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Ákos Baráth, Ph.D. Newborn Screening Laboratory Department of Pediatrics University of Szeged

Ákos Baráth, Ph.D. Newborn Screening Laboratory Department of Pediatrics University of Szeged Hungary. Newborn screening for metabolic diseases past, present and future.

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Ákos Baráth, Ph.D. Newborn Screening Laboratory Department of Pediatrics University of Szeged

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  1. Ákos Baráth, Ph.D. Newborn Screening Laboratory Department of Pediatrics University of Szeged Hungary Newborn screening for metabolic diseases past, present and future

  2. In 1994, screening has been defined as: „the systematic application of a test or enquiry to identify individuals at sufficient risk of a specific disorder to benefit from further investigation or treatment, amongst persons who have not sought medical attention on account of symptoms of the disorder”. Any newborn baby is potentially at risk of a variety of inherited metabolic diseases that would be treatable. What is Newborn Screening (NBS)?

  3. Principles and practice of screening for disease In 1968, Wilson and Jungner defined the 10 principles of early disease detection, or screening. The condition should be an important health problem. There should be an acceptable treatment for patients with recognised disease. Facilities for diagnosis and treatment should be available. There should be a recognised latent or early symptomatic stage. There should be a test or examination for the condition. The test should be acceptable to the population. The natural history of the disease should be adequately understood. There should be an agreed policy on whom to treat. The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole. Case-finding should be a continuous process, not just a "once and for all" project.

  4. The goal of NBS is: early detection of children at increased risk for selected metabolic, genetic, endocrinological or hematological diseases so that medical treatment can be promptly initiated to avert metabolic crises and prevent irreversible neurological and developmental impairment. These disorders may cause severe mental retardation, illness, or death if not treated early in life. If treated, infants may live relatively normal lives Purpose of NBS

  5. Purpose of NBS (Cost effectiveness) • NBS results in savings in medical costs over time • Prevents mental retardation and even death • Saves on hospitalization costs resulting complications of metabolic disorders • Saves on costs for special education and therapy if early treatment is missed • Saves children from a life of complete dependence • Saves families from the frustrating and heartbreaking task of caring for an affected child

  6. Other benefits of NBSprogram • Provide the total participation of the specified population • Notification and education of all parents • Prompt and reliable laboratory testing • Avoid diagnostic Odyssey • Rapid follow-up of positive tests • Accurate diagnosis of confirmed positive cases • Appropriate treatment and counseling

  7. „No action is without its side effects.” -Barry Commoner

  8. Harms of NBS programs False positives: The importance of reducing the false positive rate is obvious, as it leads to unnecessary familial anxiety as well as increased costs in the work-up. False negatives: Potentially causing a delay in diagnosis in missed cases. Well-chosen cut-offs are necessary!

  9. „Cut-offs” A laboratory term meaning the upper limit of the normal range of age-matched samples (sometimes a lower limit is defined). Cut-offs are determined by statistical analysis of large data sets generated in a pilot study Most programs use a two-tier cut-off system to assign risk (e.g. „abnormal” and „alert”) Cut-offs are laboratory-specific variables, not universal constants, and may need to be adjusted periodically

  10. History of NBS (USA) • In 1957 - Dr. Willard Centerwall, discovered that application of a ferric chloride solution to a wet diaper of a baby with untreated PKU would produce a green color („nappy test”), to detect phenylpyruvate in urine. It was not reliable until a child was several weeks old and damage had already occurred. • In 1961 – Robert Guthrie developed the bacterial inhibition assay to test for the presence of phenylalanine on a filter paper spot collected from a heel stick. • In 1963 - Massachusetts legislature passed a law requiring that all newborns in that state be tested. • In 1966- PKU screening was mandatory in the majority of states.

  11. History of NBS (USA) • Over the years additional disorders were added, such as galactosemia, biotinidase deficiency, congenital hypothyreoidism, sickle cell disease, cystic fibrosis etc... • In 1997 – North Carolina began piloting the use of MS/MS for NBS. • In 1999 – North Carolina and Massachusetts began NBS with MS/MS. • In 2006 - The American College of Medical Genetics (ACMG) recommended that each baby regardless of birthplace, should be screened for at least 29 conditions.

