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Molecular Genetics and Metabolism 101 (2010) 99–109
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Molecular Genetics and Metabolism
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
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Suboptimal outcomes in patients with PKU treated early with diet alone:
Revisiting the evidence
G.M. Enns a,⁎, R. Koch b, V. Brumm, E. Blakely c, R. Suter d, E. Jurecki d
a
Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA
University of Southern California/Keck School of Medicine, Los Angeles, CA, USA
University of Rochester, Rochester, NY, USA
d
BioMarin Pharmaceutical Inc., Novato, CA, USA
b
c
a r t i c l e
i n f o
Article history:
Received 5 April 2010
Received in revised form 27 May 2010
Accepted 28 May 2010
Available online 22 June 2010
Keywords:
Phenylketonuria
Diet
Suboptimal
Outcomes
NIH Consensus Statement
Recommendations
a b s t r a c t
Background: The National Institute of Health (NIH) published a Consensus Statement on the screening and
management of Phenylketonuria (PKU) in 2000. The panel involved in the development of this consensus
statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and
the need for further research into treatment options. In subsequent years, the approval of new treatment
options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone
have become available. We hypothesized that a review of the PKU literature since 2000 would provide
further evidence related to neurocognitive, psychosocial, and physical outcomes that could serve as a basis
for reassessment of the 2000 NIH Consensus Statement.
Methods: A systematic review of literature residing in PubMed, Scopus and PsychInfo was performed in order
to assess the outcome data over the last decade in diet-alone early-treated PKU patients to assess the need
for new recommendations and validity of older recommendations in light of new evidence.
Results: The majority of publications (140/150) that contained primary outcome data presented at least one
suboptimal outcome compared to control groups or standardized norms/reference values in at least one of
the following areas: neurocognitive/psychosocial (N = 60; 58 reporting suboptimal outcomes); quality of life
(N = 6; 4 reporting suboptimal outcomes); brain pathology (N = 32; 30 reporting suboptimal outcomes);
growth/nutrition (N = 34; 29 reporting suboptimal outcomes); bone pathology (N = 9; 9 reporting
suboptimal outcomes); and/or maternal PKU (N = 19; 19 reporting suboptimal outcomes).
Conclusions: Despite the remarkable success of public health programs that have instituted newborn
screening and early introduction of dietary therapy for PKU, there is a growing body of evidence that
suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology and maternal
PKU outcomes are suboptimal. The time may be right for revisiting the 2000 NIH Consensus Statement in
order to address a number of important issues related to PKU management, including treatment
advancements for metabolic control in PKU, blood Phe variability, neurocognitive and psychological
assessments, routine screening measures for nutritional biomarkers, and bone pathology.
© 2010 Published by Elsevier Inc.
Contents
Introduction . . . . . . . . . . . .
Methodology . . . . . . . . . . . .
Results . . . . . . . . . . . . . . .
Limitations . . . . . . . . . .
Neurocognitive and psychosocial
Children and adolescents
Adults . . . . . . . . .
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outcomes:
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early-treated diet-alone
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therapy
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⁎ Corresponding author. Biochemical Genetics Program, Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford,
CA, 94305-5208, USA.
E-mail address: [email protected] (G.M. Enns).
1096-7192/$ – see front matter © 2010 Published by Elsevier Inc.
doi:10.1016/j.ymgme.2010.05.017
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G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
Quality of life outcomes: early-treated diet-alone therapy . . . .
Children and adolescents . . . . . . . . . . . . . . . .
Adults . . . . . . . . . . . . . . . . . . . . . . . . .
Brain pathology outcomes: early-treated diet-alone therapy . . .
Growth and nutrition outcomes: early-treated diet-alone therapy
Children and adolescents . . . . . . . . . . . . . . . .
Adults . . . . . . . . . . . . . . . . . . . . . . . . .
Bone pathology outcomes: early-treated diet-alone therapy . . .
Children and adolescents . . . . . . . . . . . . . . . .
Adults . . . . . . . . . . . . . . . . . . . . . . . . .
Maternal PKU outcomes: early-treated diet-alone therapy. . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
Phenylketonuria (PKU) is a rare autosomal recessive inborn error
of phenylalanine (Phe) metabolism and a form of hyperphenylalaninemia (HPA) characterized by elevated blood Phe levels as a result of
reduced PAH enzyme activity caused by a mutation in the phenylalanine hydroxylase (PAH) gene [1]. Newborn screening combined with
a Phe-restricted therapeutic diet implemented within the ﬁrst few
weeks of life and continued throughout childhood has ameliorated
the most severe clinical manifestations of PKU [1]. However, three
decades worth of clinical PKU experience in the US revealed that
inter-clinic variations in PKU management practices lead to suboptimal outcomes in diet-treated PKU patients. These variations coupled
with persisting suboptimal outcomes in the PKU populations resulted
in the National Institute of Health (NIH) convening an expert panel in
2000 to develop and publish the ﬁrst national Consensus Statement in
the screening and management of PKU [2].
