pku academy newsletter - excemed · 4 | pku newsletter issue 3 summer 2012 quality in the balance...

ADVANCES & CHALLENGES IN PKUADVANCES & CHALLENGES IN PKU

Meeting report from the 4th European Phenylketonuria Group Symposium & 2nd Dietitians’ Workshop, Rome, Italy, 22-24 March 2012

ISSUE 3 SUMMER 2012

PKU ACADEMY NEWSLETTER

Welcome to Issue Three of the PKU Academy NewsletterIn this edition of the PKU Academy Newsletter, we report on the highlights of the 4th European Phenylketonuria Group Symposium & 2nd Dietitians’ Workshop. These meetings attracted over 200 delegates from 30 countries to Rome, Italy, between the 22nd and 24th of March 2012.

We also feature two more of the

popular ‘PKU Perspectives’ interview

features which give a personal

view from the people behind the

presentations and papers.

Mrs Nicole Pallone, vice president

of Canadian PKU and Allied

Disorders, Ottawa (Canada) tells us

about how she felt when asked to

consider putting her daughter, aged

18 months, in a clinical study.

Prof François Feillet of the Centre de

Réferénce des Maladies Héréditaires

du Métabolisme, Vandoeuvre les

Nancy (France), shares his concerns

about the need to understand the

lifetime effect of a PKU diet.

Contents2nd Dietitians’ Workshop ..... 2

4th European Phenylketonuria

Group Symposium ............ 6

Feature interview with

Prof François Feillet ......... 9

Feature interview with

Mrs Nicole Pallone ..........10

In the next issue .............12

Read and share the online version of the newsletter - http://bit.ly/PKUnews03

2 | PKU Newsletter Issue 3 Summer 2012

Dietitians, nutritionists and physicians

from across the world met in Rome

(Italy) on March 22nd 2012 to discuss

the latest research and developments

in the dietary management of PKU.

A packed agenda for the day provided

delegates with the opportunity to

hear presentations detailing the latest

research in PKU management. Delegates

had the opportunity to discuss issues

raised by the main presentations,

compare and contrast local practices

and share best practice by participating

in roundtable discussions and workshop

sessions. Themes explored included:

!" micronutrient status in PKU

!" the assessment of nutritional status of PKU patients

!" issues arising from combining diet with sapropterin (tetrahydrobiopterin-BH

4) treatment

!" working effectively with, educating and motivating patients

!" the management of maternal PKU

!" considerations of quality of life for

patients on strictly controlled diets.

!"#$%&'#%(%)*+%,-./-*00#1%abstracts, a selection of presentations and videos – http://bit.ly/PKUnews03-DW2

Micronutrient issues in PKU

The workshop opened with presentations

from Prof François Feillet1 and Prof

Anita MacDonald2 focusing on th e

challenges of ensuring patients on PKU

diets have correct levels of essential

micronutrients. Both speakers expressed

concerns that lack of monitoring of

the nutritional status of PKU patients –

principally due to considerations of

practicality and cost – could be exposing

patients to risk of poor health in the long

term. Prof MacDonald highlighted

&'#%2"3(%45+&"#6%.3%*66#66")/%7"&*0")%

and mineral status such as blood

sample quality, sample storage, inter-

laboratory variation and lack of age-

6,#4"(%4%-#3#-#)4#%-*)/#68%97#)%"3%&'#6#%

sources of variation could be minimised,

results could still be affected by

diurnal variation, fasting status, acute

")3#4&".)6%*)2%"):%*00*&.-;%6&-#668

Prof Feillet reminded the audience

that while vitamins are present in high

levels in many supplements to counter

2#(%4"#)4;1%&'#;%*-#%).&%)#4#66*-"+;%

in a form that is readily bioavailable.

With reference to key vitamins such as

B12

, linked to neurological symptoms in

PKU patients, Prof Feillet stressed the

importance of monitoring vitamin levels

and supplementation when necessary.

Prof MacDonald discussed the current

research into mineral levels in PKU

patients, pointing out that ‘we provide

copious quantities of nutrients

within our special protein substitutes,

but it is the quality of that nutrient

source that counts.’ Prof MacDonald

concentrated on selenium, iron and

zinc, reviewing the importance of

these minerals to metabolism and

discussing the results of studies showing

reduced levels of selenium and zinc in

patients following a restricted diet.

In the discussion that followed,

Dr Júlio César Rocha3 stressed the

importance of testing for vitamin D3

levels, which can result in reduced

bone mineral density over time.

Watch Prof Anita MacDonald’s lecture – http://bit.ly/PKUnews03-11

110 delegates from 26 countries attended the 2nd Dietitians’ Workshop in Rome, Italy

2nd Dietitians’ Workshop

www.pkuacademy.org | 3

1 Prof François Feillet (Centre de

Réferénce des Maladies Héréditaires du

Métabolisme, Hôpital d’Enfants, CHU

Brabois Vandoeuvre les Nancy, France)

2 Prof Anita MacDonald (Dietetic Department,

The Children’s Hospital, Birmingham, UK)

3 Dr Júlio César Rocha (Centro de Genética

Médica, Jacinto de Magalhães, Instituto

Nacional de Saúde, Porto, Portugal)

4 Ms Katharina Dokoupil (Department of Metabolism

and Nutrition, Dr von Hauner Children’s Hospital,

University of Munich, Munich, Germany)

5 Dr Hulya Gokmen-Ozel (Faculty of Health

Sciences, Department of Nutrition and Dietetics,

Hacettepe University, Ankara, Turkey)

6 Prof Friedrich K Trefz (Medical Centre

Gammertingen, Kreiskliniken Reutlingen

GmbH, Gammertingen, Germany)

7 Mrs Kirsten Ahring (PKU Department, The

Kennedy Center, Bagsværd, Denmark)

Introducing sapropterin

A series of case studies were presented

at the meeting. The presentations

were followed by a panel discussion.

