Download The introduction and use of PKU sphere™, a Glycomacropeptide

The introduction and use of PKU sphere™,
a Glycomacropeptide (GMP) based protein substitute,
in children and adults with PKU
Vitaflo in Association
With You
Supporting education in the
dietary management of rare diseases
Disclaimer
These guidelines should be read in conjunction with local guidelines for the dietary management of
Phenylketonuria (PKU). They are based on the most recent scientific evidence available on the use of GMP
based protein substitutes in PKU. PKU sphere is a protein substitute consisting of a blend of GMP and free
amino acids (GMP-AA) for use in the dietary management of children 6 years + and adults with PKU.
These guidelines are for use by health care professionals working with children and adults diagnosed
with PKU.
They are not for use by parents/caregivers of children or adults with PKU.
They are for general information only and must not be used as a substitute for professional medical
advice.
Any product information contained in these guidelines, although accurate at the time of publication,
is subject to change.
The most current product information may be obtained by referring to product labels.
PKU sphere is a food for special medical purposes (FSMP) to be used under medical supervision.
PKU sphere is not suitable as a sole source of nutrition and is designed to supplement a low
phenylalanine (Phe) diet. A low Phe diet should provide essential Phe requirements, energy,
nutrients and water to supply fluid and general nutritional requirements.
PKU sphere contains Phe - 36mg per 20g PE; this must be taken into consideration when
introducing PKU sphere into the dietary management of PKU.
The example for introducing PKU sphere in section 2.3A is based on data from a clinical trial (soon
to be published) where natural protein/exchanges remained the same throughout introduction of
PKU sphere. Introducing PKU sphere gradually, in a systematic way, allows monitoring of metabolic
control and discussion with patient/caregiver at each step.
It is the responsibility of the managing health care professional to use their clinical judgment to
introduce PKU sphere in the most appropriate way for their individual patients.
Allergies/intolerances
As GMP is the dominant protein source in PKU sphere and it is derived from cow’s milk there may be
a risk of a reaction for those with cow’s milk allergy.
Collaborators
Vitaflo® dietitians in collaboration with:
Professor Anita MacDonald PhD, BSc, OBE (Consultant Dietitian, Birmingham Children’s Hospital, UK)
Anne Daly MSc, RD (Senior metabolic dietitian, Birmingham Children’s Hospital, UK)
1
Contents
Foreword
3.0 Example case Study
1.0 GMP
1.1 What is GMP and how is it produced?
4.0 Guideline references
1.2 What is PKU sphere?
1.3 Features of PKU sphere
5.0 Appendices
5.1 Appendix 1 – Summary of references
related to GMP potential benefits
2.0 Application of PKU sphere
2.1 Who is PKU sphere for?
5.2 Appendix 2 – Safety of GMP
2.2 Considerations for the use of PKU
sphere
5.3 Appendix 3 – Why is GMP classed as
a whole protein?
2.3 How to introduce PKU sphere
A. For an individual with good
metabolic control
B. For an individual on a relaxed
or non-adherent diet
2.4 Practical points and troubleshooting
Abbreviations
AA
Amino acids.
GMP
Glycomacropeptide.
GMP-AA
Protein substitutes based on GMP supplemented with the limiting free amino acids
+/- micronutrients and essential fatty acids. May vary in format - powder, liquid or
bar.
L-AA supplement Phenylalanine free protein substitutes based on synthetic amino acids +/
micronutrients and essential fatty acids. May be powder, liquid, bar or tablet.
LNAAs
Large neutral amino acids.
PE
Protein equivalent.
Phe
Phenylalanine.
PS
Protein substitute.
Unmodified GMP
Glycomacropeptide as a raw material isolated from cheese whey.
2
Foreword
In the 1950’s, the first protein substitute (PS), which was based on protein hydrolysate, was developed to
treat the first patient with PKU managed with diet therapy1. For the last 30 years, the most commonly used
PS have been Phe-free L-amino acid supplements (L-AA supplements). They were originally developed
using human breast milk as the reference protein.
Dietary treatment of PKU is multifaceted, challenging and lifelong2-4. Key dietary behaviours associated
with optimal control of blood Phe levels include the avoidance of high protein foods plus evenlydistributed consumption of the L-AA supplements throughout the day3-5. PKU is a chronic condition, and
although it is not unusual for adherence to be poor6 particularly in teenagers and adults, it is essential
that treatment is lifelong in order to achieve optimal neuropsychological functioning. Common issues
with PS adherence in patients of all ages is their palatability, smell, taste, texture and aftertaste2, 7, 8.
In PKU, any new dietary option that offers an alternative to L-AA supplements should be considered as it
may help to improve adherence and quality of life9, 10.
Glycomacropeptide (GMP) is a well-researched protein that offers an alternative approach to PS
provision in PKU. GMP is a natural protein that is produced as a by-product of the cheese making process.
Unmodified, it has an incomplete amino acid profile; it is not only low in Phe, but it is also low in other
important amino acids in PKU such as tyrosine, leucine and tryptophan11-13. Thereby, GMP requires
measured and appropriate supplementation of these amino acids (apart from Phe) in order to
aid attainment of satisfactory blood Phe levels as well as have potential to correct some large neutral acid
(LNAAs) deficiencies in the brain14. GMP combined with these limiting essential amino acids (GMP-AA)
and additional micronutrients ensure its suitability as an alternative to L-AA supplements9, 15, 16.
Due to its structure, GMP may also have other potential health benefits (see Appendix 1). The vast majority
of evidence is from animal studies, however short-term cohort studies and case studies have been
reported9, 16, 17.
Vitaflo has carefully developed and researched a new GMP-AA (PKU sphere) suitable for PKU. We now
have over 2 years’ experience of using this product in children and teenagers with PKU in the UK; we
have assessed its acceptability and tolerance plus its effects on plasma amino acid profiles, micronutrient
levels and growth when compared with conventional L-AA supplements (See Appendix 2 for further
information on the safety of GMP).
Vitaflo have developed guidelines on the use and introduction of PKU sphere in children over the age of
6 years and adults. Like any GMP-AA, it does contain some Phe (36 mg/20g protein equivalent), so
it is essential that every patient with PKU is assessed individually taking into account their current
adherence to PS and diet, Phe tolerance, metabolic control and this residual amount of Phe within PKU
sphere. Following the suggested step wise system for introducing PKU sphere will aid its successful
introduction without loss of metabolic control. Some patients may be able to fully or partially replace their
conventional L-AA supplement with this new PS.
Anita MacDonald
3
1.0
1.0
GMP
1.1
What is GMP and how is it produced?
