University of Groningen
PKU
Hoeksma, Marieke
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Chapter 8
Brain dysfunction in phenylketonuria (PKU): Is phenylalanine
toxicity the only possible cause?
Francjan van Spronsen, Marieke Hoeksma, Dirk-Jan Reijngoud
J Inherit Metab Dis 2009;32:46-51
103
Chapter 8
ABSTRACT
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 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 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.
104
Brain dysfunction in phenylketonuria (PKU)
INTRODUCTION
The pathogenesis of brain dysfunction in phenylketonuria (PKU; OMIM 261600) is still unknown. 1;2
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.1 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.2 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. 3 However,
some of the data used in their review were based on the rat model of hyperphenylalaninemia, which
is now considered an inadequate animal model of PAH deficiency. From 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 Figure 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), effects of high cerebral
concentrations of phenylalanine, and the effects of low cerebral concentrations of other large
neutral amino acids (LNAA).
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, neurophysiological and neuropsychological dysfunction,
possibly caused by decreased synaptic plasticity and/or reduced axonal outgrowth
Figure 1. the pathophysiology of brain dysfunction in phenylketonuria
105
Chapter 8
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 concentrations
in brain as observed in others.4-6 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).7;8 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.9 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 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 next paragraphs.
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 phenyalanine concentrations are
almost normal.4-6 The study of Schindeler et al.10 showed that a short period of supplementation
of LNAA resulted in improvement of neuropsycho-logical functions without a decrease of cerebral
phenylala-nine concentrations.
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.11-13 Phenylalanine was also
106
Brain dysfunction in phenylketonuria (PKU)
shown to inhibit the activity of both human tyrosine and tryptophan hydroxylase as expressed in
E-coli.14 Still, the influence of high cerebral phenylalanine concentrations on this neurotransmitter
synthesis is an issue of ongoing debate.15 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.16-18 When brain cells in culture were exposed to high phenylalanine concentrations in
the medium, net protein synthesis was decreased. 19 High phenylalanine concentrations were also
found to decrease the activity of HMG-CoA reductase, resulting in impaired cholesterol synthesis. 20
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 mice21 and in brains of deceased
PKU patients (Bauman and Kemper 1982). Acute application of high concentrations of phenylalanine
to cell cultures of neurones reduced glutaminergic synaptic transmission22;23, synaptogenesis, and
activity of pyruvate kinase.24 Acute application of high concentrations of phenylalanine to cell
cultures of neurons reduced glutamatergic synaptic transmission 23;22, synaptogenesis, and activity
of pyruvate kinase.24 A decreased activity of pyruvate kinase may relate to the in vivo finding of
decreased energy metabolism in PKU patients using positron emission tomography. 25
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.26-31 Similar observations were made in brain tissue of PKU mice. 11;12 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 5-hydroxytryptophan resulted in
improvement of ataxia, and rigidity.32
Dopamine deficiency is suggested to result in prefrontal cortex deficiency and is thought to
be of significant importance in brain dysfunction in PKU. 33-42 However, such a clearly defined
neuropsychological deficit was neither found in PAHenu2 mice43;44;45, which best resemble human
PKU, nor in more recent studies on PKU patients.46-49 Moreover, dopamine deficiency, which
underlies Parkinson and attention deficit hyperactivity disorder50, 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.51
Deficiencies in serotonin are thought to have a more general effect than dopamine deficiency 42,
and may result in psychosocial dysfunction rather than impairment of cognitive function.33;52
Therefore, deficiency of tryptophan does not present a full explanation of the brain dysfunction in
PKU.
107
Chapter 8
Second, decreased availability of essential amino acids results in a decreased synthesis of
protein in general.53 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.54 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.55 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. 65
Theoretically, the low concentration of any LNAA results not only in reduced amounts of myelin but
also in low amounts of other proteins, including cerebral enzymes such as tyrosine and tryptophan
hydroxylase, HMG-CoA reductase, 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.55;57 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. 58 These data
underlined the involve-ment 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.58 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. 59
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. Consequently, cerebral deficiency of LNAA 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 hogh cerebral phenylalanine
concentra-tions. Following this line of reasoning, the aim of treatment in PKU would be to normalize
cerebral concentrations of all LNAA 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 animal and human studies are needed
108
Brain dysfunction in phenylketonuria (PKU)
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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