Donati, M. A

La Marca, Giancarlo

Padrini, Letizia

Pasquini, E.

English

Florence Research

Early Human Development 89S4 (2013) S10–S11Metabolic newborn screening: between past and futureM.A. Donati *, L. Padrini, G. La Marca, E. PasquiniMetabolic and Muscular Diseases Unit, Department of Neurosciences, Anna Meyer Children’s Hospital, Florence, ItalyA R T I C L E I N F O A B S T R A C TKeywords:Newborn screeningTandem mass spectrometry (MS/MS)The introduction of new technologies such as tandem mass spectrometry (MS/MS) has lead to a major rev-olution in newborn screening for metabolic diseases: from “a test for a disease” (i.e. Guthrie test) to “a testfor many diseases”. On a single drop of blood it is now possible to analyze and quantify various metabo-lites, not only acylcarnitines and amino acids, but also adenosine and 2’-deoxyadenosine (for the detection ofADA-SCID) and lysosomal enzymes. Therefore a great potential can be seen in near future for the diagnosis ofdiseases for which there may be a specific and effective therapy.© 2013 Elsevier Ireland Ltd. All rights reserved.The introduction of new technologies such as tandem massspectrometry (MS/MS) has lead to a major revolution in newbornscreening programs: from the old wiew “a test for a disease”(i.e. Guthrie test) to the new concept “a test for many diseases”.Using a single drop of blood on Guthrie card (DBS, dried bloodspot), indeed, it is now possible to search and quantify variousmetabolites (acylcarnitines, amino acids) at the same time, thusdiagnosing numerous metabolic diseases: organic acidurias, fattyacids beta-oxidation defects, aminoacidopathies, urea cycle defects.From the late Nineties newborn screening programs experiences invarious Countries (Australia, USA, United Kingdom, Germany) madepossible the diagnosis of metabolic diseases in neonatal age, oftenin a pre-symptomatic phase [1].These diseases are rare individually, but show a high frequencywhen considering them as a group. If not correctely diagnosed, theycan lead quickly to death, or cause severe neurologic impairment.Early diagnosis by newborn screening allows the begin of thetherapy in a pre-symptomatic phase, than to performing a geneticcounseling. For these group of diseases, therapy consists in avoidingprolonged fast (i.e. beta oxidation defects) and/or following adietary regime (i.e. low provision of natural protein or fat) and,in some cases, supplementation with specific formulas. Otherpossibles therapies are vitamines and/or drugs [2].After a pilot study performed in 2002, Metabolic diseasesUnit at Meyer Children’s hospital in Florence started to managethe neonatal screening program using MS/MS since November2004, for all the babies born in Tuscany. Since 2010, we alsoprovide neonatal newborn screening for all the babies born inUmbria, with a total amount of 45,000 newborns screened peryear. To date, over 350,000 newborns had been analyzed, witha diagnostic rate of 1:1800. In our experience, some diseasesconsiderated rare or non esistent show conversely an high incidencein italian population. This is the case, for istance, of MCAD* Corresponding author.0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.(medium chain acylCoA dehydrogenase) deficiency. This conditioncan be associated to death after an acute illness, i.e. for Reyesyndrome, or even to Sudden infant death syndrome (SIDS). Innon-screened newborns and childrens, it is possible to hypotize amissed diagnosis whenever a sudden and unexpected death occurs.In Tuscany and Umbria (two regions in central side of Italy) MCADdeficiency shows an incidence of 1:27,000 screened newborns;diagnosed infants maintain to date good clinical condition byfollowing a simple dietary regime (regular meals and avoidanceof prolonged fasting, expecially during acute infectious illness).Newborn metabolic screening programs are at the moment carriedon in numerous others italian regions, with full or partial coverage:Liguria, Emilia Romagna, Campania, Sardinia, Lazio and Sicily.Moreover, newborn screening in LC-MS/MS allows the diagnosisof some inherited or acquired metabolic defects in the mother, i.e.sistemic carnitine’s defect (which can be associated to cardiomy-opathy) so maternal diagnosis can be considered another beneficialeffect of newborn screening programs. This is the case of maternalmethilmalonic acidaemia with hyperomocisteinaemia due to vita-mine B12 deficit. Propionylcarnitine (C3) is a metabolite includedin newborn screening programs for the detection of propionic/methilmalonic acidaemia and disorders of cobalamine metabolism.In mothers, vitamin B12 deficiency may be due to malabsorptionor vegan diet. In newborns and infants, cobalamin deficiency ismainly due to maternal vitamin deficiency and may be wors-ened by prolonged exclusive breastfeeding. Severe haematologic,metabolic and neurological disorders may occur in infants exclu-sively breastfeed by mothers who follow a strict vegetarian diet.We underline the importance of newborn screening with secondtier test (search for free methilmalonic acid on DBS) and combinedanalysis of acylcarnitines and omocisteine on mother’s blood in allcases of elevated C3. This approach allows a properly diagnosisof unrecognized vitamin B12 deficiency in the mother. Therapywith i.m. hydroxocobalamin in newborn and in the mother mayprevent potential damages. There is a debate on how many andwhich diseases should be screened, but certainly the availability ofM.A. Donati et al. / Early Human Development 89S4 (2013) S10–S11 S11an effective therapy in early stage is an important prerequisite forintroducing a disease in the panel. In 2006, The American College ofMedical Genetics (ACMG), a group made up of specialists in publichealth, health policy, ethics, and other sectors involved in