1.2
What is PKU sphere?
1.3
Features of PKU sphere
4
1.1
What is GMP and how is it produced?
Glycomacropeptide (GMP) is a 64 amino acid (AA) glycophospho-peptide produced as a by-product during
the cheese making process. GMP is formed at the coagulation stage when rennet (a complex of enzymes)
is added to the milk, to produce a mixture of curds and whey. An enzyme in rennet specifically hydrolyses
kappa (k)-casein (a protein in milk) at the peptide bond between the Phe 105 and methionine 106 amino
acid residues. It therefore splits into para-k-casein containing Phe, which remains in the cheese curd,
whilst the GMP drains off with all the whey proteins forming the whey fraction11 (see figure 1.).
Figure 1. illustrates how GMP is formed and isolated through the cheese making process.
The cheese making process
Milk + rennet
Curds
Coagulation stage
curds + whey
Hydrolyses the
peptide bond between
Phe 105 + Met 106
Cheese
Whey fraction drained and separated
Mixture of whey proteins
For GMP to be suitable for use
in the dietary management of
PKU it must be isolated from
the whey fraction and further
purified.
15-20%
GMP
80 - 85% other whey
proteins including BLG* &
ALA**
GMP Isolation + purification
process
Patented fractionation
process+.
During this isolation process GMP
becomes contaminated with other
whey proteins that
contain Phe15
Unmodified Isolated GMP
The purification process reduces the Phe
level, however, all GMP based products
on the market will contain some Phe.
*BLG = beta-lactoglobulin
**ALA = alpha-lactalbumin
+ The patent for this process is held by the manufacturer.
5
Amino acid profile of isolated, unmodified GMP
Isolated, unmodified GMP has an unusual amino acid profile. It contains low levels of Phe and other
aromatic amino acids and has two to three times the amount of the LNAAs threonine and isoleucine
compared to other proteins12, 15.
Unmodified GMP
Ile
Thr
High levels of LNAAs:
Pro
Ala
Threonine
Low levels of the
Met
Lys
following amino acids:
Thr
Isoleucine
Glu
Valine
Gln
Ile
Ile
Pro
Asn
Glu
Histidine
Asp
Pro
Thr
Ser
Gly
Leucine
Tryptophan
Methionine
Ala
Phenylalanine
Tyrosine
Cysteine
Arginine
Addition of free amino acids
Isolated, unmodified GMP must be supplemented with the limiting indispensable amino acids (apart from
Phe) to ensure it is a viable alternative to L-AA supplements in PKU.
GMP-AA
GMP supplemented with the limiting essential amino acids provides a low-Phe ‘protein*’ for individuals
with PKU. The inclusion of micronutrients and DHA in GMP-AA provides a more nutritionally
comprehensive product.
Ile
Thr
Pro
Ala
Lys
Met
Tyr
His
Thr
Gly
Glu
Ile
Ile
Pro
Gln
Asn
Glu
Tyr
Pro
Thr
Trp
Ser
Gly
Ala
Leu
Arg
Asp
+
Trp
Leu
Met
Arg
Tyr
Trp
Leu
Tyr
+
Micronutrients
&
DHA
His
Trp
Gly
Leu
GMP
Met
Free Amino Acids
All commercial GMP-AA contain Phe and therefore partial or full replacement of the L-AA
supplements will depend on an individual’s blood Phe control.
* See Appendix 3 for more information on why GMP is classed as a whole protein
6
1.2
What is PKU sphere?
PKU sphere is a blend of isolated unmodified GMP and free amino acids with added micronutrients
and DHA.
Isolated unmodified
GMP
AA
r
c
opep
a
m
o
t
c
i
y
Low in Phe.
Naturally high in the LNAAs
threonine, isoleucine and
valine.
Low in a number of essential
amino acids.
G
l
7
mb
Added amino acids to
complement GMP.
e
cin
u
Le
Ensures overall good quality
protein* for growth, repair and
development.
an
toph
p
y
r
T
DHA
Vitamins and
minerals
Prevents essential amino acid
deficiencies which would be rate
limiting for protein synthesis.
Histidine
Met
hio
Ar
gi
Achieves an overall balanced
amino acid profile to optimise
blood Phe control.
nin
e
ni
ne
* When coupled with tolerated Phe allowance.
e
in
yc
Gl
Sy
Ty
ro
si
ne
e
d
Palatable source of natural
protein.
iotic relatio n s
p
i
h
8
1.3
Features of PKU sphere
Optimal nutritional profile
Low volume
Gl
High volumes of protein substitute can be difficult to manage
especially in addition to maintaining a healthy food intake.
Sy
mb
e
in
uc
Le
Tryp
DHA
Vitamins and
minerals
toph
an
Histidine
Met
hio
Ar
gi
nin
e
ni
ne
e
in
yc
Gl
PKU sphere has been designed to deliver a set protein
equivalent in a low volume to help aid adherence.
Ty
ro
si
ne
acropep
om
ti
yc
de
Amino acid profile - PKU sphere is formulated
using the latest nutritional science to ensure the
combination of the added LNAAs and GMP are in
balance to optimise blood Phe control.
iotic relatio n s h
The added LNAAs in PKU sphere are key
and may compete with Phe both at the
blood brain barrier and in the gut.
Contains DHA
Comprehensive
micronutrient
profile
ip
Low volume of PKU sphere allows it to fit easily into a ‘3-a-day’
protein substitute approach.
Low in energy
PKU sphere has been designed to be low in calories and
sugar.
PKU sphere contains 120 calories per 20g PE and is similar
in energy content to L-AA supplements such as PKU
express, PKU cooler and PKU air.
Volume per sachet PKU sphere20 x 3/day - 60g PE
PKU sphere
500
400
Obesity is a global issue. The calorie content and overall
nutritional intake should be monitored closely in PKU with
encouragement and advice on how to maintain a healthy
weight, an important aspect of dietary care, particularly in
teenage and adult patients. It is expected that most of the
energy requirements will be met by low Phe food.
ml
300
200
100
140ml
140ml
140ml
Breakfast
Lunch
Dinner
PKU cooler20
= 420ml per day
0
1 sachet PKU sphere20 + 120ml water = 140ml
Palatable
Convenient
Interchangeable
PKU sphere offers an alternative tasting product to L-AA
supplements.
PKU sphere is available in 2 different flavours:
Vanilla and Red berry.
Due to its palatability, PKU sphere could improve adherence
in a patient group where it may waver.
PKU sphere has been
developed in line with the
micronutrient profile of other
PKU products in Vitaflo’s
portfolio.
