Download Phenylketonuria

Phenylketonuria
Michelle Bradley, Lourdes Al Ghofaily and Ramya Srinivasan
Phenylketonuria (PKU) is a monogenic autosomal recessive disease. Mutations in
the PAH locus encoding the phenylalanine hydroxylase enzyme lead to impaired
functioning of the enzyme, hyperphenylalaninemia, and mental retardation.
Hyperphenylalaninemia (HPA), one of the core traits of PKU can also result from
mutations at regions distinct from the PKU locus. One form of non-PKU HPA is caused
by a defect in the synthesis and recycling of tetrahydrobiopterin, a cofactor essential for
the function of the PAH enzyme.1 HPA has thus been studied as a trait that exhibits both
locus heterogeneity and allelic heterogeneity (in the PAH gene, for instance). PKU and
other forms of HPA have also been found to be multifactorial; being the results of both
genetic (mutant genotypes) and environmental (dietary phenylalanine) causes. High
correlation between mutant genotype and variant phenotype has not been seen in the case
of PKU, suggesting the roles of genotypes at other loci in addition to environmental
factors1.
In the 1980s the PAH gene was mapped to human chromosome 12q24.1 and over
400 mutant alleles have been detected. These, predominantly missense, are expressed at
levels far below the wildtype and most genotypes are heteroallelic. Mutant PAH proteins
have decreased stability and undergo a process of degradation triggered by structural
abnormalities. Missense mutations lead to improper protein folding, altered
oligomerization, and increased aggregation of mutant PAH. 1 The phenotype of affected
individuals can be altered by the actions of chaperone proteins which can modulate the
solubility of mutant PAH proteins. Chaperones provide a protective environment for
partially folded proteins, thereby preventing them from entering non productive
pathways. Variation in chaperone functioning among individuals can thus modify the
disease phenotype associated with a particular missense mutation. Altered protein folding
and degradation are therefore implicated in the pathogenesis of the variant phenotype and
it is therefore difficult to correlate in vivo catalytic activity with the predicted effect of an
allele. 1 In other words, PKU exhibits variable expressivity and discordance between
phenotype and genotype is often seen.
The homotetrameric PAH enzyme catalyzes the conversion of phenylalanine to
tyrosine. The hydroxylation is the key determining reaction of a catabolic flux that
eventually leads to the oxidation of phenylalanine to carbon dioxide and water. In normal
individuals, this pathway accounts for 75% of the disposal of dietary phenylalanine.
Metabolic homeostasis of the phenylalanine pool is actually a complex process involving
intestinal absorption followed by hepatic uptake of dietary phenylalanine, its
incorporation into proteins, and disposal via hydroxylation, transamination, and
decarboxylation. 1
Affected individuals have impaired enzymatic function which leads to
accumulation of phenylalaline. Excess phenylalaline has toxic effects on the development
and functioning of the brain. This leads to mental retardation which is the major disease
phenotype of PKU. However, not all affected individuals suffer from impaired cognitive
development. IQ is a complex trait affected by many factors and levels do not always
correlate with those predicted by the mutant PAH genotype. In addition, individuals with
similar metabolic phenotypes may show distinct cognitive phenotypes. The discordance
can be explained by variations in the functioning of the blood-brain barrier and
modulation in the free phenylalanine content in the brain. The genotypes of loci involved
in the mediated transport of phenylalanine into the brain are therefore among the factors
that control the severity of mental retardation. 1
Phenylketonuria (PKU) is screened for early on in life. It is tested most commonly
through the Guthrie microbial inhibition test. This test is done on all newborns in the
country. A drop of blood is taken from the newborn's heel in the hospital and sent to a
national lab where an excess of phenylalanine is tested for by growing a phenylalaninedependent culture of bacteria with the blood sample. If there is adequate bacterial growth,
then it is a sign that there is a significant amount of phenylalanine in the newborn's blood.
Normal range is about 1 mg/dl of phenylalanine. PKU is suspected at any level above 30
mg/dl. Because there are many other diseases that cause hyperphenylalaninemia, further
testing must be done to diagnose PKU. For the purposes of genetic counseling, however,
sequencing of the PAH gene is done to rule out or ascertain whether the newborn will
develop PKU or any kind of hyperphenylalaninemia.
The symptoms of PKU can result from defects in the biopterin pathways. This
includes deficiencies in the metabolism of tetrahydrobiopterin (BH4)- both in its synthesis
and recycling. BH4 is a required cofactor in the hydroxylation of various amino acids
such as phenylalanine, tyrosine, and tryptophan. A defect in BH4 synthesis is due to
deficiencies in any one of the following enzymes: guanosine triphosphate cyclohydrolase
(GTPCH), 6-pyruvoyl tetrahydrobiopterin (DHPR), or pterin-4-acarbinolamine
dehydratase (PCD).
Hyperphenylalaninemia resulting from BH4 deficiency is passed down as an
autosomal recessive disorder and not as an autosomal dominant disorder, as classic PKU
is. There are some common symptoms between BH4 deficiency and PKU including
mental retardation, irritability, abnormal movements and microcephaly. BH4 deficiencies
only account for 2% of all cases of hyperphenylalaninemia, but they must be
differentiated from PKU for appropriate treatment. Interestingly, although BH4
deficiencies and PKU are due to different causes, BH4 supplements can provide a
sufficient therapy for "up to 10% of individuals with classic PKU" 2,3.