NIH Consensus and State-of-the-Science statements are prepared by
independent panels of health professionals and public representatives
on the basis of (1) the results of a systematic literature review prepared
under contract with the Agency for Healthcare Research and Quality
(AHRQ), (2) presentations by investigators working in areas relevant to
the conference questions during a 2-day public session, (3) key
questions and statements from conference attendees during open
discussion periods that are part of the public session, and (4) closed
deliberations by the panel during the remainder of the second day and
morning of the third [2,3]. The NIH Conference Development Programs
are structured around key questions [3]. Ordinarily, four to six questions
are posed, including questions on the efﬁcacy, risks, and clinical
applications of a technology, plus a ﬁnal one on directions for future
research. These questions determine the scope and substance of the
conference and the ﬁnal draft of the Consensus Statement.
The 2000 NIH Consensus Statement on PKU includes recommendations such as target blood Phe ranges of 120–360 μmol/L (2–6 mg/dL)
for infants through 12 years of age, 120–900 μmol/L (2–15 mg/dL) after
12 years of age and 360 μmol/L (6 mg/dL) three months pre-conception
and maintained at 120–360 μmol/L (2–6 mg/dL) throughout pregnancy
[2]. The positive effects of maintaining control of Phe levels lifelong
through a restricted-Phe diet are recommended, but not reinforced with
outcome data [2]. Questions regarding the potential for subtle
suboptimal outcomes of early diet-treated PKU also remained controversial at the time of the 2000 NIH Consensus Statement [2].
This review assesses PKU patient outcomes since the 2000 NIH
Consensus Statement publication to determine if the data reveal the
presence of suboptimal neurocognitive, psychosocial, quality of life,
growth, nutrition and bone pathology outcomes in early diet-treated
PKU and maternal PKU. The accumulated data lay the groundwork for
re-evaluation of the 2000 NIH Consensus Statement based on:
observed effectiveness of current target blood Phe levels; the effects
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of Phe levels on PKU patients' offspring; nutritional outcomes;
compliance issues; and the Food and Drug Administration (FDA)
approval of sapropterin dihydrochloride (sapropterin, Kuvan®), the
ﬁrst adjunctive therapy to a Phe-restricted diet to help control blood
Phe levels.
Methodology
An initial screen of PubMed, Scopus, and PsychInfo databases using
the search criteria of [{PKU} OR {Phenylketonuria}] in the article title
identiﬁed literature published from 2000 to Feb 11th, 2010. Each
independent search was inputted into a database format using
Reference Manager v12.0 and subsequently compared for duplication.
A main database was created containing unique entries.
The database was reviewed by titles, abstracts and/or full
publications to identify entries that reported at least one measurable
outcome in a diet-only treated PKU population. An outcome was
deﬁned as a qualitative or quantitative measure, other than blood Phe
level monitoring, in which there is basis to compare diet-only treated
PKU patients with relevant control population(s). Meta-analyses that
reported on at least one outcome for diet-only treated PKU patients
were included. Publications lacking diet-only treated patient outcomes were excluded.
The new database reporting on diet-only treated PKU patient
outcomes published since 2000 was screened for inclusion into one or
more of the following topical headings based on the outcome(s)
measured: 1) Neurocognitive/PsychoSocial, 2) Quality of Life (QOL),
3) Brain Pathology, 4) Growth/Nutrition, 5) Bone Pathology and
6) Maternal PKU (Fig. 1). Diet-only treated suboptimal outcome
categorization was based on the criteria of reporting at least one
outcome that was suboptimal in the context of known reference values,
standardized norms or relevant control population(s). To be categorized
as a diet-only treated optimal outcome(s), each measured outcome
reported in the publication had to be optimal in the context of known
reference values, standardized norms or relevant control population(s).