For example, 1 sachet of PKU
sphere, which contains 20g PE,
is equivalent to one sachet of PKU
express20 or 1 pouch of either PKU
cooler20 or PKU air20.
PKU sphere is presented in a convenient pre-measured
sachet which can be made up accurately, quickly and easily.
Providing blood Phe control
is maintained, PKU sphere
is interchangeable with an
equivalent amount of PE from
these L-AA supplements.
9
10
11
2.0
Application of PKU sphere
2.1
Who is PKU sphere for?
2.2
Considerations for using PKU sphere
2.3
How to introduce PKU sphere
2.0
A. For an individual with good metabolic control
B. For an individual on a relaxed or non-adherent diet
2.4
Practical points for introducing PKU sphere
12
2.1
Who is PKU sphere for?
PKU sphere:
• Is for children aged 6 years + and adults with PKU.
• Offers an alternative to L-AA supplements for individuals experiencing taste fatigue or struggling
with adherence.
• May be appealing to those who are interested in the potential health benefits of GMP-AA.
• Offers a new palatable option to those who are ‘off diet’ and would like to go back on diet.
Teenagers and adults
There may be particular interest in using PKU sphere in teenage and adult patients.
PKU is a life long condition and it is not unusual for adherence to be poor in such conditions6. A high
percentage of blood Phe levels are above target range18, particularly in teenagers and adults, indicating
inadequate adherence.
Common issues with adherence to protein substitutes, found in patients of all ages, are the palatability,
smell, taste, aftertaste and texture of these protein substitutes2, 7, 8. Also often through teenage years, with
growing independence, changes at school, peer pressure, condition resentment, adherence with diet and
protein substitutes may deteriorate.
Published studies reveal patients may prefer GMP-AA, are able to take them frequently spread
through the day and in many cases do not want to switch back to L-AA supplements9, 17, 18.
All individuals who want to try PKU sphere need to be assessed on an individual basis. Progressing
with PKU sphere will depend on metabolic control, adherence to the low protein diet and the clinical
judgement of the managing health care professional.
Section 2.3 gives an example of (a) how to introduce PKU sphere to an individual with good metabolic
control and (b) an individual on a relaxed or non-adherent diet.
13
2.2
Considerations for the use of PKU sphere
Managing Phe intake and blood levels
The potential impact the extra Phe from PKU sphere will have on blood Phe levels will likely
be less in an individual with a higher natural protein/exchange tolerance.
If a child/adult is taking 60g of protein equivalent from PKU sphere (108mg Phe) the percentage extra they
will receive will depend on their natural protein/exchange tolerance.
Natural protein tolerance / day
Extra phe from PKU sphere
4g
50%
10g
20%
20g
10%
In addition, the target Phe levels varies per population group, as teenagers and adults have a higher
maximum target Phe level than children below the age of 124.
There are certain individuals where the introduction of a GMP-AA requires additional consideration.
Careful monitoring is required and some may only tolerate partial replacement of their L-AA
supplement with a GMP-AA, or reduction of natural protein/exchanges could be considered.
A reduction in the amount of natural protein intake can reduce variety, quality and adherence of the diet.
A recent publication reported that although individuals were advised to reduce the Phe in the diet to
compensate for the Phe in the GMP-based products they did not do so17.
Introducing PKU sphere gradually, in a systematic way, allows monitoring of metabolic control and
discussion with patient/caregiver at each step. A decision can be made as to continue to increase PKU
sphere, remain on a combination of PKU sphere and L-AA supplements or consider reducing natural
protein/exchanges depending on blood Phe control, individual preference and circumstance.
Considerations
Pregnancy
Excellent blood Phe control prenatally and during pregnancy is crucial to minimise any risk of birth
defects especially microcephaly and congenital heart disease19.
It is common for natural protein/exchange tolerance to be extremely low prenatally and particularly
in the first trimester of pregnancy. There are no published data of GMP-AA use in pregnancy. A few
cases have been reported in the USA, however all 4 cases were taking sapropterin with higher natural
protein/exchange tolerance20.
For those individuals struggling to adhere to L-AA supplements during pregnancy, PKU sphere may be
an alternative choice given under careful supervision.
If PKU sphere is introduced the 36mg Phe per 20g PE should be accounted for and introduction carried
out cautiously. It should be noted, that the use of GMP-AA may not be appropriate in some cases of
maternal PKU.
Young children
The micronutrient profile for PKU sphere is suitable from 3 years of age however as yet there is no
published evidence of use in young children under the age of 6 years. Research is ongoing in children
from the age of 6 years, with preliminary results suggestive of the need for a gradual systematic
introduction of PKU sphere for those with good metabolic control (See Section 2.3).
Long term data is required to enable evidence based guidelines to be written for the use of GMP-AA in
the younger population under the age of 6 years.
14
2.3
How to introduce PKU sphere
A. For an individual with good metabolic control
Maintaining or improving metabolic control is of the upmost importance. PKU sphere contains 36mg Phe / 20g
PE; this should be taken into consideration when introducing and increasing PKU sphere.
The following is an example demonstrating how to introduce PKU sphere.
PKU sphere should be increased and titrated with the L-AA supplement gradually with blood Phe levels
monitored regularly.
PKU sphere should be carefully introduced in a systematic way. This approach will help build the
confidence of the patient/caregiver and health care professional regarding the Phe content of PKU sphere
and metabolic control.
Some individuals may only partially transition, ultimately taking a combination of PKU sphere and
L-AA supplement. Others will transition fully to PKU Sphere. This will depend on their blood Phe control,
Phe tolerance and individual preference.
Assuming a daily intake of 60g PE from PS, taken as 3 x 20g PE
throughout the day.
Key:
L-AA
Start
20g PE
20g PE
Stage 1
20g PE
20g PE
Stage 2
20g PE
20g PE
20g PE
sphere
L-AA
L-AA
L-AA
L-AA
Taking 3 x L-AA supplements
with good blood Phe control
L-AA
Replace 1 dose of L-AA supplement with 1 sachet of
PKU sphere
Discuss PKU sphere as an
alternative PS and the pro’s and
con’s of GMP.
Consider starting transition to
PKU sphere.
Advise on keeping the natural
protein / exchanges intake the
same throughout introduction of
PKU sphere.
Liquid or powdered
L-AA supplement
sphere
Stage 3
20g PE
20g PE
20g PE
20g PE
20g PE
sphere
sphere
sphere
sphere
sphere
L-AA
Replace another dose of L-AA supplement with
1 sachet of PKU sphere
Monitor fasting blood Phe levels weekly/
fortnightly
Monitor fasting blood Phe levels weekly/
fortnightly
If blood Phe control maintained over 3 consecutive
tests - Progress to stage 2.
