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Jaume Campistol and Sankar Surendran
292
and without side effects and improving quality of life [58]. The
normalization of concentrations of trace elements and vitamins, but also of
polyunsaturated fatty acids, has been demonstrated in children treated with
BH4 [59, 60]. It has also been shown that the higher protein intake in these
patients allows a better bone mass [58, 59, 60]. Currently its use is
recommended as early as the neonatal period [61].
Another option is large neutral amino acid supplements that compete
with the same system of transport of the Phe through the blood-brain
barrier [62]. Supplementation with large neutral amino acids (tyrosine,
tryptophan, threonine, isoleucine, leucine, valine, methionine and histidine)
would thus have a competitive effect on the transport of Phe to the brain
through the blood-brain barrier [22, 62, 63].
6.2. Therapeutic Options for the Future
Substitution therapy is based on the use of an alternative enzyme,
phenylalanine ammonium lyase (PAL, EC 4.3.1.5), a recombinant enzyme
derived from Rhodosporium toruloides that transforms Phe into
transcinamic acid (which is excreted in the form of hippurate) and traces of
ammonia [50, 64, 65, 66]. It has the advantage over PAH that it does not
require a cofactor, even if it does require Tyr supplementation, since this
amino acid is not the product of the reaction and therefore, it continues to
be an essential amino acid, just as in dietary treatment [50, 65-67]. This
treatment is currently used in PKU patients over the age of 16, but it has
some side effects, especially at the level of immune adverse reactions
against the enzyme, requires a daily subcutaneous dose and for the moment
is an expensive treatment.
Gene therapy is based on the introduction of a functional PAH gene
into somatic cells from PKU patients and the first therapeutic trials are in
advanced stages [23, 50].
The use of pharmacological chaperones to stabilize or promote the
correct folding of the mutated PAH protein represents a promising therapy
for the future, especially considering that many PKU patients have
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293
mutations that cause folding disorders [23, 50]. Another of the primary
goals of treatment, apart from reducing Phe levels, is to achieve an
improvement in the quality of life of all patients with PKU [68-70]. More
and more work is being done for these purposes and the improvements are
truly remarkable with the scientific advances, the PKU monitoring units
and the role of associations.
CONCLUSION
Phenylketonuria (PKU; OMIM 261600) is an inborn error of
metabolism caused by mutations in the phenylalanine hydroxylase (PAH)
gene (EC 1.14.16.1). These mutations lead to a total or partial decrease of
PAH activity, which catalyzes the hydroxylation of Phe into tyrosine (Tyr),
using tetrahydrobiopterin (BH4) as a cofactor. The biochemical
consequences are Phe accumulation in biological tissues and fluids, as well
as a deficit in the availability of Tyr. It is well-known that untreated PKU
causes severe neurological disorders such as intellectual disability,
epilepsy, progressive motor disorder, and severe behavioral disorders.
Treatment of PKU should begin in the first weeks of life as early as
possible and consists of a Phe restricted diet combined with the
administration of a special formula, or alternatively with BH4 and total or
partial diet liberalization in patients who respond to it. Phenylketonuria is
known for several decades. Several treatments have been applied to cure
the disease. BH4 effect in treating PKU patients is limited to the type of
mutation. Although BH4 reduces blood Phe levels, the drug is effective
only in some PKU patients with the improvement in quality of life. Long
term application of BH4 affects micronutrients intake and therefore,
patients under chronic BH4 therapy needed to be advised with
micronutrients supplementation. Work is being done to improve the quality
of life of PKU patients. The prognosis of PKU has improved dramatically
with the introduction of screening, diet, clinical-biochemical -nutritional
controls, neuropsychological follow-up, and the consolidation of PKU
diagnostic, treatment, and follow-up units.
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294
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