Dosage of sapropterin in over-weight patients, Dr Katharina Dokoupil4

Dr Dokoupil discussed how obese patients

present two problems for the clinician:

!" the correct dose needs to be determined – this can take time

!" the cost of maintaining an effective 2.6#%4*)%.5&$#"/'%&'#%<#)#(%&6%.3%

treatment.

Dr Dokoupil detailed the case of an

obese patient who was initially given

a dose of 4.7 mg/kg but required an

eventual dose of 7 mg/kg to give a

50% reduction in blood Phe levels.

Managing illness with diet and sapropterin, Dr Hulya Gokmen-Ozel5

problems with the fetus. The mother

experienced no side effects either

during gestation or after delivery. There

were no health problems with the baby.

Managing a second diagnosis with sapropterin, Mrs Kirsten Ahring7

Mrs Ahring described how PKU with

insulin-dependent diabetes mellitus

(type 1 diabetes) presented particular

problems for diet with reference

to the case of a girl with mild PKU

(BH4-responsive) who was diagnosed

with type 1 Diabetes aged 3 years.

Because the patient had mild PKU

she could have been expected, were

it not for the diabetes, to achieve

good control of blood Phe with a free

diet plus 5 mg BH4/kg of sapropterin.

However, the required diets to give

best control of PKU and diabetes

4.):%"4&8%=&%$*6%)#4#66*-;%&.%,-.7"2#%

higher doses of BH4 (up to 20 mg/kg)

in order to give adequate control of

both blood sugar and BH4. Observations

that there was a stabilisation and

New PKU Academy Online Course

The PKU Academy website provides

opportunities to learn about PKU

through a variety of educational

resources and online programmes.

We are pleased to announce

a new online course, ‘Clinical

Management of PKU’, which looks

at treatment strategies for PKU.

The course provides suggestions

on how PKU management can

be optimised. Dietary treatment

lowering of blood sugar while taking

the highest dose of BH4 prompted

further investigation into whether BH4

was affecting blood-sugar level and

the consumption of insulin. However,

closer attention to diet brought better

4.)&-.+%.3%&'#%2"*<#&#6%*)2%&'#%(%)*+%

conclusion was that the BH4 had not been

responsible for the observed effects.

is examined alongside medical,

gene, enzyme and cell therapies.

There is also an overview of

future trends in research.

The course will have CME

accreditation from the European

Accreditation Council for Continuing

Medical Education (EACCME).

Visit the PKU Academy online – www.pkuacademy.org

Increased blood Phe levels in patients

$"&'%")3#4&".)6%*)2%"):%*00*&".)%4*)%

create a dilemma for the physician said

Dr Gokmen-Ozel. Although on one hand

it is important to lower blood Phe levels,

introducing too restricted a diet

can reduce the patient’s ability to cope

with infection. With reference to two

cases, Dr Gokmen-Ozel recommended

that sapropterin dose should be

increased along with a reduction in

animal protein and the provision of

additional protein supplements.

Managing pregnancy with sapropterin, Friedrich K Trefz6

Prof Trefz reported success in treating

maternal mild PKU in a BH4-responsive

pregnant woman who was intolerant

of a Phe-restricted diet and had poor

metabolic control. Adequate control

was achieved with sapropterin and a

low Phe diet. There were no health

Treating MPKU with sapropterin


Quality in the balance

For PKU patients, happiness comes at a

price, said Prof Anita MacDonald2 in her

closing presentation to the workshop.

Supporting patients, particularly

adolescents, to make decisions about

their diet must take their feelings

about quality of life into account.

Adherence to a strict PKU diet is not

easy and can be especially hard for

adolescents. Maintaining blood Phe

levels in the advised ranges puts huge

pressure on patients and their families.

For this reason, successfully treated

patients often report a reduction in

their health-related quality of life

(HRQoL). Because HRQoL is a subjective

measure of an individual’s satisfaction

with parts of their life that affect

their health, or are affected by it,

the happiest adolescents tend to

be those with the highest blood Phe

levels and the least inconvenience

from a restricted diet. These tests do

not, however, properly take account

of the negative effects of having

PKU with poor dietary control.

Relaxing dietary control may well

improve the quality of a patient’s

life, but at what cost? In children,

relaxing control has a detrimental

effect on the cognitive ability of the

patient and should not be considered.

In adults, ceasing dietary control

does not cause a major decrease in

IQ, however, high blood Phe is still

*66.4"*&#2%$"&'%2#(%4"&6%")%#>#45&"7#%

function (neuropsychological

performance) and poor mood.

of the opportunities offered by

technology to individualise their

patient communications? Reminding

patients to send in their monthly blood

samples by sending a text message

to their mobile phone is a valuable

tool to aid compliance according to

Miss Boocock. In her presentation,

Miss Boocock outlined the results of

a year-long study involving 25 adult

patients (aged 16+ years). Sending

the patients monthly text message

reminders when their samples were

due increased the total number of

blood spots returned by 65% (p=0.03).

Therefore, dietary freedom and the

associated lack of control of blood Phe

does come at a price. Patients need

to be educated that the potential

advantages of going off diet have to be

balanced against the negative effect

on mood and executive function (loss

of attention, etc). For many, a Phe-

restricted ‘Diet for Life’ will still be the

best option, Prof MacDonald concluded.

Additionally, 44% of patients increased

the amount of blood spots sent in by 2

or more. The more adherent patients

")%&'#%/-.5,%<#)#(%&#2%0.6&%3-.0%&'#%

reminders and were the most improved.

The messages did little to improve

adherence in the unmotivated patients.