If blood Phe control maintained over 3
consecutive tests - Progress to stage 3.
NB: 1 sachet of PKU sphere is unlikely to have
any impact on blood Phe levels.
Encourage adherence with L-AA supplement
during this transition stage.
Continue to monitor
fasting blood Phe
levels as per local/
national policy.
Replace last dose of L-AA
supplement with 1 sachet
of PKU sphere
If blood Phe control
maintained over 3
consecutive tests
continue on PKU sphere.
If blood Phe level is high
Check all other reasons or causes for high levels.
NOTE: Take into consideration any
significant calorie difference between
current L-AA supplement and PKU sphere;
advise on nutritional intake accordingly.
If no other cause suspected, consider reducing PKU sphere by 1 sachet and replace with L-AA
supplement.
Monitor blood Phe levels and once there are 3 consecutive results within target treatment range increase
again by 1 sachet and continue transition.
If blood Phe levels have increased and no other cause detected - some indiviuals with a higher Phe/
natural protein tolerance may prefer to reduce natural protein in the diet rather than reduce PKU sphere.
15
GMP-AA =
36mg Phe
16
2.3
How to introduce PKU sphere
B. For an individual on a relaxed or non-adherent diet
Those adults on a more relaxed diet or individuals who are struggling to take their recommended
amount of L-AA supplements may find a GMP-AA easier and more manageable to take. Discuss PKU
sphere as an alternative PS, the pro’s and con’s and potential health benefits of GMP-AA .
PKU sphere may help individuals to return to diet and/or regain control of blood Phe levels. Consider
introducing PKU Sphere taking into account the below points.
The amount of Phe in
PKU sphere is unlikely to
be as much of a concern in
this group.
The introduction and increase
of PKU sphere could therefore be
much quicker, or the full required
amount started at once should the
individual desire.
How PKU sphere is introduced
will depend on the individual’s
ability to cope, tolerance
of the product and
motivation.
However, this may be unrealistic for
some and therefore aiming for 1 or 2
PKU sphere sachets per day may be
more manageable which would still be
beneficial.
A gradual systematic introduction could
aid adherence.
Consider the amount of protein and
energy being consumed from foods
in addition to that from PKU sphere.
Advise accordingly where possible
to aim for recommended/target
amounts.
Ideally the amount of
PKU sphere, coupled with
the natural protein from
food, would meet protein
requirements.
In those individuals
previously nonadherent who start taking
PKU sphere, blood phe levels
may significantly improve.
Advising to start off with 3 sachets
per day (if required) of PKU sphere
could be overwhelming for those
already finding the diet difficult.
NOTE: Continue to monitor fasting blood Phe levels as per local policy.
17
2.4
Practical points and troubleshooting
How PKU sphere is introduced into the dietary management of PKU will very much depend on the
individual. Outlined below are some practical reminders of what to take into consideration and how
to encourage an easier transition.
olic
l, metab
dividua
in
e
c
th
n
ing o
a realisti
Depend
e, agree
c
n
a
r
le
to
re to
and Phe
KU sphe
control
unt of P
o
m
a
e
tute
oal for th
in substi
target g
tal prote
to
f
o
%
e.g. 50
be taken
0%.
ed or 10
d but a
prescrib
is agree
t
n
u
o
m
lower a
d or vice
e that a
achieve
y
ll
It may b
a
tu
n
eve
mount is
higher a
versa.
Emphasise the im
portance of
continuing to take
the usual
protein substitute
whilst building up
the amount of PKU
sphere taken.
When first build
ing
up PKU sphere ch
oose a
time in the day
which is
more convenient
to
prepare and take
PKU sphere.
PKU sphere
has a diffe
rent taste to
L-AA supp
lements. It
may take a
week or tw
o to accust
om to the n
ew
taste of PK
U sphere.
Many indiv
iduals onc
e establish
ed
prefer their
GMP-AA a
nd find it
easier to ta
ke and spre
ad through
the day.
Explain that droppin
g off any
L-AA supplement
can affect blood
Phe control and co
uld also delay
progression with PK
U sphere.
Regular contact with
regular blood Phe testing
is important not only to
assess tolerance but to
enhance motivation and
Those taking a liquid L-AA
supplement may feel a switch
back to a powdered product more
inconvenient, however the pre
measured sachet and provided
sports beaker help to ‘normalise’
the product and make it quick and
easy to prepare.
18
adherence.
Trouble shooting
High Phe levels
Possible cause
Action
Fever/infection/trauma
• Increase energy intake
• Ensure intake of PS
• Identify and treat source of infections, as clinically
indicated
Excess natural protein intake
• Check PKU sphere has not been increased of the
patient’s own accord
• Check adherence (at home, school, work, out socialising)
• Check understanding/calculation of exchanges/Phe
allowance, dietary adherence and hidden sources of
natural protein
• Check any special products used are low protein and
not gluten free by mistake
Inadequate intake of protein substitutes
• Check adherence (at home, school, work, out socialising)
• Check intake of usual PS has not dropped off whilst
introducing PKU sphere
• Timing of PS intake (should be spread evenly
throughout the day)
• Check adequate home supply of PS
• When necessary recalculate PS requirements and
adjust dosage appropriately
Incorrect protein substitute taken
• Check which PS is being taken. Occasionally the wrong
PS may be prescribed or delivered
Hormonal fluctuations
• Example menstruation
No obvious reason or explanation
• Reduce PKU sphere by 1 sachet and replace
the equivalent amount of protein with usual PS
• Consider decreasing natural protein intake from foods
by approximately 0.5 – 1g per day. Monitor blood Phe
levels carefully
Adapted from Ref 21.
Advice for illness
It is still important to continue to take PKU sphere during illness to assist the stabilisation of blood Phe
levels. However it may be necessary to recommend taking the same daily dose but in smaller amounts
more frequently through the day. Parents/patients should be given written advice on how to manage
illness.
19
3.0
Example Case study
3.1
Case study
3.0
20
3.1
Case study
Changing from L-AA supplement to PKU sphere.
