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Phenylketonuria: Dietary and therapeutic challenges

Article  in  Journal of Inherited Metabolic Disease · May 2007

DOI: 10.1007/s10545-007-0552-8 · Source: PubMed

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J Inherit Metab Dis (2007) 30:145–152
DOI 10.1007/s10545-007-0552-8

ICIEM 2006

Phenylketonuria: Dietary and therapeutic challenges

M. Giovannini · E. Verduci · E. Salvatici · L. Fiori ·
E. Riva

Received: 4 January 2007 / Submitted in revised form: 31 January 2007 / Accepted: 1 February 2007 / Published online: 8 March 2007

C SSIEM and Springer 2007

Summary PKU subjects need special attention in the defi- IQ intelligence quotient
nition of optimal supplementation of nutrients, which may be LC-PUFA long-chain polyunsaturated fatty acid
insufficient in relation to the type of diet and may otherwise LNAA large neutral amino acid
manifest symptoms of deficit. In particular, it is necessary MHP mild hyperphenylalaninaemia
to pay great attention to the long-chain polyunsaturated fatty PAH phenylalanine hydroxylase
acid (LC-PUFA) levels in relation to correct development of Phe phenylalanine
the central nervous system. On the basis of numerous bene- PKU phenylketonuria
ficial effects currently known, a permanent supplementation PUFA polyunsaturated fatty acids
with LC-PUFAs, in particular with docosahexaenoic acid, Thr threonine
should be considered. Moreover, new formulas, Phe-free pep- Tyr tyrosine
tides, and ‘modulated’ amino acid preparations might help VEP visual evoked potentials
in preventing nutritional deficiencies and imbalances, with
the ultimate aim of improving growth. New strategies—such Introduction
as supply of tetrahydrobiopterin—need to be optimized in
terms of targets, patients and expected outcomes. Hyperphenylalaninaemia (HPA) is a disorder caused usu-
ally by deficiency of the enzyme phenylalanine hydroxy-
Abbreviations
lase (PAH; OMIM 261600), which converts dietary pheny-
ALA α-linolenic acid
lalanine (Phe) to tyrosine (Tyr) (Scriver et al 1995). The
AA arachidonic acid
range of disease severity observed among patients with this
α-TQ α-tocopherolchinone
form of HPA is primarily due to allelic heterogeneity at
BH4 tetrahydrobiopterin
the PAH locus. More than 450 different mutations at the
CNS central nervous system
PAH locus have been reported to date (Hoang et al 1996).
DHA docosahexaenoic acid
Various combinations of mutations result in a full spec-
DHPR dihydropteridine reductase
trum of metabolic phenotypes ranging from severe, mod-
GMP glycomacropeptide
erate and mild phenylketonuria (PKU, blood Phe concen-
HPA hyperphenylalaninaemia
tration >360 mmol/L), which require dietary management,
to mild hyperphenylalaninaemia (MHP, blood Phe 120–
Communicating editor: Verena Peters 360 mmol/L), in which dietary restriction is not necessary
Competing interests: None declared (Guttler and Guldberg 1996). A minority of cases of HPA are
due to mutation of one of the enzymes involved in the syn-
References to electronic databases: Phenylalanine hydroxylase (PAH;
OMIM 261600) thesis or recycling of its cofactor, tetrahydrobiopterin (BH4 ).
Differential diagnosis between the two forms of HPA is made
M. Giovannini () · E. Verduci · E. Salvatici · L. Fiori · E. Riva
with the BH4 loading test, analysis of urinary pterins, and
Department of Pediatrics, San Paolo Hospital, University of
Milan, Milan, Italy determination of dihydropteridine reductase (DHPR) activ-
e-mail: marcello.giovannini@unimi.it ity in blood.

Springer
146
In PKU children, severe neurological and functional dis-
orders can be prevented through an early strict dietary regi-
men aimed at reducing blood Phe to nontoxic concentrations
(120–360 mmol/L) (Scriver et al 1995). However, structural
changes in the brain (Bick et al 1991) and abnormalities of
visual function (Korinthenberg et al 1988) have been shown
in otherwise well-treated children with hyperphenylalani-
naemia, raising questions about the adequacy of the dietary
intervention (Medical Research Council Working Party on
Phenylketonuria 1993).