Low plasma zinc and selenium widespread, Miss Sarah Boocock9

Miss Boocock provided further

information from recent work in

Birmingham (UK) revealing, in her

presentation, results suggesting

that low plasma zinc and selenium

Teenagers with poorest control

are happiest

Dietitians’ Workshop oral presentation highlights

Sapropterin effective at managing Phe levels in toddlers, Mrs Nicole Pallone8

Mrs Pallone discussed the case of

patient RP, her daughter Rosie. RP is

currently participating in a clinical

6&52;%")&.%&'#%#3(%4*4;%*)2%6*3#&;%.3%

sapropterin in treating infants under

4 years (PKU-015 study). Despite

close adherence to diet, RP had blood

Phe levels that were occasionally

above the recommended range

(120–360 µmol/l). With sapropterin,

RP’s blood Phe is consistently in the

range 120–240 µmol/l while at the same

time her Phe tolerance has doubled.

TXT 4 PKU, Miss Sarah Boocock9

In a n era of ‘Individualised Medicine’

are clinicians taking advantage

Technology offers opportunities to

personalise patient communications

A less restricted diet, even for infants, remains a therapeutic goal


!" risks to the developing child can be minimised by ensuring the mother keeps her weight and blood Phe levels under control (100–300 µmol/l) through an adequate diet that includes folic acid and essential fatty acids (200 mg DHA/day) which are not part of the normal PKU diet. Care needs to be &*?#)%$"&'%(%6'%."+%<#4*56#%.3%"&6%

vitamin A content

!" regular nutritional and biochemical assessment is essential throughout pregnancy

!" it is vital to provide information to both parents to increase adherence to diet

!" breastfeeding is encouraged.

Delegates further discussed the

assessment of nutritional status in

a workshop led by Dr Júlio César

Rocha3 and Dr Hulya Gokmen-O zel5.

The restricted diet of PKU children

4*)%+#*2%&.%2#(%4"#)4"#6%.3%7"&*0")61%

minerals and omega-3 fatty acids. This

leads to growth retardation. Obesity

is a risk due to low physical activity

coupled with excessive caloric intake.

Only a supplemented and balanced

diet can minimise these problems.

The ‘introducing sapropterin with

diet’ workshop was led by Dr Margreet

van Rijn14 and Dr Amaya Bélanger -

Quintana15 who reviewed a number

of case studies and led discussion

on the best methods for introducing

sapropterin with diet in mild PKU BH4-

responsive patients. In these patients,

sapropterin allows patients to reduce

the level of protein restriction but

they still require some amino acid

supplementation. It is important to

monitor the patient and adjust dosing

according to metabolic control, age-

targeted guidelines for blood Phe levels

and under special circumstances (e.g.

25-")/%")3#4&".)%.-%"):%*00*&".)@8

8 Mrs Nicole Pallone (vice president of Canadian

PKU and Allied Disorders, Ottawa, Canada)

9 Miss Sarah Boocock (Nutrition and

Dietetics Department, Queen Elizabeth

Hospital, Birmingham, UK)

10 Dr Natalia Usurelu (The National Center of

Reproductive Health and Medical Genetics,

Chisinau, Republic of Moldova)

11 Prof Laurie E Bernstein (Department of

Pediatrics, University of Colorado School

of Medicine, Denver, Colorado, USA)

12 Mrs Eleanor Weetch (Nutrition and Dietetics,

National Society for Phenylketonuria, UK

& Adult Metabolic Dietitian, Northern

A#)#-*+%B.6,"&*+1%C'#3(%#+21%DE@

13 Ms Kristina Motzfeldt (Department of Pediatrics,

Women and Children’s Division, Section for

Specialized Medicine and Unit for Newborn

Screening, Oslo University Hospital, Norway)

14 Dr Margreet van Rijn (Section of Metabolic

Diseases, Beatrix Children’s Hospital, University

Medical Center Groningen, Netherlands)

15 Dr Amaya Bélanger-Quintana (Unidad de

Enfermedades Metabólicas, Servicio de Pediatría,

Hospital Ramón y Cajal, Madrid, Spain)

concentrations are common in patients,

whether or not they have adequate

metabolic control of blood Phe

through use of dietary supplements.

Education about PKU must go beyond the family, Dr Natalia Usurelu10

Dr Usurelu is both a physician and a

parent of a PKU child. Her son was

*+6.%'#-%(%-6&%FED%,*&"#)&8%G-%D65-#+5%

reminded the delegates that a diagnosis

.3%FED%0#*)6%6"/)"(%4*)&%4'*)/#6%")%

the lifestyle not only of patients and

their parents but also of their relatives,

friends, teachers, caregivers, etc.

Dr Usurelu discussed how education

about PKU must not be directed only

at patients and their families, but to

society as a whole. This is vital if PKU

patients and their families are to be

properly supported by the institutions

with which they have to deal on a

day-to-day basis, such as schools.

Dietitians’ Workshop session highlights

A range of workshops enabled

delegates to discuss local practices

and share best practice.

Prof Laurie Bernstein11, leading the

wo rkshop on the education and

motivation of patients, reviewed

a range of tools. Key points in

the discussion included:

!" psychological support is a valuable tool that can help counteract children’s embarrassment and frustration

!" improving the way children and young people feel about their PKU can, in turn, improve family cohesion and diet adherence

!" age-appropriate educational programmes and group activities are valuable as they build the ‘people skills’ of children and young people and increase the level of responsibility they take for their PKU.