Patient: 8 year old girl
Weight: 24 kg (25th percentile)
Height: 125 cm (25th percentile)
PE from L-AA supplement: 60g/day (3 x 20gPE L-AA supplement)
Natural protein tolerance: 4g/day
Total protein intake: 2.7g/kg/day
Target phe range:
120-360μmol/L
Background
An 8-year-old girl taking conventional L-AA supplements three times a day expressed an interest in
taking a new GMP-AA product after tasting it in the PKU clinic. The median blood Phe concentration for
her previous 12 months was 245 µmol/L with 76% of her blood spot Phe levels within the recommended
target range for age. This was considered good control. Her growth, both weight and height were on the
25th centile, with an appropriate body mass index. She ate a limited variety of foods (low protein bread,
potato products, salad and low protein biscuits only) despite many attempts to try to expand the variety of
foods eaten in her diet. She was taking 60g/day protein equivalent from 3 x 20g PE L-AA supplement (2.5g
protein/kg) and 4g/day of natural protein (200 mg/day Phe).
Introduction of (GMP-AA) PKU sphere20 sachets
The guidelines suggested in this publication for the introduction of GMP-AA sachets to replace the L-AA
supplement were followed. No adjustment or reduction of Phe exchanges was required.
Stage 1
1. One packet of PKU sphere20 replaces one L-AA supplement
2. Continue taking 2 x L-AA supplement
3. Weekly fasting capillary blood spots
4. Growth monitored frequently
Table 1 Introduction of one PKU sphere20 (20g PE) in addition to 2 x L-AA supplements (40g PE)
Week
Phe µmol/L
Tyr µmol/L
Comments
1
240
40
No difficulties were observed
2
190
50
and the new product was
3
120
40
taken well. Weight stable.
4
280
50
After 4 weeks of introducing one packet of PKU sphere20, blood Phe concentration remained within target
reference age.
Therefore, PKU sphere20 increased to 2 packets per day with 1 x L-AA supplement.
21
Stage 2
1. Two packets of PKU sphere20 replace 2 x L-AA supplements
2. Continue taking 1 x 20g PE of L-AA supplement
3. Weekly fasting capillary blood spots
4. Growth monitored frequently
5. Review after 4 weeks and change to all PKU sphere20 providing Phe levels are consistently below
the target reference range
Table 2 Introduction of two PKU sphere20 (40g PE) in addition to 1 x L-AA supplement (20g PE)
Week
Phe µmol/L
Tyr µmol/L
Comments
5
260
30
No illness.
6
400
50
Reported taking all
7
120
40
protein substitute.
8
580
50
Weight stable.
Comments
There appeared to be no obvious reason for the increase in the blood Phe concentration. The patient had
no illness and appeared to be adherent with her diet. However, her parents noticed she was reluctant to
finish all her L-AA supplement making total PS intake less consistent than usual. A home visit established
a few potential causes:
a) It was holiday time and the familiar daily routine of taking PS was changed.
Each morning she had a ‘lie in’ in bed therefore took the protein substitute later in the mornings.
b) Intake of food was less regular and Phe exchanges had not been measured accurately when eating
outside the home.
c) She had attended a ‘sleep-over’ on two occasions and delayed taking her PS till later in the morning.
Plan
As it appeared the fluctuating Phe control may have been either due to inadequate PS intake or extra
natural protein intake when eating out, it was agreed to repeat stage 2 and review after 4 weeks.
Table 3 Continuation of two PKU sphere20 (40g PE) in addition to 1 x L-AA supplement (20g PE)
Week
Phe µmol/L
Tyr µmol/L
9
270
40
Routine established.
10
130
50
Weight stable.
11
190
40
12
260
50
22
Comments
Once her usual routine returned and she was back in school, the Phe concentrations returned to the
patient’s usual high standards. She was able to change to 3 packets/daily of PKU sphere20 after 4 weeks of
following 2 sachets of PKU sphere20 and 1 pouch of L-AA supplement.
Stage 3
1. Increase to three packets of PKU sphere20
2. Stop L-AA supplement
3. Weekly fasting capillary blood spots
4. Growth monitored frequently
Table 4 Increase to three PKU sphere20 (60g PE)
Week
Phe µmol/L
Tyr µmol/L
Comments
13
180
40
No illness.
14
220
50
Reported taking all
15
190
40
protein substitute.
16
240
40
Weight stable.
This young girl continued to have regular assessment of blood concentrations and she demonstrated
good control of both Phe and tyrosine concentrations (see Table 4.). Her growth continued to follow the
25th percentile for both height and weight and she continued to do well with her GMP-AA; PKU sphere20.
Key messages
1. Transitioning to any new protein supplement needs regular monitoring.
2. If Phe control deteriorates it is important to consider changes to daily routine, in addition to other
common causes of poor Phe control.
3. A methodical change highlights when difficulties arise, and gives the family confidence when
finding the cause of a problem and enabling a solution to be found.
Case study by Anne Daly MSc, RD (Senior metabolic dietitian, Birmingham Children’s Hospital, UK).
23
4.0
Guideline references
4.0
24
References
1. Bickel H, Gerrard J, Hickmans EM. The influence of phenylalanine intake on the chemistry and
behaviour of a phenylketonuria child. Acta paediatr. 1954;43(1):64-77.
2. MacDonald A, Gokmen-Ozel H, van Rijn M, Burgard P. The reality of dietary compliance in the
management of phenylketonuria. J Inherited Metab Dis. 2010;33(6):665-70.
3. Singh RH, Cunningham AC, Mofidi S, Douglas TD, Frazier DM, Hook DG, et al. Updated, web-based
nutrition management guideline for PKU: An evidence and consensus based approach. Mol Genet
Metab.2016; 118(2): 72-83.
4. Van Spronsen FJ, Van Wegberg AMJ, Ahring K, Belanger-Quintana A, Blau N, Bosch A, et al. European
guidelines on diagnosis and treatment of PKU. J Inherited Metab Dis. 2016;39 (Suppl 1):S101.
5. MacDonald A, Chakrapani A, Hendriksz C, Daly A, Davies P, Asplin D, et al. Protein substitute dosage in
PKU: how much do young patients need? Arch Dis Child. 2006;91(7):588-93.
6. Burkhart PV, Sabaté E. Adherence to long-term therapies: evidence for action. J Nurs Scholarsh.
2003;35(3):207.
7. MacDonald A, Daly A, Davies P, Asplin D, Hall SK, Rylance G, et al. Protein substitutes for PKU what’s new? J Inherited Metab Dis. 2004;27(3):363-71.
8. Hoeks MP, den Heijer M, Janssen MC. Adult issues in phenylketonuria. Neth J Med. 2009;67(1):2-7.
9. Ney DM, Gleason ST, van Calcar SC, MacLeod EL, Nelson KL, Etzel MR, et al. Nutritional management of
PKU with glycomacropeptide from cheese whey. J Inherited Metab Dis.2009;32(1):32-9.