Since the first attempt to treat a PKU patient with a low-
Phe diet, many advances have been made in the treatment
of PKU. Many patients together with many specialists (pae-
diatricians, nutritionists, biochemists, geneticists, etc.) have
tracked the natural history of PKU and PKU dietary treat-
ment. After more than 50 years, we must be proud of the
results in the prevention of mental retardation, but we must
be aware of the new challenges in the management of this
disease (optimal growth, optimal nutritional status, optimal
compliance and quality of life of the patients).
PKU dietary treatment
The main goals of treatment for PKU are to maintain
the blood Phe concentration within safe limits (i.e. 120–
360 mmol/L; for pregnant women 120–240 mmol/L), to pre-
vent mental retardation, and to ensure normal growth and
normal life with good health through adulthood. These can
be achieved by introduction of a low-Phe diet. When started
in the neonatal period, this modifies the metabolic phenotype
and prevents the neuropsychological consequences of hyper-
phenylalaninaemia (Scriver et al 1995). Indeed, it is known
that high blood Phe concentrations are neurotoxic, mainly be-
cause of the inhibitory action of Phe on the transport of free
L-amino acids (leucine, isoleucine, valine, tyrosine, trypto-
phan and lysine) necessary for protein and neurotransmitters
synthesis (dopamine and serotonin). The aim of the dietary
treatment is to avoid acute and chronic increased concentra-
tions of Phe in plasma and consequently in cerebral tissue,
responsible for significant worsening of the neuronal per-
formance and behaviour (Scriver et al 1995). Prognosis and
outcome depend strongly on the age at which the diagnosis
is made and treatment is introduced, but also on the type
of mutation. Because of evidence that early ending of treat-
ment might impair later neuropsychological performance,
the treatment of PKU is recommended for life (Scriver et al
1995).
Characteristics of the PKU diet
A semi-synthetic diet low in phenylalanine and adequate in
other nutrients is used to treat PKU patients. The PKU diet
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J Inherit Metab Dis (2007) 30:145–152
provides minimal amounts of animal products (usually milk)
to achieve the Phe supply necessary for growth processes,
and is mainly made up by vegetables and fruits (poor in Phe)
and Phe-free synthetic products providing essential amino
acids in suitable proportions.
PKU probands and normal subjects have similar nitrogen
requirements, though the WHO-defined protein requirement
for the PKU diet is higher than recommendations for healthy
people because the bioavailability of amino acids mixtures
is not equivalent to that of natural protein (FAO-WHO 1985,
1991).
Thus, this type of dietary regimen provides high carbohy-
drate, low saturated and polyunsaturated fat, and low choles-
terol intake because of the very low intake of Phe-containing
animal foods.
The evidence for structural alteration of brain tissue and
anomalies of the visual function, evaluated by visual evoked
potentials (VEP), also in well-nourished PKU children who
show optimal compliance to the dietary treatment, has raised
questions concerning the efficacy of this treatment. In fact,
it has been observed that this type of diet may produce nu-
tritional deficits (Acosta and Stepnick-Gropper 1986), with
consequences for growth and development. Studies highlight
inadequate intake of taurine (Agostoni et al 1990), carni-
tine (Schulpis et al 1990) and other micronutrients mostly
contained in animal-derived food that is not permitted in
the diet of PKU patients. In particular, the diet of PKU
patients gives a low intake of long-chain polyunsaturated
fatty acids (LC-PUFAs) such as arachidonic acid (AA) and
docosahexaenoic-acid (DHA), which are present only in food
from animal sources (Lands 1986). Therefore, PKU patients
must rely on the endogenous synthesis of LC-PUFAs from
their precursors, the content of which also is often subopti-
mal in dietary products for patients with PKU, particularly
that of α-linolenic acid (ALA), the precursor of DHA. In
other words, ‘successful’ dietary treatment of PKU appears
to result in an iatrogenic decrease of circulating DHA levels.
The dietary mode of treatment has other drawbacks. First,
the poor organoleptic properties (taste, smell) of the commer-
cial low-phenylalanine diet are likely to affect compliance
adversely. Second, in the absence of a full understanding of
pathogenesis, and without assurance that phenylalanine lev-
els in brain can be normalized using only the dietary treat-
ment, it is unclear whether addition to the diet of certain free
L-amino acids (leucine, isoleucine, valine, tyrosine, trypto-
phan and lysine) is necessary or advisable.
Progress in dietary treatment
Some success has been obtained regarding amino acid sup-
plements (MacDonald et al 2003, 2006):
J Inherit Metab Dis (2007) 30:145–152
r Palatability and caloric content: better taste of amino acid
powder/lower calories (lipid and carbohydrate composi-
tion of preparations have been improved).
r Compliance (all ages): better compliance due to different
formulations (powder, tablets, shake, creams, etc.)
r Age-related problems with diet (adolescence, adult age,
childbearing age): different age-related formulas and com-
position allow more individualized dietary treatment.