The management of maternal PKU

(MPKU) was discussed in the workshop

led by Mrs Eleanor Weetch12 and

Ms Kristina Motzfeldt13. Key points

in the discussion included:

!" the best time to start controlling 2"#&%&.%<#)#(%&%&'#%<*<;%"6%<#3.-#%"&%

is conceived

Breastfeeding is encouraged


The symposium ‘Advances and

Challenges in PKU’ took place in Rome

(Italy) on March 23rd and 24th 2012. The

2-day programme gave an international

audience of physicians and researchers

the opportunity to attend a wide range

of presentations and workshops.

!"#$%&'#%(%)*+%,-./-*00#1%abstracts, a selection of presentations and videos – http://bit.ly/PKUnews03-EPG4

The themes explored included:

!" strategies for providing essential amino acids in the diet of PKU patients, comparing and contrasting glycomacropeptide and large neutral amino acids as supplements

!" diagnosis and treatment of BH4

2#(%4"#)4"#6

!" strategies for improving adherence to PKU treatment

!" the importance of effective and reassuring communication between physicians and parents at diagnosis.

The event culminated in the Asbjørn

Følling lecture, given this year by

Prof Harvey Levy16.

View a video interview with Prof Harvey Levy recorded at the symposium - http://bit.ly/PKUvideo_levy

The Italian problem

Prof Marcello Giovannini17 gave the

opening presentation, providing

the delegates with an overview of

PKU in Italy. Neonatal screening

for hyperphenylalaninemia (HPA)

has been compulsory in Italy since

1992 but has been a common

practice in some areas for longer

than this; in the Lombardy region of

Northern Italy, screening began in

1977. Since 2010 there has been a

National Registry for PKU patients.

The incidence of all types of HPA in Italy

is 1 in 3,494 live births with 1:8,681

babies affected by forms of HPA that

require treatment. The incidence of

Type I HPA (classical PKU) is 1:17,905.

Similar numbers of newborns, 1:17,362

are diagnosed with Type II (mild PKU)

and 1:5,907 with Type III (mild HPA).

The Clinical Department of Pediatrics,

San Paolo Hospital, University

of Milan, is Lombardy’s Regional

Reference Centre for the diagnosis

and treatment of PKU patients.

There are 660,550 patients currently

being followed by the centre (200 of

whom have been followed for over

18 years). The ages of the patients

range from newborn to 50 years of

age, with a mean age of 14.5 years.

The majority of the patients are

ethnic Europeans (93.8%).

Prof Harvey Levy gives the Asbjørn Følling lecture to the 231 delegates from 30 countries who attended the EPG Symposium

Prof Marcello Giovannini outlines

the status of PKU in Italy

4th European Phenylketonuria Group Symposium


BH4 beyond blood Phe

The ability of BH4 to reduce blood

Phe levels in some PKU patients,

the so-called BH4-responders, is

changing the way the disease is

being treated across the world.

Prof Nenad Blau18 discussed other

,.&#)&"*++;%<#)#(%4"*+%#33#4&6%.3%HB4

that are attracting research interest:

!" the effect of BH4 in non-responder

PKU patients, particularly those with neuropsychiatric symptoms ")4+52")/%I&&#)&".)%G#(%4"&%

Hyperactivity Disorder, anxiety and depression

!" the role of BH4 on endothelial

function in cardiovascular

disorders, including diabetes linked to the effects of BH

4 on

nitric oxide synthesis

!" the potential role of BH4 to reduce

oxidative stress in the brain due to its ability to cross the blood–brain barrier and its involvement with the synthesis and catabolism of catecholamines and serotonin

!" the possibility that BH4

pharmacotherapy could have the potential to target other diseases.

Watch Prof Nenad Blau’s lecture – ‘Mode of action of BH

4 beyond

blood Phe control’ - http://bit.ly/PKUnews03-10

Prof Nenad Blau discusses the ‘other’ properties of BH4

Exploring complexity through bioinformatics

PKU is a complex trait, acknowledged

Dr Søren Gersting19. Although it is

caused in 98% of case s by a mutation

in the phenylalanine hydroxylase (PAH)

gene, there are more than 600

mutations characterised to date.

In addition, the clinical phenotype

is affected by other factors: the

amount of dietary Phe, the degree to

which ingested Phe is absorbed, the

metabolic state of the patient and

the degree to which Phe in the blood

passes across the blood–brain barrier.

Dr Gersting described how

bioinformatics can be used to help

correlate genotype with phenotype

has been available since 2009 for

patients over 4 years of age but not for

younger patients. In France, however,

its use has been allowed in certain

circumstances. Using retrospective

data from 15 children under 4 years

old who had received BH4 in this way,

Dr Labarthe argued that BH4 is both

safe and effective in the treatment of

mild PKU in BH4-responsive patients

under 4 years old. Studied subjects had

received a BH4 dose of up to 20 mg/kg/

day to achieve age-target Phe levels

$"&'%*%6"0,+"(%#2%2"#&8%I3&#-%J%;#*-61%

blood Phe levels had normalised and

stabilised with satisfactory neurological

outcomes. No side effects were seen.

Worth the weight?

Physicians treating PKU patients need

to consider developing strategies for

encouraging sustainable enhanced

physical activity levels in their patients,

said Prof Berthold Koletzko21. Patients

with PKU have a high risk of being

overweight or obese due, in no small

part, to the PKU diet. Prof Koletzko

detailed a study of 33 early-treated

PKU patients aged 25 years or over.

The Body Mass Index (BMI) and energy

expenditure of the PKU patients were

compared with controls, matched

for age with similar levels of formal

education. The PKU patients had

higher BMIs and lower activity levels.

Although it is impossible to attribute

which is the cause and which the

effect, there is certainly a real need

to intervene to prevent the cycle of

weight gain and decreasing activity.through the analysis of enzyme kinetics

and molecular structure. This could

allow tailored diagnosis and therapies

to be developed and may help:

!" understand the molecular mechanisms behind loss of function

!" 2#(%)#%65<K/-.5,6%.3%,*&"#)&6%$"&'%

respect to treatment

!" identify novel biomarkers that could be useful in the development of the next generation of drugs to assist PKU management.

