Newborn Screening: A Revolution in Need of Reform

Written by: Alexander Pralea '24
Edited by: Ishaani Khatri '21

Infants with Pompe disease–also known as glycogen storage disease type II–look like all other infants at birth, yet after several months the onset of the disease occurs [1]. Infants soon present with reduced muscle tone; when most babies their age are learning to crawl and stand up, babies with Pompe disease struggle to move at all. They then develop cardiomegaly, or heart expansion. If left untreated, infants typically die by the end of their first year due to respiratory failure, exacerbated by repeated lung infections

Thankfully, since Pompe disease was first discovered in 1932 by its namesake, Dutch pathologist Johannes Pompe, treatments have been developed that ameliorate the disease’s symptoms [2]. Given that the disease is caused by the absence of enzyme GAA, a defect which causes glycogen to accumulate in cells, enzyme therapy replacement treatment introduced a recombinant (genetically engineered) form of GAA, known as rhGAA. This treatment is hardly perfect; cardiac muscle, but not skeletal muscle, responds well to rhGAA, meaning that poor muscle tone and weakness persist, but rhGAA dramatically improves life expectancy and quality of life. With the development of promising second-generation drugs, there is hope that these problems could soon be addressed.

Still, to maximize the effectiveness of treatment, treatment cannot wait several months for the symptoms to develop. Instead, treatment must be started within days of birth, when the neonate is still asymptomatic. This raises a much larger question: how can one diagnose a disease in newborns if there is no clinical presentation?

In 1962, physician-scientist Robert Guthrie found the answer to this pressing question through the first instance of newborn screening (NBS) [3]. Phenylketonuria (PKU), a metabolic disorder characterized by the inability to produce a specific enzyme that helps breaks down the amino acid phenylalanine, was traditionally diagnosed by the presence of phenylalanine in one’s urine. Sadly, this test only detected PKU after PKU-associated neurological deficits had already occurred, making it ineffective for symptom prevention.

The Guthrie test responded to this problem by directly measuring one’s blood phenylalanine levels through a bacterial inhibition assay. Although one amino acid, β-2-Thienylalanine, inhibits the growth of bacteria, phenylalanine does not, so the response of the bacteria to the blood of someone with PKU (i.e., for the bacteria to grow) would indicate the disease, even before its symptoms manifested themselves. As a result, a patient could be put on a specialized diet low in phenylalanine that would prevent cognitive impairment. Given the ease of diagnosis and treatment, this test was rapidly expanded to all fifty states through mandatory NBS. 

Since PKU testing marked the beginning of NBS, other diseases have been added to the screening boards across every state; congenital hypothyroidism, sickle cell disease, and galactosemia are just a few of the diseases that all infants, regardless of background, are screened for through minimally invasive tests [4]. Still, while PKU is an example of a resounding success story with regard to NBS, Pompe disease, at least now, does not share in the victory, in part due to the decentralized structure of NBS panels. 

Currently, the Department of Health and Human Services (HHS) issues a recommended uniform screening panel (RUSP), but the problem lies within the name itself: the panel is merely “recommended. It is up to the discretion of each state as to whether it listens to the federal guidelines. As a result, despite the thirty-five diseases recommended for screening, Arizona only screens for thirty-one; while Arkansas and Missouri are neighbors, the former screens for thirty-two diseases and the latter seventy-six [5]. The case of Pompe’s disease, in which only twenty states mandate screening for it despite its “recommended” status, is clearly not an anomaly, but a canary in a coal mine, urging the federal government to take action.
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Instead of merely “recommending” screening for specific diseases, HHS has an ethical obligation to set binding, nationwide requirements and thereby promote fairness. While federalism, the system of government giving extensive latitude to states to influence policy, has its advantages, when lives are at stake, one’s state of birth cannot be a death sentence. Economic concerns are relevant given how rare these diseases are, but cost-benefit analyses have consistently found that the costs of NBS (including those of NBS for Pompe’s disease) are well worth the quality-adjusted life years gained through early diagnosis and intervention [6] [7]. Clearly, universal NBS is necessary to prevent mortality and reduce morbidity; the only question is whether political gridlock will handicap adequate response in this era of polarized politics. If politicians listen to the scientists, they will realize that a failure to act will result in undue suffering for thousands. 

References:

1. Taglia A, Picillo E, D'Ambrosio P, Cecio MR, Viggiano E, Politano L. Genetic counseling in Pompe disease [Internet]. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. Pacini Editore SpA; 2011 [cited 2020Nov8]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298105/ 
   
2.  Lim J-A, Li L, Raben N. Pompe disease: from pathophysiology to therapy and back again [Internet]. Frontiers in aging neuroscience. Frontiers Media S.A.; 2014 [cited 2020Nov8]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135233/ 
   
3. The Embryo Project Encyclopedia [Internet]. The Guthrie Test for Early Diagnosis of Phenylketonuria | The Embryo Project Encyclopedia. [cited 2020Nov8]. Available from: https://embryo.asu.edu/pages/guthrie-test-early-diagnosis-phenylketonuria 
   
4. Recommended Uniform Screening Panel [Internet]. Official website of the U.S. Health Resources & Services Administration. 2020 [cited 2020Nov8]. Available from: https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html 
   
5. Conditions Screened By State [Internet]. Conditions Screened by State | Baby's First Test | Newborn Screening | Baby Health. [cited 2020Nov8]. Available from: https://www.babysfirsttest.org/newborn-screening/states
   
6. Saich R, Brown R, Collicoat M, Jenner C, Primmer J, Clancy B, et al. Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective [Internet]. MDPI. Multidisciplinary Digital Publishing Institute; 2020 [cited 2020Nov8]. Available from: https://www.mdpi.com/2409-515X/6/1/1/htm 
   
7. Vallejo-Torres L, Castilla I, Couce ML, Pérez-Cerdá C, Martín-Hernández E, Pineda M, et al. Cost-Effectiveness Analysis of a National Newborn Screening Program for Biotinidase Deficiency [Internet]. American Academy of Pediatrics. American Academy of Pediatrics; 2015 [cited 2020Nov8]. Available from: https://pediatrics.aappublications.org/content/136/2/e424 ​