PKU: the nutritional challenges
Breast milk and breast feeding: a role for early long-chain
polyunsaturated fatty acid and low protein and low Phe
intakes?
The neurodevelopment of early-treated PKU patients has
been found to be poorer than in the general population
(Weglage et al 1995). Several hypotheses have been advanced
to explain these observations, such as the type of feeding in
the first 6 weeks of life before the diagnosis; the dietary com-
pliance, especially in the first 4 years of life; and the role of the
low-Phe diet in deficiency of micro- and macro-nutrients im-
portant for correct development of the central nervous system
(CNS).
The starting age of the treatment clearly influences the
patient outcome, as revealed by previous studies (National
Institutes of Health Consensus Development Panel 2000)
which show an inverse relationship between the starting pe-
riod of the dietary therapy and the intellectual quotient, even
in early-treated PKU subjects. The type of feeding of the
newborn before the diagnosis plays also a fundamental role.
A study by Riva and colleagues (1996) showed a benefi-
cial effect of breast feeding, although practised for only a
short period (20–40 days), on the behavioural development
in term newborns treated and followed for classical PKU. In-
deed, PKU children who had been breast-fed as infants scored
significantly better (IQ advantage of 14.0 points, p = 0.01)
than children who had been formula fed. A 12.9-point ad-
vantage persisted also after adjusting for social and mater-
nal education status (Fig. 1). Several factors regarding the
composition of human milk have been considered as pos-
sible explanations, for example the lower content of Phe
compared with the standard infant formulas (Raiha 1989),
the optimal Phe/Tyr ratio, and the presence of LC-PUFAs,
particularly AA and DHA, which positively influence the
brain’s growth and functional development (Horrocks and
Yeo 1999). Human milk contains both AA and DHA, and
their concentrations are maintained within a narrow range.
Their levels in Western populations seem to be quite stable
from colostrum through 12 months of life (Marangoni et al
2000), ranging around 12–16 mg/dl for AA and 6–8 mg/dl
for DHA. Therefore, it is very important to support PKU
147
110
P=0.01
105
IQ score
100
95
105.8 91.8
90
(10.2) (16.8)
85
80
Breast-feeding Formula-feeding
Fig. 1 Intellectual quotient (IQ) in PKU subjects, evaluated by WISC
score, in relation to the type of feeding in the first weeks of life
patients’ mothers in breast feeding their newborn, consider-
ing the low breast-feeding rates found in PKU populations
(Agostoni et al 2000). Human milk has a low Phe content and
therefore breast feeding can be continued despite the PKU
diagnosis, with a periodic follow-up of blood Phe concentra-
tions through the Guthrie test (Berry 1988). Thus, after di-
agnosis of PKU, mothers need psychological and technical
support to maintain breast feeding in order to gain the ex-
pected advantages in infant outcome and the mother–infant
relationship.
LC-PUFA in infancy and childhood
Because the first few months of life represent the most vul-
nerable period for brain development, early supplementation
with preformed LC-PUFA could be an important addition to
the nutrition of infants with PKU. Early breastfeeding ap-
pears to be associated with a better developmental outcome
of older children with PKU (Riva et al 1996). Because human
milk is a rich source of preformed LC-PUFA, it is tempting
to suggest that this is the reason for the better developmental
outcome (Lanting et al 1994).
Infancy is the most critical postpartum stage for neuro-
logical development. The striking variations that have been
found in the DHA content of prefrontal brain cortex in breast-
fed compared with formula-fed infants provide convincing
evidence of the effects of a dietary supply of LC-PUFA on the
structure of the brain (Farquharson et al 1995; Makrides et al
1994). There have been several studies on the effects of LC-
PUFA supplementation of the diets of healthy term infants,
some (Birch et al 1998; Makrides et al 1995) having shown
a beneficial effect of a direct supply of LC-PUFA whereas
others (Auestad et al 2001; Jorgensen et al 1998) have shown
no improvement. Subtle neurological deficits have been ob-
served in later life in treated PKU (Weglage et al 1995),
and some have speculated that this may be a consequence
of poor intakes of LC-PUFA during infancy (Cockburn et
al 1996). The effects of LC-PUFA supplementation in in-
fants with PKU have been subjected to a randomized, con-
trolled trial (Agostoni et al 2006). This has shown that a
phenylalanine-free formula supplemented with LC-PUFA
Springer
148
positively influenced erythrocyte DHA status in PKU infants.