Results
From the initial combined database of 771 articles, 150 were selected
that described outcomes in a diet-only treated PKU patient population
[4–153]. The 150 articles were sorted into one or more categories based
on their outcomes as follows: 1) Neurocognitive/PsychoSocial (n= 60;
58 reported suboptimal outcomes [4–61], 2 reported optimal outcomes
[62,63]), 2) Quality of Life (n= 6; 4 reported suboptimal outcomes
[40,52,64,65], 2 reported optimal outcomes [66,67]) , 3) Brain Pathology
(n= 32; 30 reported suboptimal outcomes [7,8,13,37,49,68–92], 2
reported optimal outcomes [42,93]) , 4) Growth/Nutrition (n= 34; 29
reported suboptimal outcomes [38,39,94–120], 5 reported optimal
outcomes [121–125]), 5) Bone Pathology (n= 9; 9 reported suboptimal
G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
101
Fig. 1. Flow diagram of selection and output.
outcomes [126–134]) and 6) Maternal PKU (n= 19; 19 reported
suboptimal outcomes [135–153]) (Fig. 1). The total of 160 articles
categorized is greater than the initial 150 article database as ten articles
contained multiple outcomes that fell into more than one category
[7,8,13,37–39,42,49,52]. The majority, 140/150 of the primary literature
database, had at least one suboptimal outcome in the diet-only treated
PKU population.
Limitations
The goal of this review was to identify and categorize publications
since the year 2000 with primary study data on PKU population
outcomes or primary statistic analysis of prior literature (metaanalyses). We did not reinterpret the quality of the ﬁndings, validity of
statistical analysis or appropriateness of study design. Further, we did
not analyze author compilation, interpretation of results or impact of
the outcome on patient functioning of included publications as they
all individually were accepted and analyzed by the independent
review processes of their respective journals.
Due to the breadth of information collected in the literature search,
descriptive summaries of ﬁndings in each category of this review are
primarily limited to larger study populations, including meta-analyses,
and studies demonstrating suboptimal outcomes in patient populations
that were early and continuously treated with diet therapy alone. The
inclusion of meta-analyses may be perceived as counting certain
publications twice as independent data. However, we included metaanalyses as they offer new statistical interpretation of pooled study data
which is invaluable in rare diseases where sample sizes of individual
studies are typically small. Five meta-analyses were included in the
literature search and the inherent limitations of interpreting results
from pooled data are discussed within each [5,6,21,48,57].
As a qualitative review, categorization of a publication as reporting
suboptimal outcomes included, where appropriate, presentation of
signiﬁcant statistical differences between the PKU study group and
control groups on ≥1 study parameter analyzed. When statistical
approaches were not appropriate for analysis, outcome discussions of
results were considered.
Many of the selected publications have pooled the results of children,
adolescents and adults, each of which has a distinct outcome proﬁle. Some
other difﬁculties include the challenge of recruiting an adequate number
of participants to ensure statistical power due to the rarity of the disease.
Selection bias may also occur when patients are recruited from the
available PKU patients often within specialized clinics, typically excluding
those not being regularly followed. Outcomes from the same patient
population may also have been reported in different publications.
Additionally, the majority of the literature reports comparisons between
PKU patients and healthy control subjects but not between PKU patients
on- and off-diet; thus in many instances the distinction cannot be easily
made as to whether suboptimal outcomes are due to the stress and
burden of the disease or due to lack of metabolic control of the disease.
Furthermore, expert recommendations are only as effective as their
degree of clinical incorporation with recent evidence suggesting
considerable variation in PKU management from clinic to clinic despite
the availability of expert recommendations [154–156]. For the purpose of
this review, studies that collected patient data prior to 2000 are included
as novel if published in years ≥2000. Likewise, non-US-based studies
published in 2000 or beyond were included if information was deemed
relevant to this rare disease when considering revising NIH recommendations. In regards to revising NIH guidelines, the inclusion of non-US based
publications may be perceived as a study limitation in the context that
there are different recommendations for optimal blood levels in different
countries, particularly in children over 10 years of age and in adults.
The majority of studies used normal control as comparators or
utilized assessment tools that have been standardized to large
normative control populations. However, the potential lack of validating
the various neurocognitive, psychological and QOL assessment tools for
use in the PKU patient population may be considered a limitation.
The assignment of suboptimal outcomes to diet-alone therapy may
be perceived as misleading as many suboptimal outcomes were
related to higher blood Phe levels potentially indicating lack of dietary
control in these patients. However, lack of adherence to the onerous
regimen of the diet may also be a suboptimal outcome of diet-alone
therapy: a sentiment echoed in the 2000 NIH guidance document
recommending alternative therapies to the diet [2].
