Newborn Screening for Metabolic Disorders: How Are We Doing, and Where Are We Going?

Owing to technological advances during the last decade, there has been a paradigm shift in the way that we diagnose patients with inherited metabolic disease. The introduction of tandem mass spectrometry (MS/MS),7 a technology with sufficient analytical sensitivity to measure metabolic biomarkers in small blood spot samples, has allowed us to shift from what was initially a diagnosis made after or during acute metabolic decompensation into an era in which diagnosis is made immediately in the newborn period. In this environment, the diagnosis of certain metabolic diseases frequently precedes the onset of symptoms, giving physicians an opportunity to prevent many of the catastrophic events that used to occur. To this point, disorders such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency now rarely initially present as the acute-onset liver failure that was previously seen in unscreened and consequently undiagnosed patients. Clinical outcomes for MCAD deficiency are now excellent, and data on some of the other screened disorders are starting to show the benefit of early diagnosis. Diagnostic technology continues to increase in its capability to provide early diagnosis of increasing numbers of these metabolic diseases as more biomarkers become identified. In this Q&A, 5 leading thinkers in the field provide their insights into where we presently stand in this area and where we might be headed in the future. Has there been a positive impact on patient care as a result of early diagnosis and implementation of the American College of Medical Genetics (ACMG) recommended-screening disorders? Piero Rinaldo: The implementation of the ACMG uniform panel has had a positive impact at multiple levels. The consistency of the panel has virtually eliminated the discrepancies between neighboring states, often a cause of heartbreaking events where parents have experienced significant morbidity and mortality of their child that would not have happened if their child had been born just across the state border. Given the 99% implementation of the primary targets by US programs, today it is almost irrelevant where a baby is born. Another positive outcome has been a much greater awareness that—with almost no exception—the analytes detected by MS/MS are not unique to a single, better-known condition but often entail a complex differential diagnosis. Collaboration and data sharing have also improved, creating an environment better suited for evidence-based clinical validation. Bridget Wilcken: There is no all-encompassing answer to this question. A positive impact on patient care can mean many things— earlier diagnosis, more-appropriate treatment in specialized centers, and, most importantly, an improved outcome. But it also means that the benefits should outweigh the harms—again a difficult call, as one is comparing different things. There is no doubt that screening has resulted in earlier diagnosis for most patients, and it is very likely that eventually there will be more appropriate treatment in experienced metabolic centers. Benefit for patients with disorders on the new expanded list has been demonstrated clearly for MCAD deficiency and glutaric aciduria type 1, and for all disorders taken together, and we have assessed this when patients and controls have been 6 years old. But the ACMG recommendations do include disorders that are now thought to be benign or nearly so, and additionally but unavoidably, screening detects patients with mild forms of significant disorders. This not only dilutes the real benefit (screen-detected patients may have mild disease and so do well, producing an apparent benefit) but may also cause harm because of unneeded treatment. Well-designed observational outcome studies are needed. Randomized controlled trials will not be possible now because of both the rarity of individual disorders and the currently perceived benefit. Kenneth Pass: Absolutely! There are numerous accounts of lifesaving interventions as a result of using positive newborn screening (NBS) results to initiate prompt and effective therapies. These are most often seen in the fatty acid and acyl-carnitine disorders now identified through the use of MS/MS. These disorders are not apparent on a physical exam, as is true of most NBS disorders, but can lead very quickly to a metabolic crisis situation. Moreover, it is without question that the quality of life for these infants has been improved by the timely intervention resulting from NBS. This was apparent from the beginning of NBS testing for phenylketonuria (PKU) and is especially true for one of the more common conditions in all panels: congenital hypothyroidism (CH). Untreated, CH can result in profound mental retardation and physical manifestations. Once a newborn is identified, therapy is easy and effective. Among the 60+ conditions in today's NBS panels, only severe combined immunodeficiency (SCID) can be completely cured through bone marrow transplantation. However, none would argue that morbidity can be greatly reduced for most of these disorders, notably CH, cystic fibrosis (CF), PKU, and sickle cell disease. Michael Watson: When the ACMG was contracted to assess 80+ conditions in 2002 to determine their appropriateness for NBS, there was significant interstate variability in what was screened. There is now near uniformity among the states in screening for a core set of conditions, and a federal advisory committee (Secretary's Advisory Committee on Heritable Disorders in Newborns and Children) coordinates a central review of evidence for conditions being considered for addition to or subtraction from the uniform panel of