Tandem Mass Spectrometry in Newborn Screening a Primer for Neonatal and Perinatal Nurses
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LWW/JPNN AS239-05 January 26, 2004 16:48 Char Count= 0 CONTINUING EDUCATION J Perinat Neonat Nurs Vol. 18, No. 1, pp. 41–58 c 2004 Lippincott Williams & Wilkins, Inc. Tandem Mass Spectrometry in Newborn Screening A Primer for Neonatal and Perinatal Nurses Sandra A. Banta-Wright, MN, RNC, NNP; Robert D. Steiner, MD Since 1961, newborn screening for errors of metabolism (EM) has improved the diagnosis, treat- ment and outcome of newborns with an EM. Recently, advances in laboratory technology with tandem mass spectrometry (MS/MS) has increased the identification of newborns with an EM. With a single dried filter paper blood spot (Guthrie R, Susi A. A simple phenylalanine method for detecting PKU in large populations of newborn infants. Pediatrics. 1963;32:338–343), MS/MS can identify more than 30 disorders of metabolism. This review will explore MS/MS to provide a better understanding of the development and application of this technology to newborn screening for perinatal and neonatal nurses. Key words: errors of metabolism, metabolic diseases, newborn screening, tandem mass spectrometry N 1961, Dr Robert Guthrie developed a sen- tion of a diet low in phyenylalanine resulted in Isitive, but simple and inexpensive, screen- normal cognitive development, rather than se- ing test for phenylketonuria (PKU).1 This vere mental retardation associated with classi- screening test used a bacterial inhibition as- cal PKU.2 By 1962, Oregon and Massachusetts say of dried blood collected on filter paper began screening every newborn in those to measure phenylalanine. With early identi- states for PKU.3 By the late 1960s, the practice fication of newborns with PKU, earlier initia- of routine newborn screening for PKU had expanded to almost every state and soon af- terward to most developed countries. Within 2 decades, all states had instituted univer- From the School of Medicine (Ms Banta-Wright sal newborn screening for PKU.4–7 Subse- and Dr Steiner), the School of Nursing, quently, newborn screening programs have (Ms Banta-Wright), the Division of Metabolism, Departments of Pediatrics & Molecular and Medical added screening tests for other disorders, Genetics, Child Development & Rehabilitation including amino acidopathies, galactosemia, Center, and the Doernbecher Children’s Hospital (Dr congenital hypothyroidism, and sickle cell dis- Steiner), Oregon Health & Science University, Portland, Ore. ease. The disorders were added based upon principles of newborn screening. Before a dis- Corresponding author: Sandra A. Banta-Wright, MN, RNC, NNP,CDRC-P,Division of Metabolism, Department ease is considered suitable for addition to the of Pediatrics, Child Development & Rehabilitation Cen- newborn screening test, it should meet the ter, Oregon Health & Science University, 707 SW Gaines following criteria proposed by Wilson and Rd, Portland, OR 97239 (e-mail: [email protected]). Jungner8: Reprints: Sandra A. Banta-Wright, MN, RNC, NNP,CDRC- 1. It should be frequent and severe enough P, Division of Metabolism, Department of Pediatrics, Child Development & Rehabilitation Center, Oregon to be a public health concern. Health & Science University, 707 SW Gaines Rd, Port- 2. It should cause a documented spectrum land, OR 97239. of symptoms. The author has no conflict of interest. 3. The screening test must be reliable, sim- Submitted for publication: October 2, 2003 ple, and have a low incidence of false- Accepted for publication: November 21, 2003 positive and false-negative results. 41 LWW/JPNN AS239-05 January 26, 2004 16:48 Char Count= 0 42 JOURNAL OF PERINATAL AND NEONATAL NURSING/JANUARY–MARCH 2004 4. The disease should be treatable to a de- per chromatography was too sensitive for uti- gree to decrease the significant negative lizing to screen newborn blood within the outcomes, such as death. first days of life when the majority of spec- 5. The appropriate confirmatory diagnos- imens are collected. Next, thin-layer chro- tic tests must be readily available. matography was explored for screening new- 6. There must be an established follow-up born urine.18 This form of chromatography program. had several disadvantages.18 First, the urine 7. There should be a positive cost-benefit specimen could not replace blood in detect- ratio to society. ing either PKU or congenital hypothyroidism. These principles emphasize the goals of The second issue was the collection of urine newborn screening.8–10 Few tests and condi- specimens after discharge from the nursery— tions, however, will fulfill all of these crite- a logistic nightmare for the parents and the ria and the effect of treatment may not be healthcare providers. Third, the concentra- known for years after a test is