Turner syndrome results from the entire or partial loss of the second X chromosome, and is associated with a number of medical problems. Affected women require long-term medical follow-up. This study investigated the status of medical follow-up focusing on the transition for young adult women with Turner syndrome (TS). The clinical profiles of 63 w...

BACKGROUND Chorioamnionitis (CAM) is an important risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. OBJECTIVES To evaluate the effects of CAM on the development of BPD using interleukin 6 (IL-6), Krebs von den Lungen 6 (KL-6), and transforming growth factor β1 (TGF-β1) in the amniotic fluid as markers for infl...

Osteogenesis imperfecta (OI) is a heterogeneous disorder that is characterized by bone fragility and systemic complications, and is mainly caused by gene mutations in COL1A1 or COL1A2. A novel COL1A1 splicing mutation, c.750+2T>A, was identified in a Japanese OI family. Only the proband in this family showed various complications, such as heart val...

Background: Inborn errors of metabolism (IEM) are rare genetic disorders in which a single gene defect causes a clinically significant block in a metabolic pathway. Clinical problems arise due to either accumulation of substrates that are toxic or interfere with normal function, or deficiency of the products that are used to synthesize essential c...

Objective: To evaluate differences between pediatricians and internists in the practice of and barriers to advance care planning (ACP) for adolescent patients with cancer. Study design: A self-reported questionnaire was administered to assess the practice of ACP, advance directives, and barriers to ACP for adolescent patients with cancer. All 33...

Background: Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes/Leigh overlap syndrome (MELAS) is caused by defects in the mitochondrial respiratory chain. It is still largely unknown how these mitochondrial respiratory chain defects affect cellular metabolisms and lead to variable clinical phenotypes. Here, we analyzed m...

Background and Aims Pediatric use of liver transient elastography (TE) is attractive for its non-invasiveness, but reference values have not been established. We aimed to determine reference values for TE in children. Methods In pediatric patients (1 to 18 years), TE (FibroScan®) with an M probe was used for both liver stiffness measurement (LSM)...

FibroScan and laboratory data of 57 adolescents. (DOCX)

FibroScan and laboratory data of 20 preschoolers. (DOCX)

FibroScan and laboratory data of 46 elementary school children. (DOCX)

Insulinoma is generally identified as a single tumor and seldom occurs in children or adolescents. A 14-year-old girl with difficulty in waking was found to have hyperinsulinemic hypoglycemia. On abdominal ultrasonography two hypoechoic masses (8 and 12 mm in diameter) were seen in the pancreatic body: the larger mass was hypervascular, whereas the...

Background: Hemizygous mutations in the immunoglobulin superfamily member 1 (IGSF1) gene have been demonstrated to cause congenital central hypothyroidism in males. We report one family with a novel mutation of the IGSF1 gene located on the long arm of the X chromosome. Patient findings: A two-month-old boy was diagnosed with central hypothyroid...

Background Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis. Methods This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n =...

Aim: To evaluate whether aggressive nutrition can improve long-term neurodevelopmental outcomes and growth in extremely low birth weight (ELBW) infants born appropriate for gestational age (AGA). Methods: This single-center cohort study included 137 ELBW AGA infants born in two epochs. The first group received standard nutrition (SN; n=79) consi...

Diabetes mellitus (DM) during pregnancy causes congenital malformation, macrosomia, respiratory distress syndrome, and other abnormalities in neonates, but whether maternal DM affects the neonatal innate immune system is unknown. Therefore we aimed to reveal the influence of DM in pregnancy on the toll-like receptor (TLR)–mediated innate immune res...

Background: We investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) on human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), which is characterized by fibrosis and changes in the alveolar epith...

In this study, we investigated the efficacy and safety of administration of Linezolid (LZD) to pediatric febrile neutropenia (FN) patients after cancer chemotherapy. The study period was from January 2008 to June 2014, and the subjects were patients under the age of 16 receiving LZD administration (9 subjects, 16 cases, average age 9.2 ± 4.4 years)...

Ring chromosome 6 is a rare chromosome abnormality that arises typically de novo. The phenotypes can be highly variable, ranging from almost normal to severe malformations and neurological defects. We report a case of a 3-year-old girl with mosaic ring chromosome 6 who presented with being small for gestational age and intellectual disability, and...

BACKGROUND: Pediatricians sometimes see patients with severe aseptic meningitis and prolonged fever or severe headache, or both. This condition generally has a good prognosis and is usually treated with supportive therapy. However, there is neither guideline nor consensus for the treatment of patients with severe aseptic meningitis. Here, we invest...

Objective: This study measured serum and follicular fluid (FF) levels of biopterin, neopterin, vascular endothelial growth factor (VEGF), and macrophage colony-stimulating factor (M-CSF) in patients receiving mild ovarian stimulation for oocyte retrieval. Patients and methods: Infertile patients who underwent ovarian stimulation were divided int...

The objective of this study was to identify factors affecting on errors in carbohydrate (CHO) content estimation during CHO counting. Thirty-seven type 1 diabetes patients and 22 of their parents and 28 physicians/dieticians were enrolled in this study. CHO counting was counted in “Carb”, with 1 Carb defined as 10 g of CHO. To evaluate the accuracy...

Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described. We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4-15years, mean 10.5years) and follo...

Background & aims: The utility of transient elastography (FibroScan) is well studied in adults but not in children. We sought to assess the feasibility of performing FibroScans and the characteristics of FibroScan-based liver profiles in Japanese obese and non-obese children. Methods: FibroScan examinations were performed in pediatric patients (...

To investigate the differences in toll-like receptor (TLR)-mediated immune responses between human neonates and adults, focusing on the cytokine profiles of monocytes, dendritic cells (DCs), and monocyte-derived DCs (MoDCs) in cord and adult blood. Purified monocytes, DCs, and MoDCs were stimulated with the following TLR ligands: lipopolysaccharide...

Phenylketonuria (PKU) is caused by a defect in phenylalanine hydroxylase (PAH). More than 500 mutations have been reported for the gene encoding PAH. However, approximately 1%-5% of these include large deletions and large duplications that cannot be detected by conventional methods. In this report we tried to fully characterize a PAH-deficient pati...