ABSTRACT
BACKGROUND: Automatic lancets have been reported to be superior to manual lancets in terms of pain and treatment time. However, no studies have yet been published comparing automatic lancet and needle puncture heel-prick blood sampling. The objective of this study was to compare the pain response and efficiency between the automatic lancet and needle at the time of heel blood sampling. The design was a randomized controlled trial. The inclusion criteria for the participants were a birthweight of â§1,500 g and a gestational age of â§30 weeks. METHODS: The study examined a total of 105 neonates who were randomized into an automatic lancet group (n = 53) and a needle group (n = 52). The parameters measured included blood collection time, number of calf squeezes, duration of audible crying, and the Neonatal Infant Pain Scale (NIPS) score. The main outcome measure was audible crying duration. RESULTS: The duration of audible crying was significantly shorter in the automatic lancet group when compared to the needle group (median 3 s, interquartile range (IQR) 0-33 s vs median 39 s, IQR 5-91.5 s, P = 0.0023). The NIPS score at the time of puncture was significantly lower in the automatic lancet group than in the needle group (median 1, IQR 0-5 vs median 5, IQR 3-6, P = 0.0060). There was no significant difference in the blood collection time and the number of calf squeezes between the two groups. The automatic lancet was found to be less painful than the needle puncture in neonatal heel-prick blood sampling with no significant difference in blood sampling time. CONCLUSION: The automatic lancet was found to be less painful than the needle puncture in neonatal heel-prick blood sampling with no significant difference in blood sampling time.
Subject(s)
Blood Specimen Collection/methods , Heel , Needles , Pain Measurement/methods , Blood Specimen Collection/adverse effects , Blood Specimen Collection/instrumentation , Crying , Female , Humans , Infant, Newborn , Male , Pain/etiology , Pain/prevention & control , Prospective StudiesABSTRACT
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.
Subject(s)
Corpus Callosum/pathology , Developmental Disabilities/genetics , Mucolipidoses/genetics , Transient Receptor Potential Channels/genetics , Child, Preschool , Developmental Disabilities/etiology , Female , Humans , Japan , Mucolipidoses/complicationsABSTRACT
Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A. Early diagnosis and treatment are important, although the diagnosis is difficult prior to 2â¯months of age. We present an unusually severe case of MD with skull fractures at the birth and repeated fractures during the neonatal period, with further examinations leading to diagnosis. The patient died due to hemorrhagic shock, due to multiple arterial occlusion despite initiation of copper-histidine therapy in early infancy. Bone fracture at birth and multiple arterial occlusion are very rare findings in MD. This unusual and severe presentation emphasizes the importance of early diagnosis and treatment. A congenital bone fracture should be considered as a possible presentation of MD, especially in cases without birth complications.
Subject(s)
Fractures, Bone/physiopathology , Menkes Kinky Hair Syndrome/diagnosis , Menkes Kinky Hair Syndrome/physiopathology , Arterial Occlusive Diseases/physiopathology , Cerebral Infarction/physiopathology , Humans , Infant, Newborn , MaleABSTRACT
An m.10158T>C mutation in MT-ND3, encoding a subunit of respiratory complex I, causes early-onset Leigh syndrome (LS), mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) syndrome, and LS and MELAS overlapping syndrome, presumably dependent on the ratio of heteroplasmy. Herein, we report a 4-year-old girl with heteroplasmic m.10158T>C mutation, showing an evolving age-dependent phenotype from LS to MELAS syndromes. She showed mild developmental delay during infancy, which was associated with magnetic resonance imaging lesions in the brain stem and basal ganglia. At the age of 4â¯years, she developed rapid neurological deterioration and intractable seizures, which was associated with recurrent multiple cerebral lesions as well as basal ganglia lesions. Her cerebral lesions were located predominantly in white matter and appeared at multiple areas simultaneously, unique characteristics that are distinct from typical MELAS. Two patients with LS-MELAS overlapping syndrome with m.10158T>C have been previously reported, however, this is the first patient with m.10158T>C showing significant age-dependent changes in clinical features and neuro-images, implying an age-dependent role of complex I in the developing brain.
