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Clinical Issues in Neonatal Care Linda Ikuta , MN, RN, CCNS, PHN , and Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editors Clinical Issues in Neonatal Care 2.5 HOURS Continuing Education Deconstructing Black Swans An Introductory Approach to Inherited Metabolic Disorders in the Neonate Nicholas Ah Mew , MD ; Sarah Viall , MSN, PPCNP ; Brian Kirmse , MD ; Kimberly A. Chapman , MD, PhD ABSTRACT Background: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy. Purpose: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult. Methods/Search Strategy: An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed. Findings/Results: Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar. Implications for Practice: When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly. Implications for Research: Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve. Key Words: autopsy , inborn errors of metabolism , neonatal screening , neonate , review ediatric and neonatal healthcare providers often An IMD is a genetic defect (or mutation) that believe that inherited metabolic disorders interferes with normal metabolism. This genetic (IMDs, or the more archaic and nearly synony- defect typically results in a deficiency of an enzyme, P mous term, “inborn errors of metabolism”) are eso- leading to accumulation of the enzyme’s substrates teric and ultra-rare, characterized by obscure but (which may be toxic), and a lack of the enzyme’s pathognomonic symptoms, and treated with idiosyn- products (which may be necessary for other chemi- cratic cocktails of unpronounceable medications. The cal reactions). See Table 1 for abbreviations used general sentiment is that metabolism is difficult to throughout this article. learn and seldom relevant, but this is far from true. The first course of action when an IMD is suspected Whereas individual metabolic disorders are rare, col- in a neonate is to consult a metabolic specialist, but lectively their incidence is approximately 1 in 1000,1 neonatal caregivers will also be called on to proceed and therefore the average neonatal intensive care unit with appropriate investigations and safe therapies in (NICU) would be expected to see several cases each the acute setting, pending specialist consultation. The year. Most NICU staff are familiar with the newborn objective of this review article is to help neonatal clini- metabolic screen, a nationwide state-sponsored pro- cians recognize when symptoms in the newborn might gram that screens virtually all newborns, sick or well, be caused by an IMD and provide guidance for the for treatable IMDs. Therefore, being able to imple- immediate management of the infant. It also describes ment a generalized approach to metabolic disorders, a general classification of IMDs, the common clinical rather than being knowledgeable about every IMD manifestations in the newborn period, and the man- that can affect newborns, is important. agement of abnormal newborn screening (NBS) results in the sick or well child. Author Affiliation: Division of Genetics and Metabolism, Children’s National Health System, Washington, District of Columbia. CLASSIFICATION OF IMD S All authors have reviewed and have contributed significantly to this manuscript. No author claims any conflict of interest. No honorarium, grant, or other form of payment was received for the production of this Metabolic disorders may broadly be classified in the manuscript. following 4 categories, based on the underlying met- Correspondence: Nicholas Ah Mew, MD, Division of Genetics and abolic defect 2 , 3 : Metabolism, Children’s National Health System, 111 Michigan Ave, NW, Washington, DC 20010 ( [email protected] ). • Intoxication-type disorders Copyright © 2015 by The National Association of Neonatal Nurses • Disorders of energy metabolism DOI: 10.1097/ANC.0000000000000206 • Disorders of complex molecule metabolism Advances in Neonatal Care • Vol. 15, No. 4 • pp. 241-247 241 Copyright © 2015 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited. AANC-D-15-00047_LRNC-D-15-00047_LR 224141 222/07/152/07/15 77:44:44 AAMM 242 Ah Mew et al TABLE 1. Abbreviations intrauterine development (no dysmorphism, struc- tural abnormalities, or impaired organ develop- ACMG American College of Medical Genetics ment). No symptoms are seen in the first hours of CSF Cerebrospinal fl uid life, and presentation typically occurs only after DNA Deoxyribonucleic acid exposure to the toxin or its precursors, between days 2 and 7 of extra-uterine life at the earliest. 