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Perspective interview - Francjan van Spronsen

Perspective interview - Francjan van Spronsen

PKU Academy Newsletter Winter 2011/2012 Francjan van Spronsen shares his excitement about the progress for patients

Francjan van Spronsen shares his excitement about the progress towards more positive outcomes for PKU patients

Prof van Spronsen, of the Beatrix Children’s Hospital, University Medical Center of Groningen (Groningen, the Netherlands), is a member of the SSIF Faculty and was a member of the organising committee for the European Phenylketonuria Group (EPG) symposium held in Lisbon, Portugal (March 2011).

He chaired a workshop at the symposium on Outcome for PKU patients (neurology, neurophysiology, quality of life, etc.) and was on the expert panel for the discussions following the Asbjørn Følling Lecture.

Prof van Spronsen first became interested in PKU when, as a student, he wanted to broaden his interests from, ‘learning, learning, learning’ and tackle some research. By chance, he became involved with some work being undertaken to better understand the issues faced by families of PKU patients.

‘I had some questions about PKU and about PKU treatment, about the physiology and so it went on and on’, he said.

The challenges of PKU treatment

Prof van Spronsen commented that when you think of PKU diagnosis and treatment you think of a success story. He reminded us of how ‘we have gone from an acceptance that a PKU patient would suffer mental retardation to the position today where the outcome for the patient would be more or less normal mental capacity with an IQ within the normal range.’

interview 2 neuron

However, Prof van Spronsen warns that we still have a long way to go before we fully understand the disease, ‘We do not understand what goes on in the brain of a PKU patient. Whether they develop mental retardation, or if they are screened and treated from early in life to adulthood, the brain of the PKU patient remains a “black box” and this is a problem. We have to better understand the pathophysiology of PKU if we are to develop new treatment strategies,’ he said.

Is sapropterin the answer?

Prof van Spronsen recalled how, in the Netherlands, the initial results with sapropterin treatment caused a great deal of excitement, as the number of patients who were responsive to treatment was much higher than expected.

This initial excitement was followed by the realisation that finding the correct balance of sapropterin treatment and diet for each patient took a great deal of time and effort.

‘What we see, and we are not happy with this, is that patients who were at Phe levels which were very nice now use sapropterin to increase the amount of protein, but at the same time have higher Phe concentrations. They are struggling with the concept of having, on the one hand, the possibility of having some more protein but still needing to be aware that they cannot tolerate too much protein.’

Changing priorities

Over the last twenty years the aim of PKU treatment has changed. At one time, treatment was thought successful if the outcome for the patient was that their IQ was within normal limits. Today, there is more to aim for.

Prof van Spronsen said: ‘When our aim is to have both a normal neurocognitive and a normal quality of life outcome we must have different measures of outcome. IQ is just too rough to measure the small issues in PKU patients so we have to think of neuropsychological testing, of speed testing. We have to integrate some measure of neurophysiological outcome in our day to day care. So, in an ideal world, when a patient comes to the clinic and gives blood to measure their Phe concentration they also have an outcome measure at a computer so that you can see in just twenty minutes whether everything is going alright, and where there is a problem you can discuss the treatment options with the patient.’

It’s all about results

Currently the delay between taking a blood sample and getting a result is too great, often several days. Prof van Spronsen looks forward to a home monitoring system where patients can see the results and learn from them, making the connection between their blood Phe levels and their behaviour.

There is also a need to better understand how brain Phe concentrations relate to blood Phe concentrations in individual patients. Prof van Spronsen feels that improving the practicality and reliability of brain Phe measurement is a vital step to understanding why some patients can tolerate higher blood Phe levels than others and why some patients, despite blood Phe concentrations that ‘seem perfect’ go on to develop neurological problems.

Prof van Spronsen is optimistic that these challenges will be overcome and reminded us that twenty years ago, the measurement of blood Phe concentration was far from reliable.

‘I remember one of the finest people in PKU treatment, Richard Koch, saying at a congress some twenty years ago, “I have a patient with a Phe concentration in the blood of 250, and at the same time 600 or even 1,200”, and I, as a student, thought, “What is happening, it cannot be that in the morning it is 250 and in the evening it is 1,250”; and he told me, “Well, we have two different methods of testing.” Nowadays, both of those methods would have given the same result but that’s how it was then. That’s not a problem anymore, whatever method you use you always get more or less the same result.’

Beyond sapropterin

‘With sapropterin’, says Prof van Spronsen, ‘we have the possibility to improve the treatment strategy in a large number of patients but still it is the minority of the PKU patient group. We have to think of other treatments: strategies which can help all patients with PKU, so that we can get them at a lower strictness of dietary treatments or maybe even skip the dietary treatment.’

Overcoming barriers

What, we asked, were the other barriers to achieving better outcome for PKU patients? Prof van Spronsen agreed with his colleagues that the lack of international guidelines for PKU diagnoses and treatment needed to be addressed.

‘Guidelines are completely different around the world, they are completely different within some countries, and we have to be sure that we can move to one guideline worldwide. We must also ensure that any guidelines agreed are actually used in more or less the same way, for when we have a guideline but don’t use it, what’s the sense of a guideline?’

Agreeing guidelines was not, however, a straightforward process, ‘To get a guideline we need knowledge, we need data. We have data for the children up to 15 years of age but after 15 there is a lack of data. This is a problem.’

Prof van Spronsen added: ‘We also lack data on other aspects of treatment. The data we have are usually about Phe concentration and other amino acid concentration in the treatment. But the real thing to understand is the pathogenesis. Currently, we think that it’s only the Phe concentration in the brain that is important and all our treatment strategies are to decrease the brain Phe concentration. But it could very well be that it’s not only the Phe concentration which has to be normalised but that it is also important to increase other amino acid concentrations at the same time.

‘We don’t know this for sure, so once again we have really to dig into the brain’, Prof van Spronsen commented adding that ‘It is certainly an exciting time to be working in PKU.’

Francjan Van Spronsen

Pediatrician metabolic diseases, Associate Professor Pediatrics
Beatrix Children's Hospital
University of Groningen
Groningen, Netherlands