BH4 for under 4?

BH4%&'#-*,;%"6%#3(%4"#)&%*)2%'*6%<##)%

demonstrated to be safe for children

aged under 4 years according to Dr

François Labarthe20. In Europe, BH4

16 Prof Harvey Levy (Medicine/Genetics, Harvard

Medical School, Children’s Hospital Boston, USA)

17 Prof Marcello Giovannini (Department

of Pediatrics, San Paolo Hospital,

University of Milan, Milan, Italy)

18 Prof Nenad Blau (Division of Inborn

Metabolic Diseases, University Children’s

Hospital, Department of General

Pediatrics, Heidelberg, Germany)

19 Dr Søren W Gersting (Department of Molecular

Pediatrics, Dr von Hauner Children’s Hospital,

Ludwig-Maximilians-University, Munich, Germany)

20 Dr François Labarthe (Médecine Pédiatrique

& INSERM U921, CHRU de Tours, Université

François Rabelais, Tours, France, &

Réseau Maladies Métaboliques Hôpitaux

Universitaires du Grand Ouest, France)

21 Prof Berthold V Koletzko (Division of Metabolic

and Nutritional Medicine, Dr von Hauner

Children’s Hospital, Munich, Germany)


‘State of the science’

What is best for PKU patients now and

tomorrow? To answer this question,

in 2000, the US National Institutes of

Health (NIH) published a Consensus

Development Conference Statement

for screening and management of PKU

to provide guidelines for clinicians.

Since then, new therapies have

emerged and new strategies for PKU

treatment have been developed.

To revise the guidelines, the NIH

.-/*)"6#2%*%LFED%C4"#)&"(4%M#7"#$%

Conference: State of the Science and

Future Research Needs’ in February

2012. Prof Harvey Levy16 reported

the highlights of the conference:

!" blood Phe levels should be monitored and controlled for the entire life of the patient

!" management in pregnancy and in early life should be stricter, with targeted use of sapropterin

!" diet and formulations should be improved and more readily available

!" analysing genotype and phenotype is key to future treatment success.

4th EPG Symposium oral presentation highlights

48-hour BH4 loading test is

cost-effective and reliable, Dr Karen Anjema22

Dr Anjema presented a study showing

that the 48-hour BH4 loading test is a

valid way to predict long-term BH4-

responsiveness in PKU patients. The

test is not as accurate as genotyping,

<5&%"6%6"/)"(4*)&+;%4'#*,#-8

The value of molecular character-isation, Dr Caroline Heintz23

Dr Heintz discussed assessing

BH4-responsiveness by molecular

characterisation of the phenylalanine

hydroxylase (PAH) gene mutations which

cause misfolding. Where these mutations

affect the PAH catalytic domain to cause

dysfunctional enzyme activity, this can

be correlated with clinical phenotypes

that are responsive to sapropterin.

Understanding the role of PAH mutations, Dr Frank Rutsch24

N'#%"):5#)4#%.3%")2"7"25*+%FIB%05&*&".)6%

on BH4-responsiveness was further

2"64566#2%<;%G-%M5&64'1%$'.%"2#)&"(#2%

mutations that can be used to predict

the degree of response (e.g. L48S).

A step towards gene therapy, Dr Hiu Man Viecelli25

Dr Viecelli reported lowered Phe levels

with improved behaviour in PKU mice

treated with minicircle-based naked-

DNA blood injections to the liver.

PAH gene transfer occurred in liver

cells with expression dependent on

dose. The effects were persistent and

consistent. Dr Hiu Man Viecelli won

the Serono Symposia Foundation (SSIF)

award for best oral presentation on

basic research at the EPG Symposium.

Strict diet vital, Dr Rianne Jahja26

Dr Jahja stressed the importance of

a stricter Phe blood level control in

&'#%(-6&%OJ%;#*-6%.3%+"3#%&.%*4'"#7#%

normal neurological outcomes in PKU.

Some aspects of executive functions

are altered even when Phe levels are

kept within currently accepted levels

between 240 µmol/l and 360 µmol/l

when compared with controls and

individuals with Phe below 240 µmol/l.

Dr Jahja won the SSIF award for

best oral presentation on clinical

practice at the EPG Symposium.

4th EPG Workshop session highlights

Amino acid supplementation in PKU

Prof Anita MacDonald2 and Dr

Margreet van Rijn14 discussed amino

acid supplementation in PKU. They

compared glycomacropeptide (GMP)

and large neutral amino acids (LNAA)

as supplements. GMP is associated with

lower fasting blood Phe concentrations

but can lead to weight gain and

tastes no better than LNAAs. The

content of LNAAs is variable but

653(4"#)&%")%4.)7#)&".)*+%3.-05+*68%

Additional tyrosine, particularly in

pregnancy, was recommended.

BH4!"#$%&#'%&#()!"&*+',(&(!

and treatment

Dr Alberto Burlina27 and Prof Friedrich

Trefz6 discussed BH4%2#(4"#)4"#6%$'"4'%

4*56#%'"/'%F'#%+#7#+6%*)2%&'#%2#(4"&%

of many neurotransmitters, with

severe neurological signs. Diagnosis

is made by BH4 loading test, and by

measuring pterins, biogenic amines

*)2%6,#4"(4%4#++K#)P;0#%*4&"7"&"#68%

Therapy requires diet, sapropterin,

neurotransmitters precursors and folates.

22 Dr Karen Anjema (Beatrix Children’s

Hospital, University Medical Center of

Groningen, Groningen, Netherlands)

23 Dr Caroline Heintz (Department of

Pediatrics, University Children’s Hospital,

University of Zürich, Zürich, Switzerland).