Neurocognitive and psychosocial outcomes: early-treated diet-alone
therapy
In spite of early and continuous treatment, children and adults
with PKU may experience cognitive symptoms as well as disturbance
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G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
in emotional and behavioral functioning [4–61]. Although early
initiation of the PKU diet has eliminated severe cognitive impairment,
evidence indicates that overall intellectual functioning and speciﬁc
neuropsychological abilities may be suboptimal. Symptoms may cover
a broad range and generally correlate with the timing and degree of
exposure to elevated Phe levels. Executive function (EF) deﬁcits,
attention deﬁcit issues, and reduced processing speed with early diettreated PKU patients have been reported by many groups [4–61].
Children and adolescents
Children with PKU treated early and continuously with diet alone
show overall intellectual functioning that is within the normal range,
but lower than the general population and their siblings [25,48].
Evidence from the National PKU Collaborative Study, a 14-year
longitudinal initiative, demonstrated that the mean lifetime Phe
level was inversely correlated with results of neurocognitive tests at
age 12; IQ was negatively correlated with age at initiation of diet and
blood Phe levels from 4 to 10 years, and was positively correlated with
the age at which they lost dietary control [13,37]. More recently, a
meta-analysis involving 43 studies showed a 1.8 to 3.8 point
reduction in IQ for each 100 μmol/L increase in lifetime blood Phe
level [57].
In addition to suboptimal IQ, early-treated children and adolescents may demonstrate speciﬁc neuropsychological compromise and
lower academic achievement [7–9,18,20,36,55]. Anastasoaie et al.
demonstrated that early–continuously diet-treated PKU children with
well-controlled blood Phe levels had suboptimal neurocognitive
outcomes as measured by full-scale IQ testing [6]. These outcomes
correlated with variability in blood Phe within the recommended
ranges. These results indicate the importance of the stability of blood
Phe levels in relation to cognitive functioning, especially in those with
classical PKU whose blood Phe levels are more prone to ﬂuctuation
based on dietary Phe intake. Executive dysfunction has also been
noted in working memory, inhibitory control, conceptual reasoning,
mental ﬂexibility and organizational strategy [7,8,42]. Most recently,
EF deﬁcits in early and continuously treated PKU children were more
closely associated with Phe:Tyrosine (tyr) ratios than Phe only
measures [51].
Attentional problems have been documented consistently in
children with PKU [8,12,20,31,32]. Attentional problems may have a
negative impact on academic progress, as well as on self esteem and
emotional development [36,55]. This can further complicate adherence to the Phe-restricted diet, determining milligrams of Phe,
inhibiting impulsive food choices, and recording dietary Phe intake,
as these all require well-developed EF.
Suboptimal IQ scores, EF abnormalities, and reduced processing
speed place children with PKU at risk for poor academic performance.
Early and continuously treated children and adolescents with PKU
present with signiﬁcantly more school problems as deﬁned by
students needing tutoring, repeating a class, or discontinuing their
studies before completing secondary school [26]. Stemerdink and
colleagues reported in a study of 30 PKU adolescents and 23 controls
that PKU subjects were more hyperactive and their school performance was lower than control subjects, but they found no statistically
signiﬁcant difference between the 2 groups in the need to repeat
classes or to require tutoring [55]. In contrast to other studies that
reported school difﬁculties, Simon and colleagues found no differences
in the level of education achieved and the distribution of highest
professional qualiﬁcations between young adult PKU patients and
control groups, with the exception that more than half of the female
patients had not completed vocational training as compared to onethird in the general population in Germany [52]. This may be
attributable to their younger age or may alternatively reﬂect a delayed
psychosocial development. These results are conﬁrmed by the study of
Bosch et al., who reported that a higher percentage of PKU patients had
attended special education classes in primary school, though the
highest level of education attained was comparable in the two groups
[66]. In addition, EF deﬁcits have been associated with difﬁculties in
forming social relationships and communicating effectively [66].
Adults
Studies examining the relationship between PKU treatment
variables and cognitive outcome in adulthood are consistent with
the pediatric literature and provide evidence of cognitive deﬁcits
despite early treatment and average IQ. Adults with PKU may
demonstrate deﬁcits in executive function, attentional problems,
decreased verbal memory, expressive naming and verbal ﬂuency
[5,13,15–17,22,23,32,37,43,46–48]. Meta-analysis of neuropsychological symptoms of early and continuously treated adults with PKU
indicated that patients with PKU differed signiﬁcantly from controls
on overall, intellectual functioning, processing speed, inhibition, and
motor control [48]. Cognitive deﬁcits in adults with PKU suggest that
functioning may have been compromised during early brain development by elevated Phe levels or that speciﬁc areas of cognitive
function may be more vulnerable to even slight elevation or variability
in Phe levels [6].
Early-treated individuals with PKU are also at risk for social and
emotional difﬁculties. Children and adolescents may demonstrate
decreased social competence, autonomy and self esteem [35,36,55].