conditions. There was limited patient care guidance (e.g., practice guidelines) and research related to the conditions to which screening was directed. Clinical histories of the conditions were poorly developed, due to the rarity of the conditions and a lack of systems that would allow for the aggregation of information about cases found in NBS that were distributed around the country. This is a critical need as we invariably learn much about the range of phenotypes associated with a genetic condition until cases are identified in a general and large population setting. In response to federal legislation in the Newborn Screening Saves Lives Act, the Eunice Kennedy Shriver National Institute for Child Health and Human Development has sponsored an evolving research program (the Newborn Screening Translational Research Network) that focuses on new technologies, treatments, and a broad range of research related to NBS and the conditions that are candidates for addition to NBS programs. Furthermore, there was significant variability between states in the performance characteristics of the screening tests (i.e., analytical and clinical sensitivity and specificity, and predictive values of screening results). There are now programs that facilitate interlaboratory comparison and improvement of NBS (Region 4 Stork) that complement the CDC's Newborn Screening Quality Assurance Program and that have worked toward minimizing the number of cases identified that don't have the conditions in question. Minimizing the number of families that are unnecessarily alarmed by notification of a screen-positive result is an important outcome. Ronald Wanders: Absolutely! However, in the Netherlands we don't screen for all of the disorders recommended by the ACMG. In 2007, NBS for inborn errors of metabolism was expanded from 1 disorder (PKU) to 14 disorders, including, among others, MCAD, various disorders of long-chain fatty acid oxidation, galactosemia, biotinidase deficiency, and maple sugar urine disease. The Dutch screening program already included CH and adrenal genital syndrome. In addition to the inclusion of 13 new inborn errors of metabolism, screening for sickle cell anemia and thalassemias was included in 2007, and CF was included in 2011. There were some initial problems with the expanded screening program, mainly due to the screening tests used and cutoff values, but these were quickly overcome. Have there been any unanticipated findings or negative impacts on patient care as a result of the implementation of these guidelines? Piero Rinaldo: There is still no consensus among experts and providers of NBS services about the clinical justification of including in the recommended panel a few secondary targets with a poorly defined natural history. Having said that, the only way to settle such issues is to gather the evidence over an extended period of time and then consider the need for revisions of the recommended panel on the basis of objective evidence, not subjective opinions. Bridget Wilcken: There have certainly been some. The inclusion in the ACMG list of very rare disorders whose clinical significance was unknown seems to have been unwarranted. With hindsight, it would have been better to support a few excellent centers that could include certain disorders, with parental consent, on an explicit research basis. This would have avoided distressing parents of babies with very rare disorders who may have been put on difficult and possibly harmful diets (low valine diet, for example, in isobutyryl-CoA dehydrogenase deficiency) for something that turns out to be apparently benign. Such babies have also been labeled for life as having a disorder. Astonishingly, the recommended list includes, in its secondary targets, one disorder that has been recorded only once. This requires a marker not used for other disorders and so was entirely unnecessary. Many screening programs are worried about the increased number of false-positive tests, but some studies show that where these are well managed and parents have accurate information, there is much more tolerance of such results. But false-positive results and, worse, those that indicate a disorder of uncertain clinical significance always have some negative impact. Kenneth Pass: Regrettably, yes. As with any population-based program (the US tests over 4 million babies each year), unanticipated things can happen. One of the more common impacts is the inability to locate a child who has a positive screening result. Despite great efforts on the part of the program's follow-up unit, it is sometimes impossible to locate a family, because of having nothing to work with except incorrect information provided to the NBS program. This can also occur when the initial specimen is not suitable for testing and the program is unable to locate the family for rescreening. In both instances, the newborn can fail to get appropriate medical care. Introduction of testing for CF also brought unanticipated changes in the operation of the national CF centers. Before NBS for CF, these centers were presented only with infants (or toddlers) who were sick and not otherwise diagnosable. In many instances, the CF center was the last resort in a long search for a diagnosis. With the addition of NBS for CF, asymptomatic infants were arriving for diagnostic workup. It was quickly realized that these NBS referrals could not be seen on a clinic day when sick children were also seen. Thus, a new day exclusively for NBS referrals had to be adopted. Additionally, the centers now had to deal with CF the infants were to This a of their diagnostic A or more after beginning NBS for PKU, the of a when children born to with were but not with were related to the