J Inherit Metab Dis (2009) 32:46–51
DOI 10.1007/s10545-008-0946-2
BH4 AND PKU
Brain dysfunction in phenylketonuria: Is phenylalanine toxicity
the only possible cause?
F. J. van Spronsen & Marieke Hoeksma &
Dirk-Jan Reijngoud
Received: 7 May 2008 / Submitted in revised form: 16 October 2008 / Accepted: 20 November 2008 / Published online: 13 January 2009
# SSIEM and Springer 2009
Summary In phenylketonuria, mental retardation is
prevented by a diet that severely restricts natural
protein and is supplemented with a phenylalanine-free
amino acid mixture. The result is an almost normal
outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive
dysfunction in phenylketonuria is unknown, although
it is clear that the high plasma concentrations of
Communicating editor: Beat Thöny
Competing interests: None declared
References to electronic databases: Phenylketonuria: OMIM
261600.
Presented at the International Conference on
Tetrahydrobiopterin, PKU, and NOS, 23–28 March 2008, St
Moritz, Champfér, Switzerland.
F. J. van Spronsen (*) : M. Hoeksma
Beatrix Children_s Hospital,
University Medical Center Groningen,
University of Groningen,
PO Box 30.001, 9700 RB Groningen,
The Netherlands
e-mail: [email protected]
F. J. van Spronsen : M. Hoeksma : D.-J. Reijngoud
Center for Liver, Digestive and Metabolic Diseases,
GUIDE Graduate School for Drug Exploration,
University Medical Center Groningen,
University of Groningen,
Groningen, The Netherlands
D.-J. Reijngoud
Laboratory of Metabolic Diseases,
University Medical Center Groningen,
University of Groningen,
Groningen, The Netherlands
phenylalanine influence the blood–brain barrier transport of large neutral amino acids. The high plasma
phenylalanine concentrations increase phenylalanine
entry into brain and restrict the entry of other large
neutral amino acids. In the literature, emphasis has
been on high brain phenylalanine as the pathological
substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral
enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large
neutral amino acids in brain may also be an important
factor affecting cognitive function in phenylketonuria.
Cerebral protein synthesis was found to be disturbed
in a mouse model of phenylketonuria and could be
caused by shortage of large neutral amino acids instead
of high levels of phenylalanine. Therefore, in this
review we emphasize the possibility of a different idea
about the pathogenesis of mental dysfunction in
phenylketonuria patients and the aim of treatment
strategies. The aim of treatment in phenylketonuria
might be to normalize cerebral concentrations of all
large neutral amino acids rather than prevent high
cerebral phenylalanine concentrations alone. In-depth
studies are necessary to investigate the role of large
neutral amino acid deficiencies in brain.
Abbreviations
BBB
blood–brain barrier
LNAA large neutral amino acids
MRS
magnetic resonance spectroscopy
PAH
phenylalanine hydroxylase
PKU
phenylketonuria
J Inherit Metab Dis (2009) 32:46–51
47
Introduction
The pathogenesis of brain dysfunction in phenylketonuria (PKU; OMIM 261600) is still unknown (Scriver
2001; van Spronsen et al 2001). PKU is a monogenetic
disease, in which mutations in the gene encoding the
enzyme phenylalanine hydroxylase (PAH) cause a
deficient activity resulting in increased phenylalanine
and low to normal tyrosine concentrations in blood and
tissues (Scriver 2001). Plasma phenylalanine, rather
than tyrosine, concentrations are related to cognitive
outcome in PKU. Furthermore, dietary phenylalanine
restriction rather than tyrosine supplementation as the
only treatment has been successful as treatment
strategy (van Spronsen et al 2001). Thus, phenylalanine affects brain function, in one way or another.
In their review on the neurochemistry of PKU,
Surtees and Blau addressed the effects of blood
phenylalanine on cerebral free amino acid concentrations, and the effect of high blood and brain phenylalanine on neurotransmitters, cerebral protein
synthesis, and myelin metabolism (Surtees and Blau
2000). However, some of the data used in their review
were based on the rat model of hyperphenylalaninaemia, which is now considered an inadequate animal
model of PAH deficiency. Since the time of publication in 2000, data on the PAHenu2 mice in particular
have added new information about the pathogenesis of
brain dysfunction in PKU.