Adults may also display low self-esteem and lack of autonomy, and
may tend to develop depressed mood, generalized anxiety, phobias,
decreased positive emotions, social maturity deﬁcits and social
isolation [53]. Psychosocial factors such as the burden of living with
a chronic illness may also contribute to psychological and psychiatric
outcomes in PKU. Not all individuals with PKU present with
psychological or psychiatric symptoms and a PKU-speciﬁc psychiatric
phenotype has not been identiﬁed [58]. The relationship between
metabolic control and severity of symptoms suggests a biological basis
of dysfunction. Longitudinal studies are required to evaluate the
impact of biochemical control and emerging therapies on psychosocial
functioning. Unidentiﬁed or untreated emotional issues may have a
signiﬁcant impact on the quality of life and social status of individuals
with PKU.
Quality of life outcomes: early-treated diet-alone therapy
Quality of life (QOL) assessment has focused primarily on adult
PKU populations. However, decreased QOL has been reported for both
adults and children with PKU that have been treated with diet alone
[40,52,64,65]. Fewer children report positive emotions and adults
report difﬁculties in adhering to the strict diet and subsequently
report higher levels of distress [64,65].
Children and adolescents
Landolt et al. 2002 assessed 37 patients with PKU between 3 and
18 years of age (mean, 10.9 years) [40]. Results suggested that most
dimensions of QOL in children with PKU were not different from
reference values; however, they were suboptimal in their reporting of
positive emotions.
Adults
Simon et al. investigated the QOL of 67 adult PKU patients
compared to the German census on an age matched control collective
[52]. The QOL of adult PKU patients measured with the Proﬁle of
Quality of Life in the Chronically Ill (PLC) revealed mean values for
capacity of performance in the patient group in the same range as in
the chronically ill control collective.
Studies have also shown that when adult patients return to diet
and lower their blood Phe levels, they may report a subsequent
improvement in QOL [64,65]. Bik-Multanowski et al. (2008) examined
whether adult patients (n = 53) returning to the diet had improved
QOL. Initial QOL assessment revealed severe distress in 17%, moderate
G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
distress in 28% and positive well-being in 55% [64]. Bik-Multanowski
et al. also highlighted the result that only 29 persons managed to
maintain the diet for at least 3 months and only 10 participants
ﬁnished the entire 9-month study protocol. In the majority of patients
with severe or moderate distress, improvement of subjective wellbeing was observed if they managed to return to the diet, highlighting
the difﬁculty in adhering to the onerous dietary regimen even
knowing that their QOL could be improved by better control of their
blood Phe levels.
Brain pathology outcomes: early-treated diet-alone therapy
Brain imaging techniques used on diet-alone treated PKU patients
have revealed white matter abnormalities (WMA), reduced cerebral
protein synthesis, altered brain Phe concentrations, altered L-DOPA,
Phe and Tyrosine (Tyr) uptake at the blood brain barrier, volume
changes of grey at white matter, and altered cerebral metabolism
[7,8,13,37,49,68–92].
Increased availability and advancements in brain imaging technology have been applied to the investigation of white matter
abnormalities in PKU. The basis of this hypothesis is reduced
myelination associated with PKU leads to aberrant brain neurosignaling and neurocognitive deﬁcits including decreased speed of
information processing. Anderson et al. assessed the relative impact
of white matter abnormalities (WMA) on cognitive functions in
children with early-treated PKU [8]. Children in the PKU group with
extensive WMA (n = 14) displayed signiﬁcant impairments across all
cognitive domains. The degree of metabolic control weakly to
moderately correlated with attention, executive, and memory/
learning factors. Regression analysis revealed that EF and attention
factors were independently related to severity of WM pathology and
age, while the memory and learning factor was independently related
to metabolic control and age. Children with early-treated PKU exhibit
a global pattern of impairment, with a particular deﬁcit in processing
speed [8]. White matter (WM) pathology extending into frontal and
subcortical regions correlates with the greatest deﬁcits and a proﬁle of
impairment consistent with diffuse WM damage [7]. Furthermore,
improvements in WM damage have been observed when patients
regain metabolic control [89].
A second hypothesis known as “the dopamine depletion hypothesis”
theorizes that reduced availability of neurotransmitters in the brain,
especially dopamine in the prefrontal cortex thought responsible for EF,
can explain some of the observed neurocognitive deﬁcits in PKU.
