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Perspective interview - Harvey Levy (PKU Heroes)

Perspective interview - Harvey Levy (PKU Heroes)

Third Issue of the PKU Academy Newsletter Harvey Levy talks about his PKU Heroes and the future of newborn screening

Harvey Levy talks about his PKU Heroes and the future of newborn screening

Prof Harvey Levy of Harvard Medical School, Boston (USA) gave the Asbjørn Følling lecture, ‘Heroes of PKU’, at the 4th European Phenylketonuria Group Symposium (Rome, Italy) in March 2012. His lecture was well received, while it failed to mention one key advocate of the expansion of newborn screening for inherited metabolic disorders, that person being Prof Levy himself!

He was awarded the Robert Guthrie Award in 1997 by the International Society for Neonatal Screening for his outstanding contribution to the field – and so, to correct the omission from his address we asked him to share his perspective on PKU with us.

As a professor of Paediatrics at Harvard Medical School, Harvey Levy has no doubt influenced many young medics to appreciate the importance of neonatal screening but who, we asked, was responsible for his initial interest in PKU?

‘Back when I was in training, before I began working in biochemical genetics and PKU, I heard a remarkable lecture by a physician in Boston at the Massachusetts General Hospital, Dr Mary Efron. She described newborn screening for PKU, how babies can be identified before they become damaged from PKU and could be put on treatment that would prevent the damage PKU would ordinarily cause. I was extremely impressed with that and decided that that was an area I wanted to devote my life to.’

Find out more about Dr Mary Efron (Nov 18, 1926 – Sep 2, 1967) in the Memorial Issue of The Archives of Pediatrics and Adolescent Medicine devoted to her and her contribution. Arch Pediatr Adolesc Med. 1969;117(1):1–3.

Evolution of Screening

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How had newborn screening evolved over his career, we asked. ‘I first began investigating, diagnosing and treating children with PKU when newborn screening meant just the old Guthrie test for PKU’ he said. ‘Today, we have techniques that allow us to screen for as many as 20 or 30 different major disorders although PKU is the most common disorder for which we screen, and the one which we have the most success in treating.’

Newborn screening for PKU with effective follow up has certainly been a great success story, but the expansion of newborn screening raises ethical as well as practical issues, the professor explained. ‘We have a saying in the USA that “there’s no such thing as free lunch”; in other words, what we see at first as an advantage can often have unintended consequence. With more accurate and specific screening for a wider range of disorders, we can identify variants of these disorders which in their severe form cause major problems but which in their variant forms may be totally benign.

‘It is not easy to sort the infants with a severe form of a disorder from those who may have a completely innocent form which would never cause problems at any point. It is certainly the case that, sometimes, infants are investigated and even treated unnecessarily. This is unfortunate, but I think that as we go along we’ll be able to find our way more clearly in this forest of disorders.’

By way of illustration, the professor pointed to the development of tandem mass spectrometry (TMS) which had enabled improved definition of PKU from the newborn screen. ‘Before TMS we had a single test that was applied to the baby’s blood specimen to identify a single metabolite, Phe. Today, with TMS, we measure not only Phe levels but also tyrosine (Tyr), the immediate metabolite of Phe. When a baby has PKU the Tyr levels will be low or certainly not elevated. This allows us to minimise false positive screens and rule out PKU in situations where an elevation of Phe is accompanied by an elevation of Tyr also.’

The only way is ethics

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When we asked what steps needed to be taken to ensure that accurate and ethical screening becomes a reality for a greater range of conditions (and variants), the professor replied ‘We need to have a great deal more information about these disorders before we can feel comfortable in being able to:

  • identify a newborn baby with a disorder
  • know exactly what that disorder means to the baby and the family
  • know what kind of treatment is most appropriate for that baby
  • relate that information to the physician who cares for the infant as well as to the family.’

 

There were no easy shortcuts: ‘We need to know more about the origins of the defects that we see. We need to know more about the way in which these defects can cause problems in the infant, the child and even in the adult. We need to know more about defining the specific type of disorder and the specific variants of the disorder. This will require better biochemical and genetic testing with better coordination between the laboratory and the clinic so that we can more fully understand the relationship that the gene has to the expression of the disorder.’

Understanding mutations

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What part, we asked, is mutation scanning already playing in the development of improved screening for PKU. ‘Mutation scanning to identify specific types of PKU is quite advanced. We can now identify a number of different genotypes (different mutations) in the phenylalanine hydroxylase gene which relate to different degrees of PKU.

‘For example, we know that certain mutations tend to be associated with a very severe classical form of PKU. We know that others tend to be associated with a milder form of PKU and we know that there are still other mutations that are associated with a form of hyperphenylalaninemia, an elevation of blood Phe that we may not even term PKU but we call mild hyperphenylalaninemia, and which may not need to be treated.

‘So by identifying the mutations in the phenylalanine hydroxylase gene (the genotype of the individual) we can pretty well, in most cases, determine whether the baby has a severe form of PKU or a much milder form. We may also be able to determine when the baby has an elevation of blood Phe that is not PKU but the result of a defect in the production or the recycling of the cofactor BH4. This produces an elevation in blood Phe that is identical to PKU by traditional screening but requires a very different type of treatment.’

The road ahead

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What, we asked, are Prof Levy’s hopes for the future and the next steps in PKU research. ‘We still don’t really understand the relationship between PKU and the biochemical abnormalities that we can measure in the blood, in the urine, of people with PKU and why, in the absence of effective early treatment, there is brain damage from those particular metabolites. We assume that somehow the high Phe in the brain is damaging the brain, but how does high Phe damage the brain?

‘We don’t know. I am very excited about the possibility that there will be new techniques coming into play within the next few years that will allow us to begin to answer that question.’

Harvey Levy

Department of Pediatrics
Harvard Medical School
Boston, United States