In the present review we try to define different
cascades, shown in Fig. 1, and how they might interact
and result in brain dysfunction in PKU. In this way, we
aim to build further the concept of pathogenesis of
brain dysfunction in PKU. Starting from the high
plasma phenylalanine concentration, we discuss the
importance of the blood–brain barrier (BBB), the
effects of high cerebral concentrations of phenylalanine, and the effects of low cerebral concentrations of
other large neutral amino acids (LNAA).
The importance of the blood–brain barrier
On the basis of two important observations, we think
that transport of LNAA across the BBB and its
impairment in PKU is essential to the pathogenesis
of mental dysfunction in PKU patients. First, the
clinical symptoms and signs of PKU almost exclusively
concern brain. Second, some untreated PKU patients
with consequently high plasma phenylalanine concentrations escape from severe brain dysfunction. Studies
with magnetic resonance spectroscopy (MRS) by
Weglage and co-workers revealed that these patients
have almost normal instead of very high phenylalanine
High phenylalanine concentration and “normal” LNAA concentrations
Plasma
Blood brain barrier
Competitive blood-brain barrier transport
Brain
High phenylalanine
Low LNAA
All LNAA
(except phenylalanine)
Decreased
Glutamatergic
synaptic
transmission
Pyruvate
kinase
HMG-CoA
reductase
Tyrosine and
tryptophan
hydroxylase
Decreased
protein synthesis
Specifically
tyrosine and tryptophan
Decreased
neurotransmitters
Defective
myelination
Cognitive deficits, neuropsychological, and neurophysiological dysfunction,
possibly caused by decreased synaptic plasticity and/or reduced axonal outgrowth
Fig. 1 The pathophysiology of brain dysfunction in phenylketonuria
48
concentrations in brain as observed in others (Möller
et al 1998; Weglage et al 1998, 2001). The studies of
Weglage and co-workers substantiated the finding of
untreated PKU women who did not show severe
mental retardation but gave birth to non-PKU children
with severe intrauterine growth restriction, including
microcephaly, mental retardation, congenital heart
defects and facial abnormalities. From the MRS
observations it was concluded that in PKU patients
transport of LNAA across the BBB is essential in the
pathophysiology of brain dysfunction in PKU.
Phenylalanine enters the brain using the L-type
amino acid transporter (LAT1, SLC7A5) in competition with eight other LNAA (i.e. tyrosine, tryptophan,
valine, isoleucine, leucine, threonine, methionine, and
histidine) (Pratt 1980; Smith et al 1987). The affinity of
the LAT1 transporter for phenylalanine is high,
resulting in a high transport velocity of phenylalanine
even at only slightly increased blood phenylalanine
concentrations (Pardridge 1998). When blood phenylalanine concentrations are elevated, phenylalanine is
preferentially transported across the BBB at the
expense of other LNAA, resulting in high cerebral
concentrations of phenylalanine and low cerebral
concentrations of other LNAA. In this respect, we
have to mention that rates of amino acid transport
across the BBB have not been estimated yet in PKU
patients. The effects of high cerebral phenylalanine
concentrations and low cerebral concentrations of
other LNAA will be discussed in the following sections.
Effects of increased cerebral phenylalanine
concentrations
With the development of MRS it became possible to
measure in vivo cerebral phenylalanine concentrations,
and to investigate the relation with all possible
outcome variables. So far, while the relation between
plasma phenylalanine and outcome is beyond any
doubt, the relationship between brain phenylalanine
concentration and outcome is less clear. The group of
Möller and Weglage showed a relation between brain
phenylalanine concentrations and outcome. However,
although the patients clearly escaped from severe
mental retardation, at least some of them do not have
a complete normal outcome either, even though brain
phenylalanine concentrations are almost normal
(Möller et al 1998; Weglage et al 1998, 2001). The
study of Schindeler et al (2007) showed that a short
period of supplementation of LNAA resulted in
improvement of neuropsychological functions without
a decrease of cerebral phenylalanine concentrations.