Landvogt et al. demonstrated that ﬂuro-L-dopamine (FDOPA) uptake
into the brain was impaired when elevated plasma Phe levels were
present and suggested that this was due to competitive inhibition at the
speciﬁc large neutral amino acid (LNAA) transporter level at the blood
brain barrier [76]. They also demonstrated that there is a signiﬁcant
reduction of decarboxylation of FDOPA reaching the brain in PKU
subjects indicating dopamine synthesis pathways may be impaired.
Hoeksma et al. determined the protein synthesis rate in relation to
the plasma Phe concentrations in vivo in adult PKU patients by
positron emission tomography (PET) brain studies [72]. Results
showed a signiﬁcant negative relationship between plasma Phe
concentration and the cerebral protein synthesis rate in 19 PKU
patients. At increased plasma Phe concentrations above 600–
800 μmol/L, the cerebral protein synthesis rate is clearly decreased
compared to lower Phe concentrations. These data suggest that
cerebral protein metabolism in PKU adults can be abnormal due to
high plasma Phe concentrations which may affect both myelin and
dopamine synthesis pathways.
Growth and nutrition outcomes: early-treated diet-alone therapy
Early diet-treated PKU patients have reported deﬁciencies in
several essential nutrients and micronutrients, increased body mass
103
index (BMI), altered folate metabolism, plasma lipid peroxidation and
other oxidative stresses [94–120].
Children and adolescents
Studies of children and adolescents following the Phe-restricted diet
in the ﬁrst years of life report growth retardation including height and
head circumference, possibly related to the low natural protein content
of the therapeutic diet or to poor compliance [94,95,98,105,106].
Excessive weight gain, as measured by BMI, or decreased fat free mass
(FFM) is also observed in diet-alone treated PKU children [94].
These patients also demonstrate deﬁcient intakes of various nutrients
including reduced calcium, fat, and cholesterol, increased intake of simple
carbohydrates, and low blood levels of preformed long-chain polyunsaturated fatty acids (LC-PUFA). These essential fatty acids are vital to normal
brain and retinal development and deﬁciencies can yield visual and
cognitive impairment [38,99,100,108]. Supplementation with LC-PUFAs,
speciﬁcally docosahexanoic acid (DHA) and arachadonic acid (AA) may
ensure adequate levels and improved outcomes [38,96,108].
Micronutrient deﬁciencies including zinc, copper and selenium
have been documented [104]. Gassio and colleagues revealed
signiﬁcant neuropsychological deﬁcits associated with selenium
deﬁciency in PKU patients [104]. Despite efforts to fortify currently
available medical food with nutrients that exceed the dietary reference
intakes (DRIs), iron, vitamin A and zinc deﬁciency commonly occur
among infants and children on the Phe-restricted diet. Lower levels of
carnitine have also been noted in PKU patients relative to controls
which can have a negative impact on CNS function [120].
Adults
The adult PKU population is understudied in regards to growth and
nutritional outcomes. Hvas et al. examined adult PKU patients living on a
protein-restricted diet and demonstrated vitamin B6 intake was below
the DRI's and 75% had signs of early biochemical vitamin B12 deﬁciency
[107]. Mosely et al. reported on the blood lipid status in adult PKU
patients who had been on Phe-restricted diets for a mean period of
22.6 years (range 7–39 years) [111]. Lipid screening identiﬁed a subset
of subjects (approximately 25%) with signiﬁcantly elevated total
cholesterol/HDL ratios and hypertriglyceridemia was documented in
approximately 70% of these cases. The fatty acid analyses demonstrated
slight but statistically signiﬁcant reductions in the concentrations of
plasma and red blood cell DHA and plasma AA. These results resembled
those reported in children and could be an important factor in observed
neurocognitive deﬁcits observed in PKU adults.
Bone pathology outcomes: early-treated diet-alone therapy
Imbalances in bone formation and bone resorption as measured by
biomarkers, decreases in bone mass density (BMD) and alterations in
appearance of permanent teeth have been reported in early diettreated PKU patients [126–134].
Children and adolescents
Bone formation and resorption markers have been found to be
signiﬁcantly reduced in diet-alone treated PKU children compared to
healthy controls [126,127,134]. Ambrokiewwicz et al. measured markers
of the alteration of bone pathology present in diet-alone treated PKU
children and adolescents signaling risk of bone disease as they age [127].
Adults
Osteopenia and osteoporosis has been detected in the adult PKU
population [131,134]. The decrease in peak BMD in adult PKU patients
may be explained by long-standing dietary deﬁciency in protein,
calcium, vitamin D or trace elements, or a primary defect in bone
turnover inherent to the disease itself [134]. Further studies are
needed to elucidate the cause of low bone density in PKU patients that
have only been treated with diet.