and of the to the condition of PKU, in which increased of in a not using the were to the Many of these were that had PKU, had been for many With programs and a of the it was possible to these so that could their Michael Watson: As of genetic diseases is by their of until those at can be identified in a general population and their outcomes The range of phenotypes of the conditions to as the true clinical histories of the conditions are have considered the need to to be a negative impact of However, it is a and critical in of the It is difficult to determine much about is a disease is sufficient to NBS. rare more is always In the these of large population-based studies of diseases would be introduction of the condition into NBS programs. However, for conditions with in the 1 to very large population-based studies would be As is apparent from the Act, the real to much data are the introduction of a and the of systems that have to be in to support that the of data to made after Ronald Wanders: there were some One was the outcome of screening for which was only on the A very of false-positive screening results was found on one of the Dutch care This was due to the use of a acid Screening for was in as it that this had not resulted in any screening results and may have to results. to screening for this disorder this with a screening on the In we detected completely clinical of Has implementation on or clinical Piero Rinaldo: it is a of which is false-positive and positive predictive values are almost always related to a failure to on all for a condition and on and Bridget Wilcken: In we the over the years from after screening is and almost all metabolic patients a follow-up testing is through that center were for patients with disorders detected by NBS of the real increase in work was to only were for of the metabolic The would be very different if there were but the would be especially as with the new screening In any most patients by significant disorders would present for clinical and care. Kenneth Pass: With the introduction of MS/MS as a screening a testing that was and and was were with the technology and This was provided through a of the of Health the Health and the as was previously when screening for sickle cell disease was through the new that technology of Furthermore, with use of the MS/MS the number of conditions in the screening panel from in most programs to almost in some programs. This has an on the clinical each screen-positive be to or the screening results. This had also been a when screening for CF was to the screening With the introduction of MS/MS technology in the screening efforts were from the clinical of and metabolic because many of these conditions could not be identified with the clinical used by initial therapy for this of disorders by a presented of and The with from the a set of that clearly the initial for this of on their with their These are now included with the NBS by programs in the Michael Watson: The as much a of the numbers of patients identified by expanded NBS as it is one of a limited genetic and clinical disease NBS patients but who out to be patients. However, the patients present and so are more would be a One would that many of the patients who would otherwise present for diagnosis after clinical would be seen by those in their diagnosis, but often of the diagnostic that many of these patients are not but it is that the benefits of early and treatment outweigh the on providers is also related to the performance characteristics of the screening tests There is significant variability across the in the clinical sensitivity and predictive values of the screening have been that to the number of screen that be true and significant has been made in this to the benefit of both the providers who the patients and the families that into the for Ronald Wanders: yes. One of the of expanded NBS has been that are with diagnostic that have to be not only during the day but also on to a patient with a positive screening result is or The number of to the centers for metabolic disorders in the Netherlands increased most who positive to be all should initially be as patients for the results of the diagnostic workup. to include conditions, and if so, which Piero Rinaldo: will be at in the by a of evidence review the of the Health and Human Advisory Committee on Disorders in Newborns and are and on the basis of the of the the of and screening tests and the and of treatment the addition of to the uniform many other conditions by the of blood have diseases are and are but there are where the treatment may indicate a great from early of may better-known conditions toward inclusion in the of these are disorders of metabolism, disorders example, and just to a Bridget Wilcken: It is that there will be new disorders. do new marker and new as well as new on what is an for NBS. that there will be an of screening for as become are and this some about opportunity There is also about the of out the life but with for some disorders. This has certainly been for where there is a benefit of early treatment for but which may not be of are and will certainly lead to new A would be for which there has been a screening for over years and for which a likely benefit has been in early trials of of for those with such a testing is to be possible as the of and many disorders disorders such as long would be easy to deal but very broad screening would have broad Kenneth Pass: a many programs are the addition of screening for The Advisory Committee on Heritable Disorders in Newborns and has recommended that become a part of the core panel of disorders, screening in the US for is likely to be from studies to screening in an NBS sponsored by the