The authors are confident that the effect observed was due to
the formula rather than to any other dietary factors, such as the
contribution to LC-PUFA intakes from breast milk or wean-
ing foods. Mothers were not discouraged from breast feeding,
although only 12 mothers elected to continue breast feeding
at entry (of 19 who had breast fed for at least 8 days from
birth), and this declined to only two infants at the 20-week
assessment. Even for these few infants, breast milk provided
only a small proportion of their nutrition; it was therefore not
surprising that breast feeding seemed to offer no protective
effect against the decline in DHA levels. Similarly, the contri-
bution from weaning foods was insubstantial. Mixed feeding
was discouraged until 20 weeks of age, and parents were in-
structed to introduce only low-protein, low-fat foods to their
infants’ diets. In clinical practice, diets that exclude protein-
rich foods tend to also be low in fat and virtually devoid of
preformed LC-PUFA. Puréed fruits and vegetables were the
most common first foods, and thus differences in weaning
practices are unlikely to have confounded the main outcome
variables.
In conclusion, this trial (Agostoni et al 2006) showed that
a dietary supply of LC-PUFA in infants with PKU prevents
the decline in DHA status associated with a diet supplying
minimal sources of LC-PUFA. Indeed, it was demonstrated
that DHA status, irrespective of any specific supplementa-
tion, is associated with earlier visual maturation in infants
with PKU, as it is in healthy infants (Malcolm et al 2003).
With the use of a phenylalanine-free infant formula supple-
mented with LC-PUFA, the risk that infants with PKU will
have suboptimal DHA status may be minimized.
Both children and adults with PKU have been found to
have poor LC-PUFA status (Galli et al 1991; Moseley et al
2002). The addition of DHA and AA (Agostoni et al 2000,
2001) or DHA and EPA (Beblo et al 2001) to the diets of
older children with PKU raises plasma levels of these fatty
acids and improves the visual response of the treated children.
However, 3 years after supplementation, no biochemical or
functional differences between supplemented and unsupple-
mented children are apparent (Agostoni et al 2003).
Pregnant women with PKU and poorly compliant pa-
tients with the condition also might benefit from preformed
LC-PUFA supplementation. Supplementation of pregnant
women should help assure maximal placental transfer of
these fatty acids during the last 3 months of pregnancy, and
supplementation of poorly compliant patients should pro-
vide higher levels of neuroprotection and lessen the theoret-
ical risk of inhibition of endogenous LC-PUFA synthesis by
toxic phenylalanine by-products. In fact, it has been observed
(Infante and Huszagh 2001) that, in patients with inadequate
metabolic control, the increased concentrations of Phe and
of its metabolites, phenylpyruvic and phenyllactic acids, can
inhibit for competition the synthesis of an important enzy-
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J Inherit Metab Dis (2007) 30:145–152
matic cofactor, α-tocopherolchinone (α-TQ), which facili-
tates the action of the desaturase in the synthesis of fatty acids
(Fig. 2).
Optimal growth to prevent early growth retardation
Several studies have shown that transient growth retardation
is common in children treated for PKU during the first years
of life, especially from birth to the age of 3–5 years (Dhondt
et al 1994; van der Schot et al 1994; van Spronsen et al 1997;
Verkerk et al 1994). A smaller number of studies focused on
the relation of head circumference and protein intake in PKU
infants, but the results of these studies were not conclusive
(Acosta and Yannicelli 1994; Acosta et al 1998). Studies that
investigated causes for the retarded height growth in PKU pa-
tients focused on low blood Phe concentrations, a deficiency
of tyrosine or a deficient intake of total protein. However, the
first two suggestions could not be shown to cause growth re-
striction in length (van Spronsen et al 1997). A French study
(Dobbelaere et al 2003) investigated the growth of PKU pa-
tients and sought nutritional and hormonal explanations for
the growth delay. In this study, the PKU group (aged 8 months
to 7 years of life) was moderately but significantly shorter
and lighter than the French healthy reference group. No cor-
relation was found between the plasma Phe concentration,
protein or caloric intake and the presence of growth retar-
dation. Theoretically, the conclusion that the total protein
intake is not related to growth (Dobbelaere et al 2003) does
not exclude the possibility of a relation between growth and
one of the fractions of the protein that PKU patients consume
(natural protein and the protein substitute). A relation with
natural protein rather than total protein would favour research
to further optimize the biological composition of protein sub-
stitutes. Indeed, a recent study (Hoeksma et al 2005) showed
that the total protein intake and natural protein intake showed
a significant relation with head circumference growth but not
with height growth during the first 3 years of age.