104
G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
Maternal PKU outcomes: early-treated diet-alone therapy
Abnormally high and prolonged intrauterine Phe levels in
expectant PKU mothers are teratogenic to the developing fetuses
and can manifest in a myriad of symptomology with varying degrees
of severity dependent upon timing and extent of Phe exposure [135–
153]. Symptoms of untreated or late-treated maternal PKU can
include developmental delay, microcephaly, congenital heart disease,
low birth weight, craniofacial dysmorphism, and neurological
abnormalities including neurocognitive deﬁcits [135–153].
The Maternal Phenylketonuria Collaborative Study detailed the
outcomes of maternal PKU offspring over an 18 year period, assessing
the efﬁcacy of a Phe-restricted diet in preventing the morbidity
associated with this disorder. A total of 382 women with PKU and
other forms of HPA were enrolled and completed 572 pregnancies.
Optimal full-scale IQ outcomes occurred when maternal blood Phe levels
between 120 and 360 μmol/L were achieved by 8 to 10 weeks of
gestation and maintained throughout pregnancy [139]. Additionally, the
Maternal PKU Collaborative Study demonstrated that timing of Phe
exposure, speciﬁcally when metabolic control is not attained until 8–
10 weeks, may determine congenital heart defects (CHD), microcephaly,
and cognitive and behavioral outcomes in the offspring [142,150,151].
Furthermore, the longer the time taken to obtain maternal metabolic
control the worse the outcomes [151]. Maillot et al. further suggests that
the offspring of mothers with PKU with well-controlled blood Phe levels
pre- and post-conception are still at risk if blood Phe variations occur
within that range [144]. However, women with PKU who are aware of
the risks of MPKU still have signiﬁcant challenges in controlling maternal
blood Phe levels. These include access to medical care, unplanned
pregnancies, ﬁnancial constraints, demographics, psychosocial issues,
and the rigors of adhering to the strict PKU diet before and during
pregnancy especially if pregnancy-related nausea and vomiting are
present [136]. Thus, evidence suggests optimal fetal outcomes occur
when blood Phe levels are controlled between 120 and 360 μmol/L prior
to and throughout pregnancy without ﬂuctuations [139,144].
Discussion
NIH Consensus Statements provide evidence based recommendations on how to best manage patients to ensure optimal patient
outcomes and often deﬁne the standard of care for a speciﬁed pathology
over a period of several years. However, that the NIH recognizes that
recommendations become out of date and are labeled for “Historical
Purposes” after 5 years suggests NIH support for readdressing historical
guidelines such as those for PKU [3]. The assertion that expert
recommendations become rapidly outdated is supported by a recent
statistical analysis demonstrating that 50% of guidelines become
outdated in 5.8 years [157].
The Shekelle et al. model of assessing the current validity of
guidelines based on expert opinion and new literature suggests that
guidelines require updating when experts and the literature determine there is new evidence to invalidate older guideline recommendations and that new guideline recommendations should be presented
[158]. Shekelle et al. utilized four points when evaluating validity:
Fig. 2. Poor dietary adherence among all age groups.
opment Conference on the screening and management of PKU in light
of new evidence. Based on this approach, the NIH recommendation for
obtaining a target blood Phe level between 120 and 900 μmol/L after
12 years of age may be considered invalid with potential improved
outcomes reported upon stricter Phe control [5,57]. Although
evidence suggests that the NIH blood Phe target ranges are otherwise
primarily valid, it is clear from the evidence that diet-alone therapy
still burdens the PKU population with signiﬁcant suboptimal outcomes, especially as individuals age. Expert recommendations are
only effective if they are followed and it is clear that a large percentage
of all age groups of PKU patients ﬁnd adherence to metabolic control
through diet-alone difﬁcult [37,159,160: Fig. 2].
Above all, the data suggest the potential for development of
questions (Fig. 3) that would provide structure for a revised NIH
Consensus Statement on PKU management. These questions would
form the basis of developing new evidence-based recommendations to
address the suboptimal outcomes persistent in the PKU population. One
such recommendation might address the need to control blood Phe
variability over time through more frequent blood Phe monitoring;
maintaining consistent blood Phe within target ranges demonstrates
improved patient outcomes [6]. An advancement that has the potential
to control blood Phe variability, in addition to being an important
motivational tool, is the development of a portable Phe monitoring
device [161–163]. Another recommendation could call for the routine
screening of PKU patients of all ages for nutritional deﬁciencies, bone
density, cognitive dysfunction, emotional well-being and psychosocial
problems. Clearly not all PKU patients are equal in terms of risks for
suboptimal outcomes and the potential beneﬁts of individually tailored
PKU management practices according the patients' needs may be of
considerable value in updated recommendations. These can include
individually tailored blood Phe target levels, the use of newer
medications, follow up appointment scheduling and strategies to
improve treatment adherence, more detailed nutritional assessments,
blood tests, and neurocognitive functioning assessments.