10 van Calcar SC, Ney DM. Food products made with glycomacropeptide, a low-phenylalanine whey
protein, provide a new alternative to amino acid-based medical foods for nutrition management of
phenylketonuria. J Acad Nutr Diet. 2012; 112(8): 1201-10.
11. Doultani S, Turhan K, Etzel M. Whey Protein Isolate and Glyco‐macropeptide recovery from whey using
ion exchange chromatography. J Food Sci. 2003;68(4):1389-95.
12. Etzel MR. Manufacture and use of dairy protein fractions. J Nutr. 2004;134(4):996s-1002s.
13. Neelima S, Sharma R, Rajput Y, Mann B. Chemical and functional properties of glycomacropeptide
(GMP) and its role in the detection of cheese whey adulteration in milk: a review. Dairy Sci & Technol.
2013; 93(1): 21-43.
14. van Vliet D, Bruinenberg VM, Mazzola PN, van Faassen MH, de Blaauw P, Kema IP, et al. Large Neutral
Amino Acid supplementation exerts its effect through three synergistic mechanisms: Proof of
principle in phenylketonuria mice. PloS one. 2015;10(12):e0143833.
15. LaClair CE, Ney DM, MacLeod EL, Etzel MR. Purification and use of glycomacropeptide for nutritional
management of phenylketonuria. J Food Sci.2009;74(4):E199-E206.
16. van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA, et al. Improved nutritional
management of phenylketonuria by using a diet containing glycomacropeptide compared with amino
acids. Am J Clin Nutr. 2009;89(4):1068-77.
17. Ney DM, Stroup BM, Clayton MK, Murali SG, Rice GM, Rohr F, et al. Glycomacropeptide for nutritional
management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr.
2016;104(2):334-45.
18. Walter JH, White FJ, Hall SK, MacDonald A, Rylance G, Boneh A, et al. How practical are
recommendations for dietary control in phenylketonuria? Lancet. 2002;360(9326):55-7.
19. Matalon KM, Acosta PB, Azen C. Role of nutrition in pregnancy with phenylketonuria and birth defects.
Pediatrics. 2003;112(6 Pt 2):1534-6.
20. Bausell H, Aspan A, Arduini K, Paras A, Burton BK. Review of maternal phenylketonuria treatment
methods including sapropterin and glycomacropeptide. 2016. Poster presented at National
Phenylketonuria Alliance (NPKUA) conference, Indianapolis, USA.
21. MacDonald A, White F. Amino Acid Disorders. In: Shaw V (ed.) Clinical Paediatric Dietetics, 4th edition,
Oxford, John Wiley & Sons Ltd. 2015. p. 391-456.
25
5.0
Appendices
5.1
Appendix 1 – Summary of references related to GMP potential benefits
5.2
Appendix 2 – Safety of GMP
5.3
Appendix 3 – Why is GMP classed as a whole protein?
5.0
26
5.1
Appendix 1
Summary of references related to GMP potential benefits
GMP scientific evidence summary
GMP has a unique chemical structure. It is highly polar with a strong negative charge and is a rich source
of sialic acid (also known as N-acetylneuraminic acid (NANA)), a carbohydrate moiety attached to the
threonine sites of the protein. Many of the biological properties of GMP are attributed to this unique structure.
Since the 1970’s GMP has been of interest for its potential benefits in many population groups and conditions.
Potential GMP benefits directly related to PKU
The vast majority of evidence is from animal studies, however
Reduction of phe in the brain
Ney et al 20081, Pietz et al 19992, Sanjuro et al 20033, van Spronson et al 20104
Increased efficacy of protein utilisation / improved nitrogen retention
Ney et al 20145, van Calcar et al 20096
Improved long term bone health
Solverson et al 20127
Better palatability
Lim et al 20078, van Calcar et al 20096, Ney et al 20169
Oral hygiene
White et al 201010, Aimutis 200411, Brody 200012
27
Specific investigations into GMP for use in the management of PKU first arose because of the natural low levels of
Phe; further potential benefits of GMP have been proposed and reported, mainly in relation to bone and gut health,
but also its impact on overall nitrogen metabolism. The following is a summary of evidence listing the potential
benefits of GMP. References marked in bold font denote research directly linked to GMP whereas references marked
in non-bold font denote research that, whilst not directly linked to GMP, are of relevance to the highlighted issue.
Other potential GMP related benefits
r short-term cohort studies and case studies have been reported.
Prebiotic effect
Brody 200012, Chen et al 201213, Sawin et al 201514
Anti-inflammatory effect
Jia et al 201115, Sprong et al 201016, Requena et al 200817, Wang et al 201218, Daddaoua et al 200519, Hvas et al 201620,
Solverson et al 201221
Binds to enterotoxins & inhibits bacterial and viral adhesion
Kawasaki et al 199222, Nakajima et al 200523, Hermes et al 201324, Dziuba et al 199625
Improved satiety
Burton-Freeman et al 200826, Macleod et al 201027
Role in weight management
Xu et al 201328, Royle et al 200829
Improvement of zinc absorption
Kelleher et al 200330
Stimulation of brain development
Wang et al 200731
28
References
1. Ney DM, Hull AK, van Calcar SC, Liu X, Etzel MR. Dietary glycomacropeptide supports growth
and reduces the concentrations of phenylalanine in plasma and brain in a murine model of
phenylketonuria. J Nutr. 2008;138(2):316-22.
2. Pietz J, Kreis R, Rupp A, Mayatepek E, Boesch C, Bremer HJ. Large neutral amino acids block
phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest.
1999;103(8):1169-78.
3. Sanjurjo P, Aldamiz L, Georgi G, Jelinek J, Ruiz J, Boehm G. Dietary threonine reduces plasma
phenylalanine levels in patients with hyperphenylalaninemia. J Pediatr Gastroenterol Nutr
2003;36(1):23-6.
4. van Spronsen FJ, de Groot MJ, Hoeksma M, Reijngoud DJ, van Rijn M. Large neutral amino acids in the
treatment of PKU: from theory to practice. J Inherit Metab Dis. 2010;33(6):671-6.
5 Ney DM, Blank RD, Hansen KE. Advances in the nutritional and pharmacological management of
phenylketonuria. Curr Opin Clin Nutr Metab Care. 2014;17(1):61-8.
6. van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA, et al. Improved nutritional
management of phenylketonuria by using a diet containing glycomacropeptide compared with amino
acids. Am J Clin Nutr. 2009;89(4):1068-77.