Contrary to these data, Acosta and colleagues (2003)
showed that PKU children undergoing nutritional manage-
ment, aged from 2 to 13 years, exhibited normal linear
growth. Moreover, the mean Body Mass Index z-scores at the
end of the study suggest that many children were overweight.
Quality of growth in preventing later overweight
development
Studies have shown that PKU children may weigh more than
normal children (Acosta et al 2003; McBurnie et al 1991;
Rolland-Cachera et al 1984). A recent study found that the
rate of overweight at age 8 years in this population is around
25%, comparable to values estimated in normal populations
(McBurnie et al 1991), with no difference between PKU
and MHP children. Moreover, this study revealed a strong
J Inherit Metab Dis (2007) 30:145–152
PKU PATIENTS IN DIETOTHERAPY
WITHOUT SUPPLEMENTATION OF LONG
CHAIN POLYUNSATURATED FATTY ACIDS
Reduced dietary intake of preformed
AA and DHA
Insufficient synthesis de novo
of AA and DHA from the
18 carbon atom precursors
INFLUENCE ON
GROWTH AND DEVELOPMENT
OF THE CNS
Fig. 2 Metabolic events in PKU patients that determine reduced levels of long-chain polyunsaturated fatty acids (AA and DHA)
negative association of overweight at age 8 years with the
age at BMI rebound, that is the age at the nadir of BMI pat-
tern proposed as predicting occurrence of later overweight in
normal populations (Scaglioni et al 2004). Therefore, even
if PKU children are routinely monitored long-term for di-
etary intake, there are is evidence for overweight in this
population.
Paediatricians and dieticians should prescribe and care-
fully monitor energy intake, physical activity and weight in
PKU patients.
New amino acid preparations
Peptides: Qualitative modifications of protein substitutes,
more than purely quantitative characteristics, may be rel-
evant in optimising absorption and utilization of nitrogen
sources and improving the nutritional status of PKU pa-
149
PKU PATIENTS WITH POOR
COMPLIANCE IN DIETARY TREATMENT
Deficit of phenylalanine hydroxylase
Increase of concentrations of
phenyllattic and phenilpiruvic acids
Inhibition of the 4-hydrossi-
Dihoxigenase-phenylpiruvate enzyme
Reduced synthesis of α-tocopherolchinone
Inactivation of mitochondrial desaturase
Reduced synthesis of 20:4 n-6 and 22:6 n-3
tients. Indeed di- and tripetides are more efficiently absorbed
than free amino acids. Therefore, di- and tripeptides result
in better N-retention, particularly useful in cases of lower-
intestinal absorption capacity (Frenhani and Burini 1999).
Among the peptides, glycomacropeptide (GMP) is the only
naturally occurring protein that is phenylalanine-free, so that
this characteristic makes GMP an excellent source of protein
for people with PKU. GMP is now being isolated commer-
cially from whey so that it can be used to formulate foods
containing protein for people with PKU (Wisconsin Center
for Dairy Research 2001). Moreover, GMP is reach in threo-
nine (Thr) (Rigo et al 2001). In a study in growing rats, there
was a negative correlation between dietary Thr intake and Phe
concentration in plasma, liver, muscles and cortex, indicating
an influence of dietary Thr on Phe metabolism (Boehm et al
1998). In humans, the data of a recent study show that the sup-
plementation of the standard PKU diet leads to a reduction of
Springer
150
plasma Phe concentration (Sanjurjo et al 2003), but they do
not allow any conclusion about the mechanisms responsible
for the observed effect. Thus, Thr supplementation could be a
suitable dietary intervention in addition to the Phe restricted
diet in PKU patients.