2 , 4 EDTA Ethylenediaminetetraacetic acid GABA Gamma-aminobutyric acid Disorders of Energy Metabolism IMD Inherited metabolic disorder The common feature of these disorders is a defi- IQ Intelligence quotient ciency in energy production or energy utilization. Because most energy is derived in vivo from carbo- NICU Neonatal intensive care unit hydrate or fat, disorders in this category primarily PKU Phenylketonuria result from defects in the enzymes that process these macronutrients. Disorders of energy metabolism fre- quently present with hypoglycemia, with or without • Disorders of neurotransmission lactic acidosis, particularly in response to a pro- Examples of disorders in each classification of longed fast. Hypoketonuria in the setting of hypo- IMDs are provided in Table 2 . glycemia is a hallmark biochemical finding in these disorders. 2 Intoxication-type Disorders The intracellular organelle—the mitochondrion— Intoxication-type disorders are characterized by the is required for both carbohydrate and fat metabo- accumulation of toxic small molecules, which may lism. Impaired mitochondria, as in the disorders of transit through cell membranes, and produce pathol- the mitochondrial electron transport chain, may ogy at a distant site. In the developing fetus, the result in symptoms of both dysfunctional carbohy- toxin is completely removed via placental exchange; drate and fat metabolism. Mitochondrial disorders therefore, there is an expectation of normal may present as early as the first day of life and affect TABLE 2. Broad Categories of IMDs and Examples of Specific Disorders Classification Examples Intoxication-type disorders Galactosemia • Aminoacidopathies Tyrosinemia, maple syrup urine disease • Organic acidopathies Propionic acidemia, methylmalonic acidemia • Urea cycle disorders Ornithine transcarbamylase defi ciency, citrullinemia Disorders of energy metabolism Carbohydrate metabolism • Disorders of glycogen metabolism Glycogen storage disease type 0 or type Ia • Disorders of glucose utilization Pyruvate dehydrogenase defi ciency • Disorders of gluconeogenesis Fructose 1,6-bisphosphatase defi ciency Fat metabolism • Fatty acid oxidation disorders Medium-chain acyl CoA dehydrogenase defi ciency Carnitine uptake defi ciency • Disorders of ketone metabolism β -ketothiolase defi ciency Impaired mitochondria • Electron transport chain disorders Mitochondrial encephalomyopathy, lactic acidosis and stroke- like episodes (MELAS) Myoclonic epilepsy with ragged-red fi bers (MERRF) Leigh disease Disorders of complex molecule metabolism Lysosomal disorders Niemann-Pick type C, mucopolysaccharidoses, Pompe Peroxisomal disorders Zellweger, neonatal adrenoleukodystrophy Glycosylation disorders Congenital disorder of glycosylation, type 1a Disorders of sterol metabolism Smith-Lemli-Opitz Disorders of neurotransmission Disorders of GABA metabolism GABA-transaminase defi ciency, succinic semialdehyde Disorders of sulfi te metabolism dehydrogenase defi ciency Disorders of glycine metabolism Sulfi te-oxidase defi ciency, Molybdenum cofactor defi ciency Glycine encephalopathy (nonketotic hyperglycinemia) Abbreviations: GABA, γ -aminobutyric acid; IMD, Inherited metabolic disorder. www.advancesinneonatalcare.org Copyright © 2015 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited. AANC-D-15-00047_LRNC-D-15-00047_LR 224242 222/07/152/07/15 77:44:44 AAMM Approach to Inherited Metabolic Disorders 243 the most energy-dependent organs, such as the brain, TABLE 3. Sample IMDs by Predominant heart, muscle, and liver. Presenting Feature Disorders of Complex Molecule Metabolism Presenting Differential Diagnosis of Common These disorders result from accumulation of large Feature IMDs molecular-weight compounds that cannot easily Altered mental Intoxication-type disorder cross membranes, and therefore, they collect and status Aminoacidopathy cause pathology at the site of production. This Maple syrup urine disease gives rise to several common features of these dis- Organic acidopathy Propionic acidemia orders. In contrast to the intoxication-type disor- Methylmalonic acidemia ders, in complex molecule metabolism disorders, Urea cycle disorder detoxification by the placenta is not possible. Accu- Disorder of energy metabolism mulation
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