  12. Evolution of NBS • The introduction of tandem mass spectrometry has turned the world of NBS upside down, because the paradigm of one disease – one test could be changed. • -Traditional model of NBS • 1 disease • 1 test • 1 marker • 1 cut-off • -Application of MS/MS technology to NBS improved efficiency and effectiveness, but increased complexity • Many conditions • 1 test • Many markers • Many cut-offs

  13. In 1968 - PKU screening was mandatory in 3 Hungarian provinces: Csongrád, Békés, Jász-Nagykun-Szolnok. Metabolic Screening Center was in Szeged. In 1975 - NBS for PKU and galactosemia began in Hungary (Centers: Szeged, Budapest) In 1985 – Congenital Hypothyreoidism and In 1989 – Biotinidase deficiency was added to the NBS panel. In 2004 – Selective screening began in Szeged using MS/MS. In october 2007 – population-wide expanded NBS was introduced with MS/MS History of NBS (Hungary)

  14. Why Use MS/MS? Tandem mass spectrometry is a powerful tool. The methodology has a high specificity, sensitivity and less sample preparation time then traditional NBS methods for PKU. It requires a very small sample size to screen for a large number of rare disorders within a short time, about 2 minutes. Cost effective

  15. Mass Spectrometry Mass spectrometer is a device that separates and quantifiesions based upon their mass/charge ratio. It does this by producing charged particles from the sample being analyzed. It then uses an electrical and magnetic field to separate and measure the mass of the charged particle. Once this is done a detection system produces a spectrograph of peaks which can be quantified using internal standards to determine the amount of each particle present.

  16. Disorders accessible to NBS by MS/MS • Type of disorders • Fatty acid oxidation disorders (e.g. MCAD, VLCAD, LCHAD deficiencies) • Disorders of carnitine transport (CUD, CPT-I, CPT-II) • Branched-chain amino acid disorders (e.g. propionic, methylmalonic, isovaleric acidemias) • Aminoacidemias (e.g. PKU, MSUD, Urea Cycle disorders) • Clinical Manifestations • Hypoglycemia, coma, sudden death, seizure,cardio-myopathies • Metabolic acidosis, lethargy, coma, respiratory distress, recurrent metabolic crises • Mental Retardation, Hyperammonemia, failure to thrive

  17. Expanded NBS in Europe • In June 2009, the EU Council Recommendation on Rare Diseases,identified rare diseases (i.e.: a life-threatening or chronically debilitating condition affecting not more than 5 in 10.000 persons in the Community) as a public health problem. • Following this Recommendation, theEuropean Commission launched a tender on neonatal screening in July 2009. • Main points of the tender are as follows: • Harmonization of disease screening panels, • Spectrum of metabolites analysed, • Size of screening laboratories, • Analytical procedures, • Follow-up management and • Proficiency and quality testing is urgently warranted on the European level.

  18. Screening Panels of Countries (including research programs)

  19. 1. Governance In Europe, each country is independentlydeveloping its own health care policy, includingpolicy on NBS. About half the responding countries (17 of 35) reported to have laws or regulationsmandating participation in NBS, and several more countries (20 of 36) indicated to have laws dealing with at least some aspect of NBS. Countries that clearly do not have legal regulation of NBS are Lithuania, Finland, Greece, and Switzerland. The majority of reporting countries (18 of 27) has a body which controlsNBS. Of the 34 responding countries 21 reported to have changed their NBS policy in the last five years.

  20. 2. Criteria for the selection of screening conditions For inclusion, and exclusion of specific conditions in the nationalneonatal screening program most countriesused epidemiological evidence or economics as the strongestarguments(both argumentswere used in 18 of the 22 countries where they said to have hadchanges in their nationalprogram in the last five years). More than half of the countries (14 out of 22) also used ethical arguments in the decision on which conditions to include/exclude in the set of screened conditions.