Subject(s)
Electron Transport Complex I/genetics , Leigh Disease/genetics , MELAS Syndrome/genetics , Mutation , Brain/diagnostic imaging , Brain/growth & development , Child, Preschool , Disease Progression , Female , Humans , Leigh Disease/diagnostic imaging , Leigh Disease/physiopathology , MELAS Syndrome/diagnostic imaging , MELAS Syndrome/physiopathology , PhenotypeABSTRACT
The purpose of this study was to determine the accuracy of mean blood flow velocity (mean V) in the internal carotid artery (ICA) for prediction of outcome in infants with hypoxic-ischemic encephalopathy (HIE) exposed to therapeutic hypothermia (TH). Five newborns with HIE who met the criteria for TH were enrolled. Ultrasonography of the right and left ICA was performed before, during, and after TH. Mean V of the sampling point in each ICA was measured. Mean V was suppressed during TH and increased after rewarming in four infants with normal neurological development. In one infant with neurological disability, however, mean V increased during TH and decreased after therapy. In conclusion, cervical ultrasonography for ICA in infants during TH may be useful for the prediction of neurodevelopmental outcome.
Subject(s)
Blood Flow Velocity/physiology , Carotid Artery, Internal/diagnostic imaging , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/therapy , Ultrasonography/methods , Child, Preschool , Female , Humans , Hypoxia-Ischemia, Brain/diagnosis , Hypoxia-Ischemia, Brain/physiopathology , Infant , Infant, Newborn , MaleABSTRACT
We describe a novel mutation in DCX in a family in which a proband boy had classical lissencephaly and his mother had extremely mild subcortical band heterotopia. No factors that would make the mother's symptoms milder, such as somatic mosaicism or skewed X chromosome inactivation, were observed. From this family, we conclude that a DCX mutation causes a pleiotropic phenotype in the female even if X chromosome inactivation pattern is not skewed, and the novel missense mutation in DCX produced relatively mild dysfunction of the doublecortin protein.
Subject(s)
Brain/pathology , Classical Lissencephalies and Subcortical Band Heterotopias/genetics , Microtubule-Associated Proteins/genetics , Mutation , Neuropeptides/genetics , Adult , Child, Preschool , Doublecortin Domain Proteins , Doublecortin Protein , Female , Genetic Testing , Humans , Magnetic Resonance Imaging , Male , Mothers , PhenotypeABSTRACT
INTRODUCTION: Congenital hyperinsulinism and hyperammonemia (CHH) is caused by gain of function of glutamate dehydrogenase (GDH). The genetic abnormalities are known to be located in three specific regions on the GDH protein. We describe here three different missense mutations identified in five new Japanese patients with CHH. And to study the genotype-phenotype correlations in patients with GLUD1 mutations, we analyzed previously reported Japanese cases. METHODS: An Epstein-Barr virus-transformed lymphoblastoid cell line was established from the 5 patients and control subjects, and was used for enzymatic and molecular analyses. RESULTS: All patients developed seizures with loss of consciousness associated with hypoglycemia and had persistent hyperammonemia. All patients had similar basal GDH activity of lymphoblasts and insensitivity to GTP inhibition. Genetic studies identified heterozygous I444M mutation in Patient 11, S217C mutation in Patient 1, and H262Y mutation in Patients 2, 3, and 4. Patients 3 and 4 were child and father, respectively. COS cell expression study confirmed that I444M and H262Y mutations were disease-causing genes. CONCLUSIONS: We identified three mutations (I444M, H262Y, and S217C), and the former is a newly described mutation. A summary of 17 reported Japanese patients (10 boys and 7 girls) with GDH mutations showed 8 patients had mutation at the site of the GTP-binding region, 2 at the site of the antenna-like structure, and 7 at the site of the hinge region. Analysis of the reported cases showed no clear association between clinical phenotype and mutation sites. However, G446D mutation seems to be associated with serious abnormalities.
