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Named one of the \"Ten must-read science histories\" by Science Magazine In a lifetime of practice, most physicians will never encounter a single case of PKU. Yet every physician in the industrialized world learns about the disease in medical school and, since the early 1960s, the newborn heel stick test for PKU has been mandatory in many countries. Diane B. Paul and Jeffrey P. Brosco's beautifully written book explains this paradox. PKU (phenylketonuria) is a genetic disorder that causes severe cognitive impairment if it is not detected and treated with a strict and difficult diet. Programs to detect PKU and start treatment early are deservedly considered a public health success story. Some have traded on this success to urge expanded newborn screening, defend basic research in genetics, and confront proponents of genetic determinism. In this context, treatment for PKU is typically represented as a simple matter of adhering to a low-phenylalanine diet. In reality, the challenges of living with PKU are daunting. In this first general history of PKU, a historian and a pediatrician explore how a rare genetic disease became the object of an unprecedented system for routine testing. The PKU Paradox is informed by interviews with scientists, clinicians, policymakers, and individuals who live with the disease. The questions it raises touch on ongoing controversies about newborn screening and what happens to blood samples collected at birth.

Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of phenylketonuria (PKU) and other amino acid disorders, allowing the antagonistic amino acid to be removed but with the safe provision of all other amino acids necessary for maintaining normal physiological function. They were first formulated by a chemist and used experimentally on a 2-year-old girl with PKU and their nutritional formulations and design have improved over time. Since 2008, a bioactive macropeptide has been used as a base for protein substitutes in PKU, with potential benefits of improved bone and gut health, nitrogen retention, and blood phenylalanine control. In 2018, animal studies showed that physiomimic technology coating the amino acids with a polymer allows a slow release of amino acids with an improved physiological profile. History has shown that in PKU, the protein substitute’s efficacy is determined by its nutritional profile, amino acid composition, dose, timing, distribution, and an adequate energy intake. Protein substitutes are often given little importance, yet their pharmacological actions and clinical benefit are pivotal when managing PKU.

Lu Yu (733-804 AD, Tang Dynasty) was an orphan raised and educated in a monastery. His profound knowledge of tea earned him the title \"the Sage of Tea.\" This paper explores the possibility that Lu Yu may have been a patient of inherited metabolic diseases (IMDs), particularly phenylketonuria (PKU), considering historical records and unique aspects of his life. Examining Lu Yu's orphaned upbringing, clinical manifestations noted in his autobiography, dietary preferences, and the significance of his name, this study postulates that he may have had IMDs, notably PKU. His life choices, such as abstaining from meat and fish and favoring a low-protein diet during his time in a monastery, align with practices recommended for managing IMDs. The linguistic associations of his name further reinforce this hypothesis. This investigation sheds light on the intriguing possibility that Lu Yu may have been affected by IMDs, notably PKU. By considering historical context, clinical correlations, dietary choices, and name symbolism, we offer a unique historical perspective on this celebrated figure's health. Further research could provide valuable insights into both his life and the broader medical practices of the Tang Dynasty.

In the years following World War II, and increasingly during the 1960s and 1970s, professional scientific societies developed internal sub-committees to address the social implications of their scientific expertise (Moore, Disrupting Science: Social Movements, American Scientists, and the Politics of the Military, 1945-1975. Princeton: Princeton University Press, 2008). This article explores the early years of one such committee, the American Society of Human Genetics' \"Social Issues Committee,\" founded in 1967. Although the committee's name might suggest it was founded to increase the ASHG's public and policy engagement, exploration of the committee's early years reveals a more complicated reality. Affronted by legislators' recent unwillingness to seek the expert advice of human geneticists before adopting widespread neonatal screening programs for phenylketonuria (PKU), and feeling pressed to establish their relevance in an increasingly resource-scarce funding environment, committee members sought to increase the discipline's expert authority. Painfully aware of controversy over abortion rights and haunted by the taint of the discipline's eugenic past, however, the committee proceeded with great caution. Seeking to harness interest in and assert professional control over emerging techniques of genetic diagnosis, the committee strove to protect the society's image by relegating ethical and policy questions about their use to the individual consciences of member scientists. It was not until 1973, after the committee's modest success in organizing support for a retrospective public health study of PKU screening and following the legalization of abortion on demand, that the committee decided to take a more publicly engaged stance.

Virtually every infant in the United States undergoes a heel stick within the first week of life to test for a variety of metabolic, endocrine, and hematological conditions as part of state-run universal newborn screening (NBS) programs. The history of this mandatory public health program is examined, as well as whether the policy was morally justifiable. Three changes in NBS practice necessitate a re-evaluation of the mandatory nature of NBS. First is the adoption of NBS for hemoglobinopathies in the 1980s that led to the identification of many sickle cell carriers and carriers of other hemoglobin variants. In all other contexts, carrier testing requires consent, and there is no moral rationale why NBS ought to be exceptional. Second is the application of tandem mass spectrometry (MS/MS) to NBS in the 1990s that led to the identification of many metabolic conditions and variants, some of which were not treatable and others of which had unknown clinical relevance. To the extent that the conditions do not need emergent diagnosis and treatment, there is less justification for mandatory screening. Third, there is great interest in using residual blood spots for research, and the cornerstone of research ethics is the voluntary consent of the participant (or his or her proxy). These three changes support revising mandatory NBS with a tiered consent process to best balance respect for parental autonomy and the promotion of children's health.

In 1960, Robert Guthrie invented a new assay to detect phenylketonuria in newborns, inspiring hope for treating mental retardation. But efforts to patent and license the test generated controversy, presaging current debates over commercialization in biomedicine. In 1960, microbiologist Robert Guthrie and technician Ada Susi invented a bacterial inhibition assay that reliably detected phenylketonuria (PKU) in newborns. The damage caused by PKU, including often profound cognitive impairment, results from an inability to metabolize phenylalanine, an amino acid necessary for protein synthesis and normal growth and development. To be effective, treatment with a low-phenylalanine diet must begin in early infancy, before the onset of irreversible neurologic impairment. Although a ferric chloride urine test for PKU existed in the 1950s, it was unreliable until the infant was 6 to 8 weeks old. The new assay was also more . . .

The genetic disorder phenylketonuria (PKU) has become an exemplar for the promise of genetic medicine. Coping with PKU has turned out to be a lifelong effort, requiring substantial psychological, financial and social support.

Although hereditary disease has been recognized for centuries, only recently has it become the prevailing explanation for numerous human pathologies. Before the 1970s, physicians saw genetic disease as rare and irrelevant to clinical care. But, by the 1990s, genes seemed to be critical factors in virtually all human disease. Here I explore some perspectives on how and why this happened, by looking at two genetic diseases — familial dysautonomia and phenylketonuria.