Tyrosine supplementation: Treatment of PKU consists of
restriction of natural protein and provision of a protein sub-
stitute that lacks Phe but is enriched in tyrosine. Large and
unexplained differences exist, however, in the tyrosine en-
richment of the protein substitutes. Furthermore, some in-
vestigators (van Spronsen et al 1996, van Spronsen et al
2001) advise providing extra free tyrosine in addition to the
tyrosine-enriched protein substitute, especially in the treat-
ment of maternal PKU. A recent study (van Spronsen et al
2001) discussed tyrosine concentrations in blood during low-
phenylalanine, tyrosine-enriched diets and the implications
of these blood tyrosine concentrations for supplementation
with tyrosine. The authors conclude that the present method
of tyrosine supplementation during the day is far from op-
timal because it does not prevent low blood tyrosine con-
centrations, especially after overnight fasting, and may re-
sult in greatly increased blood tyrosine concentrations dur-
ing the rest of the day. Both high tyrosine enrichment of
protein substitutes and extra free tyrosine supplementation
may not be as safe as considered at present, especially to
the fetus of a woman with PKU. The development of di-
etary compounds that release tyrosine more slowly could be
beneficial.
New strategies
Competing amino acids
The role of large neutral amino acids (LNAAs) and their
transport to the brain in PKU has been an issue since
1953 when Christensen proposed that the high concentra-
tion of Phe in the blood interferes with the transport of other
LNAAs into the brain (Christensen 1953). Recently, Pietz
and colleagues (1999) confirmed that LNAAs blocked the
Phe transport into the brain by giving an oral ‘Phe challenge’
with and without LNAAs and measuring the influx of Phe
into the brain. In view of the fact that many adults and adoles-
cents either are off diet or do not adhere to the Phe-restriction,
it would be prudent to offer the LNAA therapy. The use
of the LNAA therapy has been shown to improve amino
acid profiles as well as increase blood concentrations of ty-
rosine and tryptophan, which are precursors for dopamine
and serotonin (Koch et al 2003). However, a double-blind
placebo-controlled trial would be required to show long-
term efficacy and tolerance of LNAAs in the treatment of
PKU.
Springer
J Inherit Metab Dis (2007) 30:145–152
BH4 supplementation in BH4 -responsive
hyperphenylalaninaemic patients: a new ‘oral’ treatment?
Patients affected by BH4 deficiency show normalization of
plasma Phe concentrations after oral administration of BH4
(Scriver et al 1995). Indeed, a minority of cases of HPA
are due to mutation of one of the enzymes involved in the
synthesis or recycling of its cofactor, BH4 .
Recently also patients affected by PAH deficiency have
been shown to respond to oral administration of BH4 by
lowering plasma Phe concentrations. Reports of BH4 re-
sponsiveness in PAH-deficient HPA patients are numerous
in the literature (Bernegger and Blau 2002; Kure et al 1999).
Most BH4 -responsive patients are affected by MHP. The
presence of MHP mutations is a major determinant of BH4 -
responsiveness among HPA patients, as BH4 -responsiveness
is known to be a characteristic of milder forms of HPA, e.g.,
forms with different degrees of PAH residual enzyme activity
(Muntau et al 2002).
A smaller number of BH4 -responsive patients show more
severe phenotypes with low Phe tolerance undergoing a diet
therapy. In this group, BH4 may represent a valid alternative
to the standard dietary treatment. Pharmacological therapy
with BH4 was introduced as monotherapy or in combina-
tion with a less restricted diet in a number of patients and
seems to be successful (Trefz et al 2001). Clinical follow-up
under BH4 therapy demonstrated that these patients indeed
benefit from a sustained therapeutic effect of BH4 , as they
can increase their Phe tolerance to 50–100%, thus allowing
a relaxed diet. BH4 therapy may be important in these pa-
tients, especially during adolescence when compliance is less
good, and during pregnancy, to reach better-controlled Phe
concentrations (Fiege et al 2005).Thus, a reliable BH4 load-
ing protocol that ensures identification of all BH4 -responsive
patients is currently under discussion. In conclusion, BH4
could be either a good alternative or a co-adjuvant in HPA
forms with different degrees of PAH residual enzyme activ-
ity. Multicentric standardized studies are necessary to assess
responsiveness to BH4 in HPA patients so as to define safety
and provide guidelines for treatment. A significant problem
concerning BH4 therapy, apart from the problem of the iden-
tification of BH4 responsiveness, is high cost.
Conclusion
Beyond the control of plasma phenylalanine levels, new
emerging issues indicate that early nutrition may have long-
lasting effects in PKU patients. Human milk and breast feed-
ing, and early amino acid and LC-PUFA supply, seem to have
independent effects on development. New formulas, Phe-free
peptides, and ‘modulated’ amino acid preparations might
help in preventing nutritional deficiencies and imbalances,
J Inherit Metab Dis (2007) 30:145–152
with the ultimate aim of improving growth. New strategies—
such as BH4 supply—need to be optimized with regard to
targets, patients and expected outcomes.
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