7. Solverson P, Murali SG, Litscher SJ, Blank RD, Ney DM. Low bone strength is a manifestation of
phenylketonuria in mice and is attenuated by a glycomacropeptide diet. PloS one. 2012;7(9):e45165.
8. Lim K, van Calcar SC, Nelson KL, Gleason ST, Ney DM. Acceptable low-phenylalanine foods and
beverages can be made with glycomacropeptide from cheese whey for individuals with PKU.
Mol Genet Metab. 2007;92(1):176-8.
9. Ney DM, Stroup BM, Clayton MK, Murali SG, Rice GM, Rohr F, et al. Glycomacropeptide for nutritional
management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr. 2016.
Aug;104(2):334-45.
10. White A, Gracia L, Barbour M. Inhibition of dental erosion by casein and casein-derived proteins. Caries
res. 2010;45(1):13-20.
11. Aimutis WR. Bioactive properties of milk proteins with particular focus on anticariogenesis.
J Nutr. 2004;134(4):989S-95S.
12. Brody EP. Biological activities of bovine glycomacropeptide. Brit J Nutr. 2000;84 Suppl 1:S39-46.
13. Chen Q, Cao J, Jia Y, Liu X, Yan Y, Pang G. Modulation of mice fecal microbiota by administration of
casein glycomacropeptide. Microbiol Res. 2012;3(1):3.
14. 26. Sawin E, Aktas B, DeWolfe T, Stroup B, Murali S, Steele J, et al. Glycomacropeptide Shows
Prebiotic and Immune Modulating Properties in Phenylketonuria and Wild Type Mice. FASEB J.
2015;29(1 Supplement).
15. Jia Y-c, Chen Q-s, Feng Y-n, Xu Y-j, Li Y. Effect of Bovine Casein Glycomacropeptide on MUC2
Expression in Mice with Ulcerative Colitis. Food Science
. 2011;15:050.
16. Sprong R, Schonewille A, Van der Meer R. Dietary cheese whey protein protects rats against mild
dextran sulfate sodium–induced colitis: Role of mucin and microbiota. J Dairy Sci. 2010;93(4):1364-71.
17. Requena P, Daddaoua A, Martínez‐Plata E, González M, Zarzuelo A, Suárez M, et al. Bovine
glycomacropeptide ameliorates experimental rat ileitis by mechanisms involving downregulation of
interleukin 17. Brit J Pharmacol. 2008;154(4):825-32.
18. Wang H, Chen Q-s. Milk-derived casein glycomacropeptide inhibits ulcerative colitis in mice through
apoptosis resistance. Food Science
. 2012;33:230-4.
29
19. Daddaoua A, Puerta V, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O. Bovine
glycomacropeptide is anti-inflammatory in rats with hapten-induced colitis. J Nutr. 2005;135(5):116470.
20.Hvas CL, Dige A, Bendix M, Wernlund PG, Christensen LA, Dahlerup JF, et al. Casein glycomacropeptide
for active distal ulcerative colitis: a randomized pilot study. Eur J Clin Invest 2016;46(6):555-63.
21. Solverson P, Murali SG, Brinkman AS, Nelson DW, Clayton MK, Yen CL, et al. Glycomacropeptide, a lowphenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in
the murine model of phenylketonuria. Am J Physiol Endocrinol Metab. 2012;302(7):E885-95.
22. Kawasaki Y, Isoda H, Tanimoto M, Dosako S, Idota T, Ahiko K. Inhibition by lactoferrin and kappacasein glycomacropeptide of binding of Cholera toxin to its receptor. Biosci Biotechnol Biochem.
1992;56(2):195-8.
23.Nakajima K, Tamura N, Kobayashi-Hattori K, Yoshida T, Hara-Kudo Y, Ikedo M, et al. Prevention of
intestinal infection by glycomacropeptide. Biosci Biotechnol Biochem. 2005;69(12):2294-301.
24.Hermes RG, Molist F, Pérez JF, de Segura AG, Ywazaki M, Davin R, et al. Casein glycomacropeptide
in the diet may reduce Escherichia coli attachment to the intestinal mucosa and increase the
intestinal lactobacilli of early weaned piglets after an enterotoxigenic E. coli K88 challenge. Brit J Nutr.
2013;109(06):1001-12.
25. Dziuba J, Minkiewicz P. Influence of glycosylation on micelle-stabilizing ability and biological
properties of C-terminal fragments of cow’s κ-casein. Int Dairy J. 1996;6(11):1017-44.
26.Burton-Freeman BM. Glycomacropeptide (GMP) is not critical to whey-induced satiety, but may have
a unique role in energy intake regulation through cholecystokinin (CCK). Physiol Behav. 2008;93(1–
2):379-87.
27.MacLeod EL, Clayton MK, van Calcar SC, Ney DM. Breakfast with glycomacropeptide compared with
amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Mol Genet Metab.
2010;100(4):303-8.
28.Xu S-P, Mao X-Y, Cheng X, Chen B. Ameliorating effects of casein glycomacropeptide on obesity
induced by high-fat diet in male Sprague-Dawley rats. Food Chem Toxicol. 2013;56:1-7.
29. Royle PJ, McIntosh GH, Clifton PM. Whey protein isolate and glycomacropeptide decrease weight gain
and alter body composition in male Wistar rats. Brit J Nutr. 2008;100(1):88-93.
30. Kelleher SL, Chatterton D, Nielsen K, Lönnerdal B. Glycomacropeptide and α-lactalbumin
supplementation of infant formula affects growth and nutritional status in infant rhesus monkeys. Am
J Clin Nutr. 2003;77(5):1261-8.
31. Wang B, Yu B, Karim M, Hu H, Sun Y, McGreevy P, et al. Dietary sialic acid supplementation improves
learning and memory in piglets. Am J Clin Nutr. 2007;85(2):561-9.
30
5.2
Appendix 2
Safety of GMP
GMP has an excellent safety record and is already incorporated into foods, including infant formula1.
The use of GMP in the dietary management of PKU was first reported in a paper in 20081. The investigators
set out to assess if the ingestion of GMP could support the growth of mice with PKU. They also measured
both brain and plasma amino acid levels. They found that PKU mice fed a diet of GMP supplemented with
essential amino acids (GMP-AA) had a 20% decrease in their cerebellar Phe concentrations compared to
mice fed a conventional L-AA supplements. They also observed similar levels of growth when mice were
fed a GMP-AA based diet were compared with those fed a L-AA supplement.