National Institute of Child Health and Human Development and the will provide information for programs to their in the near future. the currently screening for is a using that to increased sensitivity and have been of the would be the time in which is used as the primary by NBS. will a new technology to the screening programs, to in the The and have this need and have for programs for the but a by the Advisory are critical congenital disorders, and among studies studies have been for and Michael Watson: This is no doubt the The of many and has been the of a screening that can those at for a condition for which a treatment can the of the recommended uniform NBS panel in a federal advisory the Advisory Committee on Heritable Disorders in Newborns and was and systems for conditions for with evidence-based have been put into conditions or phenotypes have been including and and and critical congenital disease have been recommended for addition to the screening conditions are in the for The of already in clinical trials for many of these of conditions is also so the is that these programs will to Ronald Wanders: The advisory for NBS on metabolic disorders has the inclusion of and aciduria into the screening program. This will be in the general screening and we to have a positive response this There is also of including screening for and disease. However, more studies are the advisory will put this on their the decade, will the present technology to be the primary for NBS, or will Piero Rinaldo: NBS in the is likely to be a of a few on and some type of A in what NBS will be in from the to which parental screening will become an of care. Furthermore, it is likely that will be out on a not state by as is currently in most Bridget Wilcken: that the present technology will in the new might include and some of metabolic As to some of and that will can be to NBS. One new might be an to numbers of for CF screening as a This could be but would be with in of uncertain as well as more with the problems that would then As a this would be will become very and NBS may a It would be difficult to from of predictive for and of or disorders would be detected very The need for genetic could be to increase related to will to for a Kenneth Pass: technology has been the for the of NBS the of NBS as a program was made possible by the of the for by in the early Before the screening for was on testing for in the of This was in and in an with for the newborn The and use of a for a specimen by that could be through the made of testing These are now as in These provided the by which NBS programs in in the US and the which most US programs now With the of the of the there was great that would today's use of such as and had previously could be from the spot and for genetic that was was a technology to allow the testing of of each the for this new studies have the because of many among which small and present especially difficult problems for a screening the NBS has systems that can biomarkers much as MS/MS had but with With a of biomarkers of conditions such as CH and CF can be identified. Thus, the of today's use of a for a condition may be Michael Watson: on the outcomes of genetic as in metabolic or for NBS. Many genetic at the are associated with of the disease and with variability in disease However, as the of and to a at which become the of an NBS may that may better outcomes of genetic and be more predictive of disease will also to The critical will be we the systems that and clinical trials of these in an environment of NBS to their and effective Ronald Wanders: to but that at for the the technology will to be the primary for NBS of inborn metabolic the clinical of such as use of these for NBS currently be the ACMG recommendations Piero Rinaldo: 99% implementation in the US of the uniform panel Bridget Wilcken: It is that the ACMG recommendations have had a not only in the US but also around the that the US in NBS consider the ACMG recommendations but are not Kenneth Pass: and states now screen for the core panel of conditions, with the of for which screening has been only in and One could to be by all US programs. information the of NBS programs in the US can be found on the and all programs would a new condition its by the Advisory Regrettably, that is not the Michael Watson: in screening for the ACMG and Advisory Committee on Heritable Disorders in Newborns and recommended of core or primary conditions to which screening is has greatly improved across the recommended conditions, such as and critical congenital are at various of and introduction into screening by many states, a now by national programs that allow for broad among early states to more data on conditions during There is greater variability in states include the secondary conditions that also may be associated with the for the primary disease. There is also some variability in states screen for conditions those in the recommended panels, such as and dehydrogenase those in states for which screening for these conditions has been will data that will allow the Advisory Committee on Heritable Disorders in Newborns and to for for addition to recommended Ronald Wanders: In the as in most the of diseases to be included in NBS programs is of the ACMG the of the NBS program in in the the Health an advisory provided the with about which diseases to This advisory of medical clinical and patient the advisory such as the one on inborn errors of metabolism, can also about inclusion of a disease. tandem mass spectrometry medium-chain acyl-CoA dehydrogenase American College of Medical Genetics newborn screening phenylketonuria congenital hypothyroidism severe combined immunodeficiency cystic fibrosis of Health Health disease