Lastly, updated recommendations should address the use of new
therapies with demonstrated potential beneﬁts in the PKU population
1. Have interventions (diagnostic or therapeutic) been superseded or
replaced by other interventions?
2. Has new evidence altered the relation between beneﬁts and harm?
3. Have outcomes not considered at the time of the original guideline
become important or have outcomes considered important now
become unimportant?
4. Is there evidence that current performance is optimal and the
guideline is no longer needed?
This systematic review of the PKU literature assessed the need for
new NIH recommendations and convening a NIH Consensus Devel-
Fig. 3. Potential questions for the framework for the new NIH consensus development
conference on PKU.
G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
such as enhancing control of blood Phe levels in those who ﬁnd
dietary adherence difﬁcult or want less dependence on dietary
restrictions and medical foods. New alternative treatment options
are currently available including sapropterin dihydrochloride
(sapropterin, Kuvan®) and large neutral amino acid therapy (LNAA)
[50,164–177]. Sapropterin is a cofactor of PAH that can increase
endogenous PAH activity and subsequently lower blood Phe levels
and increase dietary Phe tolerance in a subset of the PKU population
identiﬁed as responders [164–174]. All subtypes of PKU based on
clinical severity have shown response to sapropterin therapy.
However large and small population studies have demonstrated
that response rates correlate with disease severity, with milder forms
of PKU having a higher response frequency [173,178]. Efforts are
underway to identify genotype–phenotype relationship to sapropterin response and the only current method is a trial period on
sapropterin therapy with evaluation of pre- and post-sapropterin
blood Phe levels or Phe tolerance [167,168,173]. Evidence suggests
that LNAA therapy works by inhibiting Phe transport from the gut to
the blood stream and from the blood stream to the brain through a
common amino acid transporter mechanism [50,175–177]. Unlike
105
sapropterin, there appears to be no genotype inﬂuence to LNAA
response. However, LNAA therapy is considered a “medical food,”
which precludes formal clinical trial evaluation on its safety and
efﬁcacy for PKU. Thus, while LNAA products are deemed “safe” for
consumption, there are no guarantees of effectiveness for treating
PKU whereas sapropterin achieved regulatory approval based on
positive safety and efﬁcacy results from large controlled clinical trials.
Research is ongoing into other new PKU therapy approaches such
as glycomacropeptide (GMP) proteins, which may create more
palatable low-Phe foods and promote better long-term adherence
[166]. Additional efforts include enzyme replacement and gene
therapy which may enable PKU patients to have an unrestricted diet
without worrying about high blood Phe levels [166].
Conclusion
The evidence demonstrates that signiﬁcant suboptimal outcomes
exist in the PKU population treated with diet-alone and suboptimal
outcomes are present in all age ranges (Fig. 4). Although many of the
recommendations within the 2000 NIH Consensus Statement on PKU
Fig. 4. Suboptimal outcomes exist in all age groups of PKU.
106
G.M. Enns et al. / Molecular Genetics and Metabolism 101 (2010) 99–109
may still be valid, the literature supports the formulation of new
recommendations. However, the NIH rarely revisits Consensus
Statements and only does so when newly available data warrant a
second conference. One such rare instance occurred in 2002, when the
1997 NIH Consensus Statement on the Management of Hepatitis C
was revisited based primarily on the introduction of new therapeutic
advances in the time frame since its original publication [3,179–182].
Similarly, the availability of the new evidence in this systematic
literature review coupled with treatment advancements such as the
availability of sapropterin provides support for a new NIH Consensus
Development Conference to revisit PKU management strategies to
optimize patient outcomes.
Acknowledgments
The authors acknowledge Kurt Almquist, BScH, of MediResource
Inc. for providing medical writing assistance and Ulyana Viktyuk of
MediResource Inc. who prepared the ﬁgures. G.M. Enns and R. Koch
have previously acted as consultants for BioMarin Pharmaceutical Inc.
V. Brumm and E. Blakely consult for BioMarin Pharmaceutical Inc. R.
Suter and E. Jurecki are employees and stockholders of BioMarin
Pharmaceutical Inc. Medical writing and graphical layout assistance
was funded by BioMarin Pharmaceutical Inc.
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