J Inherit Metab Dis (2009) 32:46–51
Studies in brains of untreated PAHenu2 mice showed
decreased concentrations of neurotransmitters. It was
suggested that high brain phenylalanine concentrations
inhibited the enzyme activity of tyrosine hydroxylase
and tryptophan hydroxylase (Joseph and Dyer, 2003;
Pascucci et al 2002; Puglisi-Allegra et al 2000).
Phenylalanine was also shown to inhibit the activity
of both human tyrosine and tryptophan hydroxylase as
expressed in E. coli (Ogawa and Ichinose 2006). Still,
the influence of high cerebral phenylalanine concentrations on this neurotransmitter synthesis is an issue
of ongoing debate (Fernstrom and Fernstrom 2007).
Early in vitro studies indicated that high cerebral
phenylalanine concentrations may compete with cerebral tyrosine to be hydroxylated by cerebral tyrosine
hydroxylase, so that tyrosine is formed in brain and the
conversion of tyrosine to dopa is blocked (Ikeda et al
1965; Shiman et al 1971). When brain cells in culture
were exposed to high phenylalanine concentrations in
the medium, net protein synthesis was decreased
(Hughes and Johnson 1976). High phenylalanine concentrations were also found to decrease the activity of
HMG-CoA reductase, resulting in impaired cholesterol
synthesis (Shefer et al 2000). As protein and cholesterol
are essential parts of myelin, this finding is in line
with observations of hypomyelination and gliosis in
brain cells of PAHenu2 and wild -type mice (Dyer et al
1996) and in brains of deceased PKU patients (Bauman
and Kemper 1982). Acute application of high concentrations of phenylalanine to cell cultures of neurons
reduced glutaminergic synaptic transmission (Glushakov
et al 2005; Martynyuk et al 2005), synaptogenesis, and
activity of pyruvate kinase (Horster et al 2006). A
decreased activity of pyruvate kinase may relate to
the in vivo finding of decreased energy metabolism in
PKU patients using positron emission tomography
(Pietz et al 2003).
Effects of decreased cerebral concentrations of large
neutral amino acids
In our view, high plasma phenylalanine concentrations
are intrinsically related to low cerebral concentrations
of LNAA. Decreased cerebral concentrations of
tyrosine and tryptophan may result in insufficient
synthesis of dopamine and serotonin, respectively. In
cerebrospinal fluid and brain of untreated and treated
PKU, patients the concentrations of neurotransmitters
are clearly decreased (Antoshechkin et al 1991;
Burlina et al 2000; Butler et al 1981; Guttler and Lou
1986; Lykkelund et al 1988; McKean 1972). Similar
observations were made in brain tissue of PKU mice
J Inherit Metab Dis (2009) 32:46–51
(Pascucci et al 2002; Puglisi-Allegra et al 2000). Bonafé
and colleagues showed that in a patient with mild PAH
deficiency, resulting in moderate elevation of plasma
phenylalanine concentrations, low concentrations of
neurotransmitters can be found, and that supplementation of a combination of L-dopa, tyrosine, and 5hydroxytryptophan resulted in improvement of ataxia
and rigidity (Bonafé et al 2001).
Dopamine deficiency is suggested to result in
prefrontal cortex deficiency and is thought to be of
significant importance in brain dysfunction in PKU
(Anderson et al 2007; Diamond et al 1994; Huijbregts
et al 2002, 2003; Leuzzi et al 2004; Schmidt et al 1996;
Smith and Knowles 2000; Stemerdink et al 2000;
Weglage et al 1996; Welsh et al 1990; White et al 2002).
However, such a clearly defined neuropsychological
deficit was found neither in PAHenu2 mice (Cabib et al
2003), which best resemble human PKU, nor in more
recent studies on PKU patients (Channon et al 2004,
2005, 2007; White et al 2001). Moreover, dopamine
deficiency, which underlies Parkinson and attention
deficit hyperactivity disorder (Iversen 2006), is not
specifically related to PAH deficiency. Furthermore,
supplementation with L-dopa in PKU patients showed
no positive effect on neuropsychological functions and
visual evoked potentials (Ullrich et al 1994).