Subject(s)
Glutamate Dehydrogenase/genetics , Hyperinsulinism/genetics , Hypoglycemia/genetics , Mutation, Missense , Adolescent , Animals , COS Cells , Cell Line, Transformed , Child , Child, Preschool , Chlorocebus aethiops , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Glutamate Dehydrogenase/metabolism , Humans , Hyperinsulinism/complications , Hyperinsulinism/enzymology , Hypoglycemia/complications , Hypoglycemia/enzymology , Infant , Infant, Newborn , Japan , Male , Phenotype , Seizures/enzymology , Seizures/genetics , Transfection , Unconsciousness/enzymology , Unconsciousness/geneticsABSTRACT
INTRODUCTION: Hyperzincaemia and hypercalprotectinaemia with systemic inflammation, recurrent infections, hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive is an extremely rare disease and no therapy is reported. AIM: To evaluated the effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia in terms of serum cytokine level changes before and after treatment. METHODS: A 10-year-old girl was admitted suffering from pyoderma gangrenosum, hepatosplenomegaly, anemia that was unresponsive to iron supplementation, persistent inflammation, arthritis, and increased serum zinc. The level of serum calprotectin was extremely high; therefore, we diagnosed hyperzincaemia and hypercalprotectinaemia and started cyclosporine A treatment. Twelve cytokines in serum were measured before and one year after treatment. RESULTS: Cyclosporine A was very effective. Her skin lesion and joint pain were alleviated and quality of life was markedly improved. C-reactive protein had decreased and anemia had improved. While zinc levels had fallen, calprotectin remained at an extremely high level. Of the cytokines examined, interleukin -6 serum levels had fallen and interleukin -8 showed a marked reduction after treatment. CONCLUSION: Cyclosporine A is effective for hyperzincaemia and hypercalprotectinaemia. Serum interleukin -8 may be useful in assessing the therapeutic effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia.
Subject(s)
Cyclosporine/therapeutic use , Leukocyte L1 Antigen Complex/blood , Metabolism, Inborn Errors/blood , Metal Metabolism, Inborn Errors/blood , Zinc/blood , Child , Cytokines/blood , Female , Hepatomegaly/blood , Humans , Immunosuppressive Agents/therapeutic use , Inflammation/drug therapy , Pyoderma/blood , Splenomegaly/bloodABSTRACT
BACKGROUND: Female patients with ornithine transcarbamylase deficiency (OTCD) show a wide range of clinical severity, from asymptomatic to lethal hyperammonemia. It is important to establish a simple method to distinguish symptomatic from asymptomatic patients. METHODS: Uracil and orotic acid concentrations were analyzed in three female patients with OTCD at both the hyperammonemia-attack and interval stages. These concentrations were compared with those in asymptomatic female patients reported previously. RESULTS: Uracil concentrations in symptomatic female patients were uniformly higher than those in asymptomatic female patients at both the hyperammonemia-attack and interval stages. CONCLUSION: Uracil may present a useful index for detecting OTCD female patients who are destined to suffer from hyperammonemia attack. Further data on uracil concentrations are necessary to establish the threshold for distinguishing symptomatic from asymptomatic subjects.
Subject(s)
Ornithine Carbamoyltransferase Deficiency Disease/urine , Uracil/urine , Child, Preschool , Female , Heterozygote , Humans , Hyperammonemia/urine , Infant , Ornithine Carbamoyltransferase Deficiency Disease/genetics , Orotic Acid/urineABSTRACT
Deficiency of citrin due to mutations of the SLC25A13 gene causes adult-onset type II citrullinemia (CTLN2) and one type of neonatal intrahepatic cholestasis (NICCD). About half of the NICCD patients are detected based on high galactose, phenylalanine, and/or methionine concentrations on newborn mass screening (NMS). To clarify the perinatal and neonatal effects and the inconsistent results on NMS, we examined aminograms, the levels of bile acids and galactose in dried blood spots for NMS from 20 patients with NICCD. Birth weight was low for gestational age (-1.4 +/- 0.7 SD). Affected fetuses may have suffered intrauterine citrin deficiency. The first abnormality detected after birth was citrullinemia, and 19 of 20 patients had citrulline levels higher than +2 SD of controls. Tyrosine, phenylalanine, methionine, galactose, and bile acids were less affected than citrulline on d 5 after birth. Galactose and bile acids levels were increased at 1 mo in comparison with d 5 after birth due to impairment of the cytosolic NADH reducing-equivalent supply into mitochondria of hepatocytes. Patients with negative findings on NMS had low levels of total 20 amino acids. Citrulline/serine, citrulline /leucine plus isoleucine, and citrulline/total amino acids ratios, controlled for the confounding effect of low amount of total amino acids, were higher in all patients than +2 SD, +2 SD, and +3 SD of controls, respectively. NMS for citrin deficiency (frequency of homozygote with SLC25A13 mutation: 1/10,000-1/38,000 in East Asia) will be useful for clarification of the clinical course, treatment, and prevention of this disease.