Another preclinical study investigated the body composition of PKU mice fed a predominately GMP
based diet compared to an L-amino acid diet. They found that diet played a significant effect on body
composition2 and mice fed a mainly GMP based diet showed a significantly lower percentage of body fat
compared to mice fed an amino acid based diet, despite similar lean mass and gain in body weight in the
2 groups. The findings supported their hypothesis that a GMP based diet provides a more physiological
source of protein compared to amino acids in mice but that further work in humans was required.
The first report of GMP in an adult patient with PKU was a case study published in 20093. The study lasted
a total of 15 weeks with the first 3 and last 2 weeks requiring the patient to take his usual amino acid based
protein substitute. During the middle 10 weeks GMP based protein substitutes replaced his usual amino
acid protein substitute. The patient achieved a 10% reduction in blood Phe levels when taking a GMP-AA
compared to a L-AA supplement.
The first trial to be conducted in patients with PKU was published in 20094. Although this was a small,
short term, study investigating 11 patients over two 4-day periods, it compared patients taking both
a GMP-AA and a L-AA supplement. It investigated the safety of GMP, plasma amino acid levels and
acceptability. There were no physical concerns detected on examination or expressed by any subjects
to indicate GMP-AA had a negative effect of health and at the end of the study 6 of the 7 adult patients
expressed a strong preference to continue with the GMP-AA. A second larger scale trial was published by
the same centre in 20165, again looking at efficacy, acceptability and safety of using GMP-AA compared
with L-AA supplements. This was a two stage, randomised crossover trial including 30 early treated PKU
subjects aged 15 – 49 years. The period of treatment on GMP-AA was 3 weeks compared with 3 weeks on
L-AA supplements. A 3 week washout period separated the 2 blocks of treatment. The most important
finding of the study was that there was again no significant difference in the post prandial plasma Phe
levels over time when subjects took GMP-AA compared to a L-AA supplement.
In summary over the last 8 years, GMP products have been studied with respect to providing an
alternative protein source within the management of PKU. GMP must be supplemented with limiting
indispensable amino acids to be an appropriate alternative to some or all of a phenylalanine free L-amino
acid protein substitute. It has proved to be safe in preclinical animal models and small scale human
trials and case studies. It may have additional health benefits for the PKU individual of which further
long term research is required.
31
References
1. Ney DM, Hull AK, van Calcar SC, Liu X, Etzel MR. Dietary glycomacropeptide supports growth
and reduces the concentrations of phenylalanine in plasma and brain in a murine model of
phenylketonuria. J Nutr. 2008;138(2):316-22.
2. Solverson P, Murali SG, Brinkman AS, Nelson DW, Clayton MK, Yen CL, et al. Glycomacropeptide,
a lowphenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic
stress in the murine model of phenylketonuria. Am J Physiol Endocinol Metab. 2012;302(7):E885-95.
3. Ney DM, Gleason ST, van Calcar SC, MacLeod EL, Nelson KL, Etzel MR, et al. Nutritional management
of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis. 2009;32(1):32-9.
4. van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA, et al. Improved nutritional
management of phenylketonuria by using a diet containing glycomacropeptide compared with amino
acids. Am J Clin Nutr. 2009;89(4):1068-77.
5. Ney DM, Stroup BM, Clayton MK, Murali SG, Rice GM, Rohr F, et al. Glycomacropeptide for nutritional
management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr. 2016
;104(2):334-45.
32
5.3
Appendix 3
Why is GMP classed as a whole protein?
Protein is a macronutrient which is an essential component of everyday nutritional requirements.
It is essential for growth, tissue repair and many biological pathways within the body.
A low phenylalanine diet, the principal treatment in PKU, is prescribed to reduce intake of Phe to a safe
tolerated level. This together with evenly-distributed consumption of the protein substitute over the day
are key dietary components associated with optimal control of blood Phe levels1.
Amino acids are the building blocks of protein. There are 20
Amino acids
different amino acids, 9 of which cannot be made by the body
His
Tyr
Phe
Cys
Arg
Trp
and are therefore essential. When amino acids are not linked
Leu
Thr
together in a chain they are termed ‘free amino acids’.
Gln
Met
Phe is not added to a L-AA supplements for PKU making them
Ile
Asn
Val
Pro
Glu
‘Phe free’.
Lys
Gly
His Asp
Tyr
Phe Ser
Cys
Arg
Trp
Leu Ala
Thr
Conventional protein substitutes for PKU are based on free
amino acids.
Gln
Met
Ile
Asn
Val
Pro
Glu
Lys
Met
Gly
Asp
Ser
Pro
Ala
Thr
Ile
Ala
Lys
Peptides
Peptides are short chains of amino acids joined together by
Thr
peptide bonds.
Glu
Ile
Met
His
Cys
Ile
Ala
Pro
Trp
Tyr
Phe
joined by a peptide bond, up to around 50 amino acids all linked
Leu
Thr
together building a long chain peptide.
Lys
Arg
Thr
ThrGln
Met
Glu
Glu
Ile
Ile
Asn
Val
Pro Pro
Lys
Protein substitutes were first developed in the 1950’s using
Thr
IleLys
Glu
Thr
Gly
Asp
Peptides can be as small as 2 amino acids (building blocks)
Ser
protein hydrolysates (containing peptides) passed through
Thr
Ala Ile
charcoal to remove Phe and tyrosine.
Ile
Gln
Pro
Asn
GluGlu
Ile
Ala
Gly
Thr
Asp
Pro
Pro
Ser
Thr
Met
Lys
Met
Thr
Ile
Ile
Ala
Thr
Ile
Pro
whole protein.
Pro
Asn
Thr
Glu
Glu
Asp
Ala
Pro
Ser
It has a unique amino acid profile which is
Ala
naturally low in Phe.
Ile Met
Protein
Whole proteins are made up of hundreds or thousands of amino
acid building blocks attached to each other in long chains.
Glu
Ile
The sequence of the 20 amino acids determines each protein’s
Thr
Pro
Lys
Thr
Thr
Ile
Ile
Gln
Asn
Glu
Asp
Ala
Gly
of 64 amino acids linked together in a chain.
With this number of amino acids it can be classified as a
Gln
Lys
Gly
GMP is a ‘macropeptide’ consisting
Ala
Ser
Pro
unique 3-dimensional structure and its specific function.
In PKU, Phe is provided from whole protein food sources.
Pro
Ala
Met
33
References
1. MacDonald A, Chakrapani A, Hendriksz C, Daly A, Davies P, Asplin D, et al. Protein substitute dosage in
PKU: how much do young patients need? Arch Dis Child. 2006;91(7):588-93.
34
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