Ms Heintz obtained her PhD on 22/06/2012.

Congratulations Dr Heintz!

24 Dr Frank Rutsch (Klinik und Poliklinik für

Kinderheilkunde und Jugendmedizin,

Universitätsklinikum Münster, Münster, Germany)

25 Dr Hiu Man Viecelli (Department of

Pediatrics, University Children’s Hospital,

University of Zürich, Zürich, Switzerland)

26 Dr Rianne Jahja (Beatrix Children’s

Hospital, University Medical Center of

Groningen, Groningen, Netherlands)

27 Dr Alberto Burlina (Division of Metabolic

Diseases, Department of Pediatrics,

University Hospital Padua, Padua, Italy) !Prof Ania Muntau (left) awards

Dr Hiu Man Viecelli her prize

Prof Ania Muntau (left) awards

Dr Rianne Jahja her prize


Today’s PKU patients have a greater

range of treatment options and a

wider range of dietary supplements

than ever before. This certainly has

-#'#$!.(!/,0!12*3&.4!,/!3&/#!,/!5*.&#'.(!

but presents new challenges too. We

spoke to Prof François Feillet1 about

the issues raised by greater choice.

Prof Feillet gave the opening

presentation session of the 2nd

Dietitians’ Workshop in Rome (Italy)

on March 22nd 2012. He reviewed

the ongoing work to gain better

understanding of the bioavailability of

micronutrients supplied in supplements

and the effect on the health of patients

.3%*)%#>4#66%.-%2#(%4"#)4;%.3%654'%

vitamins and minerals. He is a member

of the Serono Symposia International

Foundation (SSIF) PKU Faculty.

Risks from PKU diet

Prof Feillet reminded us that the

biggest risk a PKU patient faces day

to day is still blood Phe levels that are

higher than the recommended range

due to a lack of compliance with diet.

However, he pointed out that there are

issues with the PKU diet over a lifetime

that concern researchers. ‘The principle

of dietary treatment for PKU has not

4'*)/#2%6"/)"(%4*)&+;%.7#-%&'#%+*6&%

60 years, but how we do it has changed

greatly. Where once patients had a

choice of just a couple of low protein

foods, today there are many more

supplements available with different

tastes, textures and compositions. Also,

patients now have a number of ways

to manage their blood Phe levels.’

As examples he cited:

!" patients without any diet or treatment – or with diet only

!" patients with BH4 plus diet – or with

BH4 only.

‘And these patients are all quite

different’ he said. ‘Some patients have

vitamin supplements while others do

not. Some have meat in their diet and

some have none. If you are taking a

long-term meat-free diet, even if you

have correct metabolic control you

can be at risk of vitamin and mineral

2#(%4"#)4"#61%,*-&"45+*-+;%7"&*0")6%+"?#%

B12

and minerals like selenium and zinc.

‘We have to be careful because we

don’t know what the effects of these

2#(%4"#)4"#6%*-#%.7#-%&'#%,*&"#)&Q6%

lifetime. We need to follow up adult

patients yearly and to adapt their

diet or the vitamin supplements or

anything they need, each time we

have the results of this follow up.’

But the professor said that, at present,

there is no consensus on the need

to identify and correct nutritional

imbalance in adults. ‘Few colleagues

are adopting a policy of active

nutritional intervention after the

yearly follow up. I think this is because

they are not yet convinced of the

4+")"4*+%-#+#7*)4#%.3%&'#%2#(%4"#)4"#68

‘This is a mistake,’ he warned

‘because we do not know the effects

&'#%2#(%4"#)4"#6%$"++%'*7#%.7#-%

30 or so years when the patients

age. I think we need to look at

'.$%6,#4"(%4%,-.254&6%4.5+2%<#%

created to address these issues.’

Improving supplements

He acknowledged that creating suitable

nutritional products is not easy.

‘Firstly, there is the question of the

harmonisation of the product. A company

that is creating a dietary supplement

needs to sell its product all over the

world, but the nutritional environment

of all countries is quite different.

‘You are not eating the same natural

proteins in France, in Japan, in the

USA or in the UK, or wherever. We have

different foods, we have different habits,

we have different ways to eat and so

on. However, to factor in these natural

foods and habits, we would need to

tailor the supplements for each country

or sub-population. Of course, it isn’t

realistic for substitutes to be adapted

for each country and, even if you tried,

you would need to have knowledge about

the real vitamin and mineral content of

the natural food and how the natural

food interacts with the dietary product.

‘I think the companies are doing their

best, but we hope that the problems we

'*7#%2#&#4&#2%&'-.5/'%64"#)&"(%4%-#6#*-4'%

will be useful in the development of new

products with improved composition.

We particularly need to concentrate on

the bioavailability of the vitamins and

minerals contained in these products.

Our research group is compiling a

database of the nutritional status of our

patients and we hope to gain a greater

understanding of the balance between

nutritional intake and nutritional status.’

Accepting variety

The best way to achieve dietary control

may vary from country to country but

why was there still no consensus on

guidelines for PKU management, we

asked. ‘The recommendations still vary

greatly from country to country,’ agreed

Prof Feillet ‘but this is because the

preferred outcomes for patients also vary.

‘In France, for example, we are

considered very relaxed because we

accept blood Phe levels of 1,200 µmol/l

in adulthood, while in some countries

even 600 µmol/l is thought too high.

Who is right? Obviously, we do not want

to put our patients in danger by allowing

poor metabolic control, but we need to

PKU Perspectives

François Feillet

François Feillet shares his concerns about the need to understand the lifetime effect of a PKU diet


consider the impact of a very strict diet

for life on the quality of the patient’s life.