Subject(s)
Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/genetics , Citrullinemia/diagnosis , Citrullinemia/genetics , Membrane Transport Proteins/genetics , Mitochondrial Proteins/genetics , Neonatal Screening/methods , Amino Acids/blood , Bile Acids and Salts/blood , Feasibility Studies , Female , Galactose/blood , Humans , Infant, Newborn , Male , Membrane Transport Proteins/deficiency , Mitochondrial Membrane Transport Proteins , Mitochondrial Proteins/deficiencyABSTRACT
Recently, a novel deoxyribonucleic acid (DNA) virus, designated SEN virus (SENV), was discovered and strong associations between the two SENV variants (SENV-D and SENV-H) and non-A to E hepatitis were reported. To clarify the character of SENV infection in children, we investigated the detection rates of serum SENV DNA by polymerase chain reaction (PCR) among children with non-A to C hepatitis, with histories of transfusions, with neither histories of transfusions nor liver diseases (control), and among pregnant women. SENV-D was detected in 60% of fulminant hepatitis, 5% of acute hepatitis, 11% of chronic hepatitis, 13% of controls, and 15% of pregnant women. SENV-H was detected in none of fulminant hepatitis, 5% of acute hepatitis, none of chronic hepatitis, 2% of controls, and 12% of pregnant women. No significant difference was found for SENV-D between acute or chronic hepatitis and controls, however SENV-D detection rate in fulminant hepatitis was significantly higher than that in controls (P < 0.05). No significant difference was found for SENV-H between any hepatitis and controls, however SENV-H detection rate in pregnant women was significantly higher than that in controls (P < 0.05). Neither SENV-D nor SENV-H was associated with acute or chronic hepatitis; however, SENV-D might be a risk factor of fulminant hepatitis.
Subject(s)
Circoviridae Infections/epidemiology , Circoviridae/isolation & purification , Base Sequence , Blood Transfusion , Child , DNA Primers , DNA, Viral/genetics , DNA, Viral/isolation & purification , Female , Humans , Japan/epidemiology , Polymerase Chain Reaction , Pregnancy , Pregnancy Complications, Infectious/virology , Prevalence , Risk Factors , Sensitivity and SpecificityABSTRACT
We analyzed the PHKA2 gene in four Japanese families with hepatic phosphorylase kinase (PhK) deficiency. Mutational analysis of PHKA2 cDNA was performed by reverse-transcribed polymerase chain reaction (RT-PCR) and direct sequencing, and each mutation was confirmed on the genomic DNA. In boys with low erythrocyte PhK activity (i.e., x-linked liver glycogenosis [XLG] type I), deletion of exon 2 (splice site mutation of 79-1 G > T) or nonsense mutation of Q1169X or R497X was identified. However, missense mutation of R295C was identified in one boy with normal erythrocyte PhK activity (i.e., XLG type II). This mutation was not found in 100 control alleles, and was considered responsible for presentation of the XLG type II phenotype. Excluding Q1169X, all mutations detected in this study represented novel mutations. All mothers were found to be heterozygous carriers of the mutations. Gene analysis was confirmed to represent a useful procedure for diagnosing XLG type II, for which liver biopsy had previously been required to detect hepatic PhK deficiency.