Deficiencies in serotonin are thought to have a more
general effect than dopamine deficiency (Anderson
et al 2007), and may result in psychosocial dysfunction
rather than impairment of cognitive function (Pietz
et al 1997; Welsh et al 1990).Therefore, deficiency of
tryptophan does not present a full explanation of the
brain dysfunction in PKU.
Second, decreased availability of essential amino acids
results in a decreased synthesis of protein in general
(Nishihira et al 1993). Owing to the PAH deficiency,
tyrosine has become an essential amino acid as well.
As a consequence, in PKU all LNAA are essential
amino acids. Cerebral protein synthesis was decreased
in PAHenu2 mice (Smith and Kang 2000). Besides this
study, no published data are available on cerebral protein synthesis in PKU.
From the field of neurobiology we know that
cerebral protein synthesis is essential for brain development and function (Ramakers, 2002). One of the
best-known specific examples of cerebral proteins is
myelin, which is often found to be abnormal in PKU.
Myelin basic protein is essential for synthesis of
myelin. The synthesis of myelin basic protein was
impaired if one of the essential amino acids was
deficient. Theoretically, the low concentrations of any
LNAA results not only in reduced amounts of myelin
but also in low amounts of other proteins, including
49
cerebral enzymes such as tyrosine and tryptophan
hydroxylase, HMG-CoA reductase and pyruvate kinase as well as cerebral receptor proteins such as the
glutamate receptor. These reductions in various proteins may result in decreased synaptic plasticity as well
as decreased axonal outgrowth. Although the relationships between these processes and mental dysfunction
have not been investigated intensively in PKU, the
processes are known to be disturbed in mental
dysfunction (Johnston 2003; Ramakers 2002). This, in
turn, may contribute to the brain dysfunction as seen
in untreated and treated PKU patients.
Cerebral phenylalanine toxicity and large neutral
amino acid deficiency
Combined, the above-mentioned studies indicate that
it is difficult to distinguish between the effects of high
cerebral concentrations of phenylalanine and low
cerebral concentrations of the other LNAA. For
example, the paper by Pietz and colleagues showed
that supplying large amounts of LNAA decreases
brain phenylalanine and improves cerebral electrophysiology (Pietz et al 1999). These data underlined
the involvement of LNAA in the brain dysfunction
of PKU patients but did not answer whether the
effects were due to a decrease in brain phenylalanine
or to increased availability of other LNAA (Pietz et al
1999). The data again show that explaining the cascade
from the gene defect to the clinical phenotype, even in
monogenetic traits, is not a simple task (Scriver and
Waters 1999).
The data of Weglage and colleagues and Pietz and
colleagues suggest the importance of normal cerebral
phenylalanine concentrations, but the cerebral concentrations of other LNAA were not measured (Pietz et al
1999; Weglage 1998, 2001). Consequently, cerebral
LNAA deficiency rather than cerebral phenylalanine
toxicity may prove to be the main cause of brain
dysfunction of PKU. Therefore, preventing low cerebral
LNAA concentrations might be of equal importance in
preventing high cerebral phenylalanine concentrations.
Following this line of reasoning, the aim of treatment in
phenylketonuria would be to normalize cerebral concentrations of all large neutral amino acids rather than
prevent high cerebral phenylalanine concentrations
alone.
Such a theory could also apply to other diseases in
which one of the LNAA is increased in plasma and
brain, e.g. maple syrup urine disease with increased
leucine concentrations, and tyrosinaemia types I to III
with increased concentrations of tyrosine. Future
50
animal and human studies are needed to confirm or
refute this theory.
Conclusion
The cascade of the pathogenesis of brain dysfunction
in PKU starts with the effect of the high blood
phenylalanine concentration on BBB transport of
LNAA into brain. In this review we emphasize that
not only direct cerebral phenylalanine toxicity but also
cerebral shortage of LNAA might cause brain dysfunction in PKU patients. Further in vitro and in vivo
studies are necessary to confirm or refute this concept
of brain dysfunction in PKU with possible consequences for treatment. As long as these data are not
available, phenylalanine restriction remains the treatment of choice, especially during childhood and in
maternal PKU.
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