The First Treatment for PKU: The Pioneers—Birmingham 1951

Green, Anne

doi:10.3390/ijns7010019

Cited by 7 publications

(9 citation statements)

References 29 publications

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“…“Sheila,” the first PKU patient treated with dietary phenylalanine restriction, 50 much improved in learning ability and attention. Since then dietary Phe restriction has become the standard therapy for PKU, and with success 51 .…”

Section: Resultsmentioning

confidence: 99%

Competitive, multi‐objective, and compartmented Flux Balance Analysis for addressing tissue‐specific inborn errors of metabolism

Liu

Westerhoff

2023

J of Inher Metab Disea

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The inborn error of metabolism phenylketonuria (PKU, OMIM 261600) is most often due to inactivation of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) into tyrosine (Tyr). The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux balance analysis (FBA) of a single‐compartment model of PKU predicts that maximum growth rate should be reduced unless Tyr is supplemented. However, the PKU phenotype is lack of development of brain function specifically, and Phe reduction rather than Tyr supplementation cures the disease. Phe and Tyr cross the blood–brain barrier (BBB) through the aromatic amino acid transporter implying that the two transport reactions interact. However, FBA does not accommodate such competitive interactions. We here report on an extension to FBA that enables it to deal with such interactions. We built a three‐compartment model, made the common transport across the BBB explicit, and included dopamine and serotonin synthesis as parts of the brain function to be delivered by FBA. With these ramifications, FBA of the genome‐scale metabolic model extended to three compartments does explain that (i) the disease is brain specific, (ii) phenylpyruvate in urine is a biomarker, (iii) excess of blood‐phenylalanine rather than shortage of blood‐tyrosine causes brain pathology, and (iv) Phe deprivation is the better therapy. The new approach also suggests (v) explanations for differences in pathology between individuals with the same PAH inactivation, and (vi) interference of disease and therapy with the functioning of other neurotransmitters.

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Section: Resultsmentioning

confidence: 99%

Competitive, multi‐objective, and compartmented Flux Balance Analysis for addressing tissue‐specific inborn errors of metabolism

Liu

Westerhoff

2023

J of Inher Metab Disea

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“…Nonetheless, effective treatments and therapeutic approaches have been developed for monogenic diseases. An early example is the use of a phenylalanine-deficient diet for patients with phenylketonuria, which is effective in preventing the development of neurological abnormalities from this metabolic disease (Green, 2021), yet challenging for patients to maintain adherence. Indeed, the effectiveness of this approach provides a compelling rationale for the inclusion of PKU in virtually all newborn screening panels.…”

Section: Traditional Drug Development Versus Gene-targeted Therapiesmentioning

confidence: 99%

Gene‐targeted therapies: Overview and implications

Brooks

Urv

Parisi

2023

American J of Med Genetics Pt C

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Gene‐targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. This article provides a brief summary of the primary types of GTTs and a brief overview of the current state of the science. It also serves as a primer for the articles in this special issue.

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“…• 2022, Reauthorization of NBSSLA, due in 2020, remains delayed. The scientific groundwork for NBS began (Boxes 1 and 2) with discoveries of a treatment for PKU in 1953 by Horst Bickel [3,4], followed by the critical development of a bacterial inhibition assay for the detection of PKU using blood absorbed onto special collection paper by Robert Guthrie [5][6][7]. Adaptations to the test made it amenable to high-volume and high throughput screening [8], making a public health program role in NBS feasible.…”

Section: Legislation Regulation and Policymentioning

confidence: 99%

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijns8030041/s1. References [1,[3][4][5][6][7][8][9][10][11][13][14][15][16][17][18][19][20][21][22][23][24][26][27][28][29]31,32,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]52,55,[70][71][72][73]...…”

Section: Supplementary Materialsmentioning

confidence: 99%

The Progress and Future of US Newborn Screening

Watson

Lloyd-Puryear

Howell

2022

IJNS

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Progress in newborn screening (NBS) has been driven for 60 years by developments in science and technology, growing consumer advocacy, the actions of providers involved in the care of rare disease patients, and by federal and State government funding and policies. With the current explosion of clinical trials of treatments for rare diseases, the pressure for expansion has grown, and concerns about the capacity for improvement and growth are being expressed. Genome and exome sequencing (GS/ES) have now opened more opportunities for early identification and disease prevention at all points in the lifespan. The greatest challenge facing NBS stems from the conditions most amenable to screening, and new treatment development is that we are screening for rare genetic diseases. In addition, understanding the spectrum of severity requires vast amounts of population and genomic data. We propose recommendations on improving the NBS system and addressing specific demands to grow its capacity by: better defining the criteria by which screening targets are established; financing the NBS system’s responsiveness to opportunities for expansion, including engagement and funding from stakeholders; creating a national quality assurance, data, IT, and communications infrastructure; and improving intra-governmental communications. While our recommendations may be specific to the United States, the underlying issues should be considered when working to improve NBS programs globally.

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The First Treatment for PKU: The Pioneers—Birmingham 1951

Cited by 7 publications

References 29 publications

Competitive, multi‐objective, and compartmented Flux Balance Analysis for addressing tissue‐specific inborn errors of metabolism

Competitive, multi‐objective, and compartmented Flux Balance Analysis for addressing tissue‐specific inborn errors of metabolism

Gene‐targeted therapies: Overview and implications

The Progress and Future of US Newborn Screening

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