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Perspective interview - François Maillot

Perspective interview - François Maillot

PKU perspective - Professor Francois Maillot

European Guidelines for PKU and the work towards formulating them were, as expected, a theme at the 5th EPG Symposium. Prof van Spronsen joined Prof Maillot to run a workshop session which built on progress so far.

Prof Maillot is both a physician and a research scientist at the University of Tours (France). He has been caring for patients with IEMs for ten years, following study in Tours and also at The Charles Dent Metabolic Unit, London (UK).

We asked him how his dual background, as medic and researcher, contributed to his practice. ‘I am an internist’ Prof Maillot told us. ‘An internist cares for people from a general point of view; we don’t look specifically at one organ but we see the patient as a whole body, a system.

‘My second background is in nutrition, so I have some knowledge in biochemistry and metabolic pathways and so on. These two backgrounds match quite well to care for PKU patients.’

Prof Maillot said that he only looks after adult patients. ‘They are referred to me by pediatric colleagues who work in my hospital. So when a patient is 16 or 18 I take them over to provide lifelong care. We also have some late-diagnosed patients who came to us as adults with the condition.’

PKU in France

We asked whether late diagnosis is a particular problem in France.  He replied that there is a well-established newborn screening program there, so every child born with PKU should be diagnosed.

‘However, occasionally we diagnose an adult patient with PKU. Most commonly, these patients are immigrants who come from a country where there is no screening program. Sometimes, but this is rare, we can diagnose the oldest patients as having PKU when they are referred because of behavioral or neurological problems.’

On specific challenges about achieving good adherence to diet with French adults, he said ‘It can be difficult encouraging adults to adhere to a Phe-restricted diet or to take supplements because in France we have no specific guidelines about keeping the diet for life. There is a risk that adults have long since passed the point where they were told they needed to follow the diet and are effectively lost to follow-up.’

What were the consequences for patients of being lost to follow-up? ‘Some do their own diet without advice’ the professor said. ‘They avoid eating meat, fish or egg so that they don’t eat much protein. I believe they think that this is the best way they can protect their brain from high blood-Phe levels.’

DIY diet danger

He added, however ‘What they often fail to realize is that this kind of “do it yourself” (DIY) diet can be dangerous for them as it can cause nutritional deficiencies. We see, for example vitamin B12 deficiencies in these patients. This is because when you don’t eat meat at all you are exposed to this. B12 deficiency can cause neurological complications, so we give them B12 and give them some dietetic advice to get better.

‘In our clinics we also see adults with minor psychological issues: depression or anxiety, sometimes anxiety to get better. We also see patients with gait problems and other neurological problems. In every case we have to ask ourselves whether these problems are related to their high blood-Phe level caused by the patients being off diet.

‘Faced by a patient with, for example, neurological problems, the first thing we do is a check for vitamins, to see if there are any deficiencies. Then we try to put them on a PKU diet just to see what is going on. If the Phe levels go down, we ask the question “Are they getting better?”

Prof Maillot: ‘Some adult patients come to us just because they have a lot of questions about their condition. We get a lot of questions about the outcome, particularly with older age. We hear questions about risk of neurological complications as they get old, particularly about the risk of Alzheimer’s or Parkinson’s diseases.’

Diet for life?

We were interested by the professor’s choice of words when talking about introducing diet, particularly the reference to monitoring for effectiveness. Did this mean that diet was NOT necessarily the preferred option?

He told us ‘I wonder whether diet for life is ALWAYS a good response to PKU as a patient. This is just because there is no clear evidence at the moment for keeping every single PKU patient on diet. This is something where the evidence base needs to be stronger.’

To answer these questions the French Government is funding a five-year multicenter study of a national cohort of adult patients with PKU (ECOPHEN). Professor Maillot is heavily involved with the study so we asked how it was going.

‘We started last year, including adult patients over 18 years old, whom we aim to follow up for five years in the first instance’ he said.

‘This is the extent of the current funding but we’re obviously hoping to continue following up for as long as possible, to see the outcome. We want to know “What is the life of an adult PKU patient now in France?” We have patients who are on diet and some who are off diet. We want to follow them up yearly, to have an assessment once a year, and to see whether there are any changes over time.

‘We aim to discover whether there is any evolution at the adult age or are people with PKU very stable over time in terms of neurological function, executive function, psychiatric state, etc. So study participants have a big assessment at their first study visit.’

The professor itemized:

  • they spend two hours with a neuropsychologist for tests of their IQ and executive function
  • there are questionnaires about their QOL and their potential anxieties
  • there are questionnaires about their health in general: do they have gait problems; do they have any other problems in life; do they work; are they married, do they have children, do they have any problem in the society? And so on.

Recruiting a large enough sample of patients within a single country sounds daunting. We asked how easy it had been to recruit. ‘We have recruited 48 patients so far and we expect to recruit 200 patients in total over the next year for follow-up over five years’ Prof Maillot said.

‘We are expecting some problems in effectively recruiting patients because so many adult patients are lost to follow-up in France.

‘To help us with recruitment we are fortunate to have the full support of the patient association, Les Feux Follets. Through their website  and their journal they are promoting the ECOPHEN study and are encouraging their members to join. We couldn’t have set up this study without the support of the patients’ association. This is very important to work with them. They have 300 families involved in their association. They are very active and I could not do anything without their help.’

And the European guidelines for PKU…

On his  role in the guidelines project, the professor said ‘We started working on this in October 2012 so it’s all very new, and we’ve got two years to get it done. Establishing the guidelines is going to take a lot of time and it means we have to work very hard. We have, so far, five working groups and we are considering setting up one more. I am involved, as you can imagine, with the group looking at adult and maternal PKU.’

Having discussed the lack of a suitable evidence base to inform decisions about diet for life, we asked whether the paucity of suitable studies would prove a barrier to creating meaningful guidelines.

Prof Maillot said ‘I think that the European guidelines for maternal PKU will be based upon very good evidence because we have the prospective maternal PKU study performed in the USA and Germany. We gained a lot of knowledge from this study (it was a 15-year prospective study) and then we have some sound conclusions.

‘However, yes, for the adults in general there is a huge lack of evidence and in my opinion the statements we are going to produce in this group will need to be based more on expert opinion than evidence-based studies.

‘Working with PKU is quite exciting at the moment because we have new drugs in development, we expect to have some enzyme therapy maybe and, of course, working on the European guidelines is exciting.’