  21. 3. Costs and resources for the NBS programs Most countries (26 of 33) reported that neonatal screening is financed through state or regional public funds. Screening was also reported to be supported in whole or supplementally from social insurances (6 of 33 cases) or funds of the hosting structure or hospital (7 of 33 cases). Annual costs reported for national neonatal screening programs range from € 70,000.- (Macedonia; 24,000 annual births, screening for 1 condition) to € 15,000,000.- (the Netherlands; 185,000 annual births, screening for 17 conditions).

  22. In percentage of gross domestic product (GDP) based on purchasing-power-parity (PPP) this ranges from 0.00021% (Romania) to 0.00323% (the Netherlands). Costs of the screeningprocedure reported range from € 0.46 per newborn (Serbia; screening for 2 conditions) to € 43.24 (theNetherlands; screening for 17 conditions). The direct health costs of confirming or rejecting a positive screening result depend on the type of condition. Costs were calculated to range between € 182,- (for UDP-galactose-4-epimerase deficiency) and € 2,439,- (for organic acidurias). Costs of disseminating informationreported ranged between € 0.013(Serbia) and € 0.541 (the Netherlands) per newborn in the population.

  23. Information to prospective parents and the public can be disseminated at different times and in different ways. In more than half of the responding countries (19 out of 35) there is a website whereanyone can get information about the neonatal screening program. About seventeen percent (6 out of 35) of the responding countries do not actively inform prospective parents, while 29 (of the 35) do. Almost half of the countries informing prospective parents (13 of the 29) do this only after birth at the time of blood sampling. The minority of the responding countries (10 out of 34) disseminate information material to the general public. This could include e.g. internet, television or radio broadcastings and publications in newspapers or magazines. In most cases this material is prepared by the screening laboratories (in 15 countries) and/or health authorities (in 11 countries). 4. Information to prospective parents

  24. 5. Informed consent Half of the countries mandate participation in the program. Different solutions have been chosen to let parents decide whether they want their baby to be screened. 17 of the 37 responding countries have an opt-out system, which entails that parents will have their child screened unless they specifically state that they do not want this to happen. Another solution is the opt-in procedure, where parents are specifically asked to agree to have their baby tested. Similar strategies can be chosen when asking parents’ consent for storage of the blood sample and usage of the material for research purposes. In almost half of the responding countries (16 out of 33) parents are informed about the fact that bloodspots are retained. In 24 of the 27 responding countries parents have the option to refuse that their baby’s blood sample be stored. In addition in 25 out of the 27 responding countries parents can opt out of the residual materials being used for research purposes.

  25. 6. Blood spot sampling Interval between birth and sampling ranges from 36h to 168h. Finland and Malta use cord blood samples. In 3 countries (Austria, Croatia, and Germany), samples may be taken before 48h. In Croatia then a second sample is requested between 4 and 7 days after birth. In Austria sampling is recommended between 36-72h. 5 countries recommend sampling before 72h but noneearlier than 48h; 15 countries between 48 and 96h, 1 country recommends between 48 and 168h but the sooner the better, 7 countries between 72 and 120h, 5 countries between 4-7 days (approximately between 96 and 168h). 1 country recommends sampling between 72 and 96h. In 25 countries the blood sample is taken before the infant leaves the hospital. Expert opinion: Blood spot sampling between 48 and 72 hours is preferable for most disorders in NBS programs.

  26. 7. Blood spot storage All countries retain the left over blood spots. The purpose is often indicated as quality control,later confirmation of a screening result and research studies. Most countries have developed a policy that for scientific research purposes an ethical approval is necessary. About half of the countries inform the parents about storage of the blood spots, but the majority provides an opt out possibility whether or not for the use for scientific research. The indicated duration of the blood spot storage ranges from 3 months in Germany to “1000” years in Denmark and Sweden. Expert opinion: Blood spot need to be stored for quality control in the NBS laboratory for at least five years

  27. 8. Laboratory procedures The number of screening laboratories rangesfrom 1 to 40 (Italy) per country. Liechtensteindoes not have its own screening laboratory andis assisted by Switzerland. Albania does notperform neonatal screening (Turkey and Kosovodid not respond to the questionnaire). Thenumber of births per screening lab and year wasfrom 2,050 (Malta) to 112,000 (Greece) (median 33,500). Expert opinion: In order to have high quality expanded screening, literature indicates that the laboratory workflow should be at least 30.000 samples/year.