R'#-#%"6%&'#%<#)#(%&%")%,5&&")/%*)%*25+&%

patient at 600 µmol/l compared with

1,200 µmol/l? In France, we feel that our

adult patients are doing well; we are very

happy with our patients. So, we think we

are not losing anything and the patients

are gaining psychological comfort,

quality of life and the opportunity to

eat a greater range of natural foods.’

Professor Feillet added ‘If evidence

emerges that at these levels patients are

suffering decreased executive functions

and it is affecting their ability to have

a job, enjoy a social life or is leading to

problems in old age, then we will look

again at our recommendations. For this

reason I don’t think the world consensus

is for tomorrow. But we do have to

build more data on the outcomes for

*25+&%,*&"#)&6%&.%(%)2%*%/..2%0#&*<.+"4%

control range. In my research group, we

have a neuropsychologist working on

a new test for assessing the executive

function in adulthood. I think it’s really

important to assess the real capacity or

the appearance of real disabilities.’

A battle won?

With so much achieved to reduce the

harmful effects of PKU and with new,

better, treatments on the horizon, is the

battle to provide patients with improved

outcomes nearly over, we asked. ‘As a

PKU specialist, my dream would be that

more and more patients in the world can

'*7#%*44#66%&.%2"*/).6"6%*)2%#3(%4"#)&%

treatment. In many countries there

is still no newborn screening, so it is

impossible to detect the patient before

they are sick. Then, once they have the

handicap it is not that easy to treat.

‘But even if you make the diagnosis, the

products are too expensive and access

&.%&-#*&0#)&%&..%2"3(%45+&8%=3%$#%4.5+2%

encourage these countries to build

low-protein products we could begin to

make a huge difference. Even if these

products were less effective than the

best currently available they could still

make a huge difference. I think this

should be done. I think it could be done.’

Watch the full interview with Prof Feillet, recorded at the 4th EPG Symposium in March 2012 – http://bit.ly/PKUvideo_feillet

Deciding to enrol in a clinical study

/,0!*!5,.#'.&*3!'#6!7#"&%&'#!0#12&0#(!

a great deal of thought. It is a decision

that no one should take lightly. So,

what must go through the mind of

a parent who is choosing whether

to enrol their infant in a study,

particularly one for a rare condition

like PKU? Inevitably, in such a situation,

the numbers who have taken the

investigational drug before will be low.

One parent who has been in exactly

that position is Nicole Pallone8. Mrs

Pallone gave a presentation at the

Dietitians’ Workshop in March 2012

(Rome, Italy) on managing blood

Phe levels in toddlers with diet and

sapropterin. The presentation featured

‘Patient Pallone’ who joined the

PKU-015 study in Vancouver (British

Columbia, Canada) at 20 months old.

From birth to diagnosis

Nicole Pallone’s daughter Rosie was

born on January 26, 2008, weighing

4.14 kg (9 lbs, 2 oz). The Pallone

family was overjoyed at the arrival

.3%&'#"-%(%-6&K<.-)%<*<;1%<5&%*3&#-%S56&%

one night at home, when Rosie was

4 days old, they were called back

to the hospital to hear that Rosie

had been diagnosed with PKU.

‘Receiving the news that Rosie had

PKU was devastating’ Mrs Pallone

said. ‘We were heartbroken and very

5,6#&8%R#%$#-#%'.--"(%#2%<;%$'*&%$#%

read about the mental retardation

associated with PKU and the need for

a special diet was also a big concern.

We were really worried about what it

would be like for her at family dinners

and special occasions like birthday

parties, Halloween and Christmas.’

Fortunately, the Pallones lived close to

a specialist clinic at the BC Children’s

Hospital. ‘We were very lucky’ Mrs

Pallone told us. ’Our clinic did a

very good job of educating us at a

rate that we were able to absorb.

They were very conscious of the

emotional state we were in and took

into account our ability to retain the

information they had to give us. When

necessary, they went very slowly.’

The diagnosis is long behind them and

Rosie is no longer a baby but a lively

little girl. How does family life compare

$"&'%&'#"-%(%-6&%3#*-6%*<.5&%4*-")/%3.-%*%

child with PKU? ‘What we have found is

that we probably worried about it more

than we needed to’ her mother said.

Embracing PKU

‘She’s only 4 years old, but at this

point she is quite happy with her

special treats. The family is very

aware of her diet and so is she. Even

though people occasionally offer

her foods she can’t have, she knows

well enough not to take them. We

try to eat meals together as much

as possible and try to make hers

similar to ours. If we’re having pasta

with chicken and vegetables we’ll

make her special pasta and a couple

of different vegetables and maybe

some kind of low Phe replacement.

We’ve really embraced her PKU.

PKU Perspectives

Nicole Pallone

Nicole Pallone tells us about how she felt when asked to consider putting her daughter, aged 18 months, in a clinical study


‘I do spend a lot of time in the kitchen’

admitted Mrs Pallone. ‘Mealtimes at our

place are quite unique; Rosie has PKU,

my younger daughter Carmella and my

husband are lactose intolerant and I

have ulcerative colitis, so we all have

different dietary needs and I’m often

cooking two completely separate meals

*&%+#*6&8%N'"6%'*6%*%<#)#(&%<#4*56#%"&%

helps us educate Rosie that different

foods are good for different people.’

And so, through diet and thanks

to close follow-up, Rosie enjoyed

stable blood Phe levels, although

occasionally these fell outside of the

clinical target (120–360 µmol/l).

8&/$%23.!"#%&(&,'(

Decision time came for her parents

when Rosie was 18 months old. The

Pallones were invited to enrol her

in PKU-015, a Phase 3b study into

&'#%#3(4*4;%.3%6*,-.,&#-")%")%;.5)/%

children with PKU. Was the decision

easy to make? ‘We were hesitant and

we took quite some time to reach it’

explained Mrs Pallone. ‘There were all

kinds of reasons that made us hesitate;

one of which was simply the stigma

of putting your child in a study and

considering them a “guinea pig”.