Subject(s)
Liver/enzymology , Mutation/genetics , Phosphorylase Kinase/genetics , Child, Preschool , Codon, Nonsense/genetics , DNA Mutational Analysis , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Erythrocytes/enzymology , Exons/genetics , Glycogen Storage Disease Type I/enzymology , Glycogen Storage Disease Type I/genetics , Hepatomegaly/etiology , Hepatomegaly/genetics , Hepatomegaly/pathology , Humans , Infant , Introns/genetics , Liver/pathology , Liver Function Tests , Male , Phosphorylase Kinase/deficiency , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND: In recent years, progressive familial intrahepatic cholestasis has been classified into at least three types by genetic analysis: PFIC1, PFIC2, and MDR3. Liver transplantation is effective for treating patients with this intractable syndrome. Confirming the correct diagnosis is of paramount importance because prognosis after transplantation differs with the genetic type of the disease. METHODS: Synthesis of cDNA was accomplished using RNA extracted from liver tissue of two Japanese patients with progressive familial intrahepatic cholestasis. Polymerase chain reaction was performed using 13 primer sets designed for amplification of the bile salt export pump cDNA. Direct sequencing was undertaken, and identified sequences were compared with the sequence for bile salt export pump gene registered with GenBank. In addition, gene sequences for nonprogressive familial intrahepatic cholestasis patients were analyzed. RESULTS: Genetic analysis of patient 1 revealed that substitutions in bile salt export pump protein sequences, namely R575X and E636G, might be the cause of the disease. In patient 2, V330X and R487H might fulfill the same role. Results of gene analysis in parents and cholestatic controls supported these conclusions. CONCLUSIONS: Absence or presence of bile salt export protein gene mutations was confirmed as representing a useful prognostic marker for clinical course after liver transplantation.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Cholestasis, Intrahepatic/genetics , Mutation , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Codon, Nonsense , DNA, Complementary/chemistry , DNA, Complementary/genetics , Female , Humans , Infant , Japan , Male , Mutation, Missense , Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
We report three patients with sporadic merosin-positive congenital muscular dystrophy (CMD) with torticollis and/or developmental dislocation of the hip in early childhood. Diagnosis of merosin-positive CMD was based on their clinical and dystrophic muscle biopsy findings. At the age 13 months, patient 1 was found to have developmental dislocation of both hips, which was surgically treated at 5 years. Patient 2 had severe torticollis and contracture of both hip joints which had been present since the neonatal period, and underwent repair of the torticollis at 2 years. Patient 3 was found to have developmental dislocation of the left hip at one month of age. Although she had generalized muscle hypotonia she learned to walk at 23 months. She had no facial muscle involvement nor contracture of joints, but had hyperlaxity of distal joints. Her muscle biopsy showed complete collagen VI deficiency immunohistochemically. In contrast to merosin-deficient CMD, merosin-positive CMD appears to be a group of heterogeneous diseases. Since collagen VI was reported to be defective in Ullrich's disease, patient 3 may be diagnosed as having Ullrich's disease but had no typical clinical characteristics of the disease. Further study is needed to identify the pathogenetic mechanism of congenital muscular dystrophy with early joint abnormalities to determine whether there is a primary abnormality of the connective tissue including collagen VI.
Subject(s)
Collagen Type VI/deficiency , Hip Dislocation, Congenital/complications , Muscular Dystrophies/congenital , Muscular Dystrophies/pathology , Adolescent , Child , Child, Preschool , Chromosomes, Human, Pair 6 , Collagen Type VI/genetics , Female , Humans , Laminin/analysis , Male , Muscular Dystrophies/genetics , Scoliosis/congenital , Torticollis/complicationsABSTRACT
BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) commonly appears as a complication of several pulmonary and non-pulmonary diseases. The hypoxia possibly inhibits Ca2+ +/- dependent K+ channels, thus resulting in membrane depolarization of pulmonary smooth muscle cells, which leads to the opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular smooth muscle. However, magnesium (Mg2+) is an antagonist of Ca2+. We studied the effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary hypertension and compared to the site of action of nitric oxide (NO). METHODS: Zero-day-old piglets were used in each experiment. The effects of Mg2+ were tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately every 10 min. In order to determine the exact mechanism of the Mg2+, Nw-nitro-l-arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with Mg2+ in some of the experiments. RESULTS: There was a significant correlation between the percent reduction of the pulmonary arterial pressure (PAP) caused by magnesium and the level of oxygen (O2) present in the pulmonary artery. The greatest amount of reduction was seen in the hypoxic condition where the least amount of O2 is found. A further reduction in the PAP was seen when NO was given at the end of the Mg2+ trials. There was no significant reduction seen in the systemic arterial pressure. CONCLUSIONS: Inhaled NO further reduced the PAP in piglets already treated with Mg2+.