  28. 8. Laboratory procedures The responses indicate a variation between 1 and 15 days between the moment of samplingand the start of analysis in the screening laboratory. For 35 reporting countries the median of the indicated maximum time is 3 days. Thirty countries perform the analysis within 7 days from sampling. In 10 countries sample cards are transported by normal mail, in 19 countries there is both transport by normal mail and courier service, in 4 countries only courier service. In 5 countries there are additional ways of transport, e.g. through parents or midwifes.

  29. Ethical dilemmaCommunication of unintended findings The German program includes the following features: First, the screeningprogram is not mandatory, but recommended. Second, written consent is required by atleast one parent. Third, any incidental findings—for example, of disorders that are necessarily detected while trying to detect the primary targets—are to be discarded and not sharedwith the infant’s physician or parents. Expert opinion: Parents should be given the possibility to be informed of any unintended finding thatcould be relevant, to the extent this is consistent with laws, individual data protectionrights and the right to privacy.

  30. Future of the NBS in Hungary EU countries have included a diversity of disorders in their NBS programs. In Hungary, the following diseases are not included in the NBS program. • Cystic Fibrosis (9 European countries and USA) • Lysosomal Storage Disorders • Congenital Adrenal Hyperplasia (15 European countries and USA) • Adrenoleukodystrophy • Hemoglobinopathies (Sickle Cell Disease, β-thalassemia)

  31. Cystic Fibrosis Cystic fibrosis is screened for in 9 European countries. Theprimary marker is immunoreactivetrypsinogen. In most current programs the second step is DNA mutation analysis using a panel of the 36 most abundant mutations. However, in the last few years attention hasshifted to a second biochemical marker, pancreatitis-associated protein. It is expected that in the next decade the CF-screening will be based on a combination of these markers.

  32. Lysosomal Storage Disorders Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria Thomas P Mechtler MD, Susanne Stary PhD, Thomas F Metz MSc, Víctor R De Jesús PhD, Susanne Greber-Platzer MD, Prof Arnold Pollak MD, Kurt R Herkner PhD, Prof Berthold Streubel MD, David C Kasper PhD The Lancet, Early Online Publication, 30 November 2011 doi:10.1016/S0140-6736(11)61266-X According to a recent study: The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected (1 in ~2300 live birth).

  33. Lysosomal Storage Disorders A pre-symptomatic phase and the development of effective treatments (enzyme replacement therapy, bone marrow transplantation or subtrate reduction drug therapy) make LSDs attractive for screening. Treatable disorders include Fabry’s, Gaucher’s, Hurler’s, Krabbe’s, Niemann-Pick A/B and Pompe diseases. NBS using the neonatal blood spot is being developed. Sample processing is more complex and more expensive than for amino acid and acylcarnitine analysis, and the treatment of these disorders can be extremely expensive.

  34. Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is screenedfor in 15 countries. In view ofthe short asymptomatic period after birth it is essential to keep the interval between birth andscreeningas short as possible. Countries consideringincluding CAH in their screening panel should be aware of this. Screening for CAH is basedon the measurement of the steroid 17-hydroxyprogesterone.

  35. Adrenoleukodystrophy Adrenoleukodystrophy is a peroxisomal storage disease whereby abnormal function of peroxisomes leads to the accumulation of very long-chain fatty acids in tissues of the body, especially the brainandthe adrenal glands. ALD can manifest at different ages with different forms of the disease. Estimated disease frequency is 1 in 21,000 males (X-linked disorder). ALD can be diagnosed by a blood test which analyses the levels of very long chain fatty acids.A method to screen for elevated VLCFA has been developed (MS/MS). Diet therapy is now commonly used and studies indicate that it may positively affect outcome when started early.

  36. Hemoglobinopathies This group of hematological disorders consists of Sickle Cell Disease andbetathalassemia. In Europe, HbPs are prevalent mainly in the Mediterranean countries. As nearly all EU countries now have migrants, this is increasingly relevant.

  37. THANK YOU FOR YOUR ATTENTION!

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