Among some of the first symptoms to appear in babies suffering from PKU
include behavioral and social problems, seizures and neurological deficits such as
uncontrolled movements, hyperactivity, eczema, microcephaly, stunted growth, and a
characteristic "musty" odor due to the excess phenylalanine in urine, breath, or skin. Even
in cases of early-detected PKU, some mild form of mental retardation can be expected.
The goal of treatment for the hyperphenylalaninemias is to keep the
concentrations of phenylalanine and tyrosine in the blood at relative steady levels. This
method will try to prevent the cognitive deficits that are attributable to PKU. The blood
concentrations should be between 120 to 360 µmol/L (2-6 mg/dL) or 40 to 240 µmol/L
(1-4 mg/dL). These levels are considered safe for normal brain function. Studies have
proven that if a strict low phenylalanine diet is not followed closely, especially while the
child is still young, and if the phenylalanine level in the blood is allowed to rise above the
recommended levels, some brain impairment is inevitable.
A diet restricted in phenylalanine should be started as soon as possible after birth
and continued at least into adolescence or for life 4. Studies have proved that people who
have an enzyme activity level below 25% and go off the strict diet have an increased
chance of decreasing their IQ levels. This is compared to others with above 25% enzyme
activity that also went off the diet. This second group maintained or increased their IQ
levels 5.
The restricted phenylalanine diet needs to be adjusted in order to suit the
individual needs for each patient. These needs are based on their own tolerance for
phenylalanine and as well as appropriate protein and energy levels for each patient age.
Blood concentrations of phenylalanine within the recommended levels and normal
nutritional status cannot be achieved by a low-protein diet alone, but with the addition of
a phenylalanine-free medical formula.
The diet must continuously be adjusted so that growth and nutritional status are
unaffected and that a deficiency of phenylalanine or tyrosine is not created. The diet
might also have to be adjusted in order to account for growth, illness, activity, etc.
Plasma phenylalanine and tyrosine concentrations must be monitored regularly6. The
treatment for patients with PKU is not easy, but through the help of a caring and
supportive medical team the correct treatment and care can be administered.
Since PAH deficiency is inherited in an autosomal recessive manner, unaffected
parents of a child with PAH deficiency are obligate heterozygotes. People who are
heterozygotes for PAH carry one disease causing PAH allele, and since the disease
requires two affected alleles in order to be expressed they never develop
hyperphenylalaninemia. The siblings of an affected child will have a 25% chance of
being affected themselves, a 50% chance of being a carrier, and a 25% chance of having
two normal alleles of PAH.
Since PAH deficiency is a highly treatable disease and most of the affected
patients have a normal intelligence and live normal lives they often reproduce. All the
offspring of a person with PAH deficiency will be an obligate carrier. It depends on the
partner if the offspring will be affected or remain a carrier for PKU. If the other parent is
a carrier for PAH deficiency then the child will have a 50% chance of being affected or a
heterozygote. If two affected people decide to have a child then the offspring will
definitely have the PAH deficiency.
If the affected parent is the mother then additional problems can arise during the
pregnancy. For maternal PKU a strict diet is necessary prior to conception in order to
prevent the fetus from having birth defects as a result of the mother’s phenylalanine
levels during the pregnancy. This will protect the fetus from having brain damage and
intellectual development problems later in life. For mothers who start the low
phenylalanine diet post-conception, the chances increase that their babies will have a
heart defect. Prenatal care is used to determine which complications will arise when the
child is born, so that proper steps can be taken to ensure the best postnatal care for the
child. This is most common approach for unplanned pregnancies which do not allow the
mother modulate her diet before conception7.
References:
1. Monogenic traits are not simple: lessons from phenylketonuria. TIG July 1999, volume
15, No. 7.
2. Scriver CR, Kaufman S (2001) The hyperphenylalaninemias. In: Scriver CR, Beaudet
AL, Sly SW, Valle D (eds) Childs B, Kinzler KW, Vogelstein B (assoc eds) The
Metabolic and Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New
York, Ch. 77
3. Bernegger C and Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness
among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to
2002. Mol Genet Metab 77:304-13
4. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ
(1998) Neurological outcome in adult patients with early-treated phenylketonuria.
Eur J Pediatr 157:824-30
5. Greeves, L. G.; Patterson, C. C.; Carson, D. J.; Thom, R.; Wolfenden, M. C.; Zshocke,
J.; Graham, C. A.; Nevin, N. C.; Trimble, E. R. :
Effect of genotype on changes in intelligence quotient after dietary relaxation in
phenylketonuria and hyperphenylalaninaemia. Arch. Dis. Child. 82: 216-221,
2000.
6. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ
(1998) Neurological outcome in adult patients with early-treated phenylketonuria.
Eur J Pediatr 157:824-30
7. Levy HL, Lobbregt D, Platt LD, Benacerraf BR (1996) Fetal ultrasonography in
maternal PKU. Prenat Diagn 16:599-604