‘In the end, we decided that the

medical knowledge was worthwhile

and that, if she responded, Rosie’s

life might be made easier. Ultimately

we decided that we would regret not

putting her on the sapropterin study if,

10 years down the road, she was having

trouble in school or trouble emotionally

and by that point the study had proved

that sapropterin could have helped and

could have prevented those issues. We

just didn’t want to have any regrets and

we felt that the possibility of exposing

Rosie to more potential harm by not

joining the study outweighed the risks

of side effects from taking sapropterin.

‘I would encourage any parent who’s

offered the same opportunity to really

weigh the pros and cons and make the

decision that’s right for their family

and their child, but to keep in mind

that this research is really crucial,

not only for clinicians to understand

what exactly the medication does

but also from the point of view of

convincing governments of the need

to fund treatments like this.

‘They really rely on proven published

0#2"4*+%*)2%64"#)&"(4%-#6#*-4'%*)2%$"&'%

a rare disorder like PKU, where the

population is so scarce, we really can’t

live up to the typical standards that

a regular medication would need for

government approval and we struggle

to get enough patients. This makes it

imperative that people take part in

these studies’ Rosie’s mother said.

Liberalising diet

The Pallones have had to take care

to introduce natural protein without

normalising Rosie’s diet. They felt

this was essential in case, at the end

of the study, Rosie has to return to a

strict diet. Sapropterin is not currently

funded through the Medical Services

Plan of British Columbia (BC MSP).

If this position doesn’t change,

sapropterin will not be available to

them after the study ends. Nicole

Pallone and the Canadian PKU and

Allied Disorders (CanPKU) are actively

campaigning for coverage of low-

protein food and sapropterin by BC MSP.

Nicole Pallone has been vice

president of CanPKU (www.canpku.

org), a charity that works to provide

news and information to families

and professionals dealing with

phenylketonuria, since October 2010.

‘We believe that knowledge leads to

better health. We encourage companies

and the medical community to continue

doing the research they are doing on

new treatments and potential cures.’

Visit the CanPKU website – www.canpku.org

Patients deserve the best

‘I sometimes think that because the

treatment of PKU with diet was such

a success story, we reached a level of

complacency. We have become very

accepting of the outcomes for PKU

patients. Even if they aren’t measuring

up to their peers they’re still thought

to be doing really well because they are

healthy and happy. What I would like to

say is that they deserve to do more. They

deserve to do the best they can. I have a

4-year-old daughter who is smart, funny,

vibrant and she wants to be a doctor.

I want to give her every tool in the

toolbox so that she can reach her goals.’

Watch the full interview with Mrs Pallone, recorded at the 4th EPG Symposium in March 2012 – http://bit.ly/PKUvideo_pallone

Rosie

Pallone,

‘A 4-year-old

who is smart,

funny, vibrant and

wants to be a doctor.’

PKU Academy Fellowship

Improving the patient’s life through medical education

Serono Symposia International

Foundation

www.seronosymposia.org

We welcome your feedback or

requests for topics in future

issues. Please contact us at

[email protected]

Follow PKU Academy on

Twitter @PKU_Academy

Editors

Alison Eden, Flaminia Masprone,

Michael Withers

Contributors

Alison Eden, Davide Mineo,

Howie Watkins

9#50#(#'.*.&:#!,/$!%#


Foundation

Salita di San Nicola da Tolentino 1/B

00187 Rome, Italy

T +39.06.420.413

F +39.06.420.413.677

;#*"12*0.#0(


Foundation

14, Rue du Rhone

1204 Geneva, Switzerland

Winter Issue

In our next issue, Winter 2013, we will

feature interviews with Prof Ania Muntau29

on communicating with parents after a

diagnosis, Prof Laurie Bernstein11 about

new techniques for supporting patients

and Dr Søren Gersting19 on advances

in bioinformatics and individualised

care. There will also be meeting

reports from the SSIEM 2012 Congress

held in Birmingham (UK) in September

2012 and the ESPKU conference in

Liverpool (UK) in October 2012.

Copyright © Serono Symposia

International Foundation, 2012.

All rights reserved

Dr Priscila Nicolao Mazzola28 was

awarded the PKU Academy Fellowship

2012 at the symposium. Dr Mazzola’s

research topic is ‘To verify the effects

of acute and regular exercise on

substrate utilisation, oxidative stress

and hormone levels in adult PKU

patients’.

The 12-month fellowship is awarded

to support planned research and to

broaden the experience of young

graduates in medicine (specialised

or specialising in metabolic

medicine), scientists and dietitians

$'.%$.-?%")%&'#%(%#+2%.3%FED8

The Asbjørn Følling Memorial Medal

The Asbjørn Følling memorial lecture

award was given to Prof Harvey

Levy for giving this year’s lecture

entitled ‘Heroes of PKU – A History’.

Left: Prof Harvey Levy (on the right)

receives the Asbørn Følling memorial

medal from Prof Nenad Blau

Dr Priscila Nicolao Mazzola receives

the PKU Academy Fellowship 2012

28 Dr Priscila Nicolao Mazzola (Departamento

de Bioquímica, Universidade Federal do

Rio Grande do Sul, Porto Alegre, Brazil)

29 Prof Ania C Muntau (Departments of Inborn

Errors of Metabolism and of Molecular Pediatrics,

Dr von Hauner Children’s Hospital, Ludwig-

Maximilians-University, Munich, Germany)

pku academy newsletter - excemed · 4 | pku newsletter issue 3 summer 2012 quality in the balance...

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