introduced. Al- tion of urine varies from being highly con- most all of the disorders screened and iden- centrated and producing false-positive results tified by newborn screening programs are to highly dilute and causing false-negative re- Mendelian conditions. However, increasingly sults. Lastly, several of the disorders identi- other conditions, such as HIV and congenital fied by urine analysis are benign, such as his- toxoplasmosis, have been included in some tidinemia and Hartnup disorder. As a result, screening programs.11,12 For a few of the dis- newborn urine screening based upon chro- orders, the evidence for efficacy of early med- matography has been discontinued.19 Univer- ical intervention that early screening allowed sal newborn screening continued to rely on was overwhelming, as with PKU and con- the “one test-one disorder” system. With ad- genital hypothyroidism.2,13 In other cases, the vances in technology, tandem mass spectrom- benefits of medical intervention are less dra- etry (known as MS/MS) has changed universal matic, but are significant enough to warrant newborn screening.20,21 The use of MS/MS al- screening; an example is galactosemia. Early lows for screening of multiple metabolic dis- identification of newborns with classical orders using a single analytical run. With this galactosemia prevents the early death from technology, a numerous array of metabolic hepatocellular damage and gram-negative disorders, including amino acids disorders, sepsis.14 However, a survey of 350 cases re- fatty acid oxidation disorders, and organic vealed that most patients with classical galac- acidemias have been identified during the tosemia, even if diagnosed early and treated, neonatal period many times prior to a catas- have lower IQ than expected, speech and trophic event (Table 1).25–29 The purpose of motor dysfunction, and growth and ovarian this review on MS/MS is to provide a bet- failure.15 The screening prevented mortality, ter understanding of this powerful technol- but not the long-term sequelae. ogy and why it is important for nurses to As more disorders were added to the orig- understand. inal screening for PKU, the laboratory needs increased as each disorder had a separate bac- terial assay. Screening needed to be more effi- MASS SPECTROMETER cient and comprehensive. The development of a single assay system that could be used A tandem mass spectrometer is a type to detect several disorders rather than a sys- of analytical instrument used in laboratories tem of separate bacterial assays for each dis- known as a mass spectrometer (Fig 1).30 order was desired. The use of chromatogra- The mass spectrometer instrument was de- phy, which provides analysis by producing veloped more than 20 years ago.20,31 This in- bands of color at different levels on a column, strument can analyze numerous compounds, rather than bacterial assays was tried.16,17 Pa- such as those in body fluids, environmental LWW/JPNN AS239-05 January 26, 2004 16:48 Char Count= 0 Tandem Mass Spectrometry in Newborn Screening 43 Table 1. Summary of disorders detectable through tandem mass spectrometry during the neona- tal period.∗ Amino acid disorders Fatty acid disorders Organic acid disorders Argininemia Carnitine/acylcarnitine 2-methylbutyryl- Argininosuccinic Acid translocase deficiency (CAT) CoAdehydrogenase deficiency (ASA) lyase deficiency) Carnitine palmitoyl transferease (2MBCD or SBCAD) Citrullinemia (ASA deficiency, type I (CPT-I) 2-methyl-3-OH butyric aciduria synthetase deficiency) Carnitine palmitoyl transferase 3-methylcrotonyl-CoA carboxylase Homocystinuria (HCU) deficiency, type II (CPT-II) deficiency (3MCC) Hyperphenylalaninemias Carnitine transport defect 3-methylgluta-conyl-CoA hydratase (PKU, HPhe) Long chain 3-hydroxyacyl-CoA deficiency Classical PKU, Hyper- dehydrogenase (LCHAD) 3-hydroxy-3-methylglutaryl-CoA phenylalaninemia, deficiency/Trifunctional lyase deficiency (HMG) Biopterin cofactor protein deficiency (TPF) Glutaric acidemia, type I (GA-I) defects Medium chain acyl-CoA Isovaleric acidemia (IVA) Maple syrup disease dehydrogenase (MCAD) Malonic acidemia (MSD) deficiency Methylmalonic acidemias (MMA) Multiple acyl-CoA Mitochondrial acetoacetyl-CoA dehydrogenase deficiency thiolase deficiency (SKAT, BKT, (MADD or GAII, Glutaric 3-ketothiolase deficiency, β acidemia, type II) ketothiolase) Very long chain acyl-CoA Multiple carboxylase deficiency dehydrogenase (VLCAD) (MCD) deficiency Propionic acidemia (PA) ∗Adapted from Millington and Koeberl,22 Zytkovicz et al,23 and Rashed et al.24 contaminates of water, foods, and pharmaceu- TANDEM MASS SPECTROMETER ticals. Simplistically, the mass spectrometer weighs molecules (Fig 2). Molecules are ex- The tandem mass spectrometer was further tremely small and cannot be weighed in the refined a decade ago for clinical use by re- usual