neonatalscreening, carried out a rewiew of the literature relative to neonatalscreening and indicated, among diseases that could be consideredfor the inclusion in screening programs, some lysosomal storagediseases (LSD) such as mucopolysaccaridosis type I (MPS I), Fabrydisease, Pompe disease and Krabbe disease [3]. Arguments in favorof the inclusion of LSD in newborn screening panels have beenthe increasing availability of therapies (i.e. enzyme replacementtheraphy, bone marrow transplant) [4] and the probable underesti-mation, in some cases very substantial, of the LDS’ real prevalencein world population [5]. In recent years, the widespread use ofDBS combined with MS/MS has constituted a turning point for theanalysis of lysosomal enzymes associated to some storage diseases(Fabry, Gaucher, Pompe, Krabbe, Niemann-Pick A/B diseases andMucopolysaccharidosis I). It’s a strong, highly sensitive, rapid, cheapand non ivasive method; it’s suitable for screening projects both inthe neonatal population that in high-risk populations, both for thetargeted analysis of patients with specific symptoms. A single DBSallows multiple enzymatic analysis and, moreover, a high numberof samples can be analyzed simultaneously. In our laboratory whehave therefore developed methods of enzyme assay using MS/MSon DBS for the diagnosis of some LSD suitable to treatment:Fabry disease (α-galactosidase), Pompe disease (α-glucosidase) andMucopolysaccaridosis type I (α-iduronidase) [6]. Numerous expe-riences of newborn screening for lysosomal diseases have alreadybeen reported in international literature. A recent study of MS/MSenzyme assay for Fabry, Pompe and MPS I disease on 100,000DBS from anonymous newborn showed a combined prevalence of1:7500 (low enzyme activity confirmed with genetic moleculartest). [7]. The study concludes that simultaneous enzyme assay onMS/MS can be introduced into neonatal screening panel, and thatthis method has a predictive value equal to or better comparingwith the methods currently used for non-lysosomal diseases. In2006, an italian study estimated the incidence of Fabry diseasediagnosed by newborn screening (fluorimetric test on DBS) tobe 1:3100 (on a population consisting of 37,104 male infants)[5]. In Taiwan, Pompe disease was diagnosed by screening witha prevalence of 1:33,333 (on a population of 132,000 screenednewborns; age at diagnosis 9–22 days) [8]. From follow-up analysisof patients with Pompe disease there is an evidence that 100% ofthe patients diagnosed by screening in a presymptomatic phase areventilator-free; on the contrary, 50% of the patients diagnosed ina symptomatic phase (even those diagnosed within six months ofage) are ventilator-dependent [9]. Regarding European experiences,a neonatal screening on DBS for four LSD (Pompe, Fabry, Gaucherand Niemann Pick A/B) was conducted in Austria from January 2010in 34,736 newborns [10]. The study identified positive sampleswhich were then correlated with a specific condition: 2 cases ofGaucher disease, 4 cases of Pompe disease and 9 cases of Fabrydisease, with a complessive prevalence of 1:2315 births. Neonatalscreening by LC-MS/MS requires great organizational commitment,and high laboratoristic and clinical experience. A positive test mustbe followed by a rapid newborn recall, for laboratory confirmationtest and clinical treatment and follow up. New test and protocols(i.e. for low birthweight newborns) have been developed and canreduce the possibility of false positive and false negative tests, thusavoiding unnecessary stress or misdiagnosis.Conflict of interestThe authors have no conflict of interest to declare.References[1] Wilcken B, Wiley V, Hammond J, Carpenter K. Screening newborns forinborn errors of metabolism by tandem mass spectrometry. N Engl J Med2003;348:2304–12.[2] Saudubray JM, Van Den Berghe G, Walter JH. Inborn Metabolic Diseases:Diagnosis and Treatment, Fifth edition. Berlin: Springer-Verlag, 2012.[3] American College of Medical Genetics Newborn Screening Expert Group. New-born screening: toward a uniform screening panel and system – executivesummary. Pediatrics 2006;117:S296–307.[4] Desnick RJ. Enzyme replacement and enhancement therapies for lysosomaldiseases. J Inherit Metab Dis 2004;27:385–410.[5] Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H,Ponzone A, Desnick RJ. High incidence of later-onset Fabry disease revealedby newborn screening. Am J Hum Genet 2006;79:31–40.[6] La Marca G, Casetta B, Malvagia S, Guerrini R, Zammarchi E. New strategyfor the screening of lysosomal storage disorders: the use of the onlinetrapping-and-cleanup liquid chromatography/mass spectrometry. Anal Chem2009;81:6113–21.[7] Scott CR, Elliott S, Buroker N, Thomas LI, Keutzer J, Glass M, Gelb MH,Turecek F. Identification of infants at risk for developing fabry, pompe, ormucopolysaccharidosis-i from newborn blood spots by tandem mass spec-trometry. J Pediatr 2013;163(2):498–503. doi: 10.1016/j.jpeds.2013.01.031[Epub 2013 Mar 1].[8] Chien YH, Lee NC, Thurberg BL, Chiang SC, et al. Pompe disease in infants:improving the prognosis by newborn screening and early treatment. Pediatrics2009;124(6):1116–25.[9] Chien YH, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treat-ment make a difference. Pediatr Neonatol 201354(4):219–27. doi: 10.1016/j.pedneo.2013.03.009 [Epub 2013 Apr 28].[10] Mechtler TP, Satry S, Metz TF, De Jesus VR, Greber-Platzer S, Pollak A,Herkner KR, Strenbel B, Kasper DC. Neonatal screening for lysosomal storagedisorders: feasibility and incidence from a nationwide study in Austria. Lancet2012;379(9813):335–41.

Metabolic newborn screening: Between past and future

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Metabolic newborn screening: Between past and future

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