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Acta Fac. Pharm. Univ. Comen. LXII, 2015 (Suppl XI): 21-26.
ISSN 1338-6786 (online) and ISSN 0301-2298 (print version),
DOI: 10.1515/afpuc-2015-0016
ACTA FACULTATIS PHARMACEUTICAE UNIVERSITATIS COMENIANAE
A current view of the diagnostics and treatment
of phenylketonuria in Slovakia
Súčasný pohľad na diagnostiku
a liečbu fenylketónúrie na Slovensku
Original research article/Review
Oto Ürge1,2
1
Slovak Medical University in Bratislava,
Faculty hospital in Bratislava, Dep. for children
and adolescents A Getlika, Bratislava, Slovak Republic
2
synlab slovakia Ltd, Bratislava, Slovak Republic
SZU, FN Bratislava,
Klinika pre deti a dorast A. Getlíka,
Bratislava, Slovak Republic
2
synlab slovakia s.r.o., Bratislava, Slovak Republic
1
/
Received June 9, 2015, accepted October 20, 2015
Abstract
An overview of the diagnostics and treatment of phenylketonuria in Slovakia is presented in this paper. The nature of diseases,
incidence and prevalence in Slovakia, its genetic characteristics, current laboratory diagnostics and treatment options are
defined. A new method of phenylketonuria screening in Slovakia, which has brought substantial improvement in early detection
of the disease and shortening time for definitive diagnosis since 1995 as well as the importance of a tandem MS/MS (mass
spectrometry) introduced in the diagnosis of inherited metabolic disorders, is presented. The current state of phenylketonuria
treatment focusing on low-protein dietary treatment and supplementation of amino acid mixtures is analysed. The use of
sapropterin, enzyme replacement therapy, large neutral amino acids supplementation and gene therapy are also discussed.
Slovak
abstract
Autor prináša súčasný pohľad na diagnostiku a liečbu fenylketonúrie na Slovensku. Definuje podstatu ochorenia, incidenciu a
prevalenciu na Slovensku, jeho genetickú charakteristiku, súčasné možnosti laboratórnej diagnostiky a liečby. Hodnotí novú
organizácia skríningu fenylketonúrie na Slovensku, ktorá priniesla od roku 1995 podstatné zlepšenie včasného zachytenia choroby
a skrátenie času definitívnej diagnózy, ako aj význam zavedenia tandemovej MS/MS do diagnostiky dedičných metabolických
porúch. Rozoberá súčasný stav terapie fenylketonúrie so zameraním na nízkobielkovinovú diétnu liečbu a suplementáciu
aminokyselinových zmesí. V liečbe upozorňuje aj na využitie sapropterínu, enzýmovú náhradnú terapiu, suplementáciu veľkými
neutrálnymi aminokyselinami a génovú terapiu
Keywords
phenylketonuria – hyperphenylalaninemia – diagnostics – screening – sapropterin
Kľúčové
slová:
fenylketonúria – hyperfenylalaninémia – diagnostika – skríning – sapropterín
INTRODUCTION
Phenylketonuria (PKU) and hyperphenylalaninemia (HPA)
are the most common inherited metabolic disorders. These
diseases have one of the highest incidences in the Slovakian
population and are usually detected with very well-developed
diagnostic and therapeutic procedures. Nowadays, its
genetic basis is already well known. Phenylketonuria is an
autosomal recessive inherited metabolic disorder of aromatic
amino acids. It manifests only in the homozygous status,
where parents are carriers (heterozygotes). They have 25%
of affected children, 25% of healthy children and 50% of
heterozygous carriers of the pathological gene. It belongs
to the most common monogenic diseases in the Caucasian
population (Strnová 2001).
According to the report of the Newborn Screening Center, the
incidence of phenylketonuria is 1:5,908 born alive over the
last 17 years in Slovakia where the prevalence is about 300
patients (Dluholucký, Knapková and Záhorcová 2014).
The cause of the classic form of phenylketonuria with a
high concentration of phenylalanine in blood is genetically
conditioned failure of phenylalanine hydroxylase (PAH)
enzyme activity in the liver. This enzyme catalyses the
hydroxylation of phenylalanine to tyrosine in the presence
of cofactor BH4. The gene for this enzyme is localized
on chromosome 12. Currently, more than 570 mutations
identified in the gene for the PAH are known. R408W is the
most common mutation of classic PKU in our population.
* E-mail: [email protected]
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Acta Fac. Pharm. Univ. Comen. LXII, 2015 (Suppl XI): 21-26.
A current view of the diagnostics and treatment of phenylketonuria in Slovakia
Among the Roma ethnicity in Slovakia, the mutation R252W
is predominant. The absence or lack of the phenylalanine
hydroxylase enzyme activity results in accumulation of
phenylalanine amino acid, lack of tyrosine and excretion of
phenyl ketones in the urine. An increase of the phenylalanine
concentration in blood mainly leads to the damage of the
central nervous system (CNS). In clinical presentation in
untreated patients, mental retardation and cramps dominate.
Children usually have light hair, blue eyes, light skin and
eczema (Strnová, Ürge and Nogeová, 2007, Procházková et al.
2005, Hyánek et al., 1996).
Currently, we can ensure an adequate somatic and mental
development of children with phenylketonuria by early
detection of the disease. It allows qualitative full-area
screening in newborns and prompt initiation of treatment.
The most optimal treatment regimen is chosen for each
patient with PKU. This regimen requires a regular and
comprehensive monitoring of treatment effectiveness, child’s
development, cooperation with family and compliance with
treatment recommendations (Strnová and Ürge, 2006).
In Slovakia, providing care for patients with phenylketonuria
is governed by guidelines published in the Journal of the
Ministry of Health of the Slovak Republic. It determines regional
diagnostic and treatment workplaces. Their main task is a
complex dispensary and therapeutic care of patients with
PKU following the confirmation of diagnosis after birth,
during childhood, adolescence and adulthood (Professional
Guidance of the Ministry of health of the Slovak Republic
42/2012).
SCREENING FOR PHENYLKETONURIA
IN NEWBORNS
The screening for phenylketonuria in Slovakia began in 1972.
Legislatively, it was introduced on 1 January 1975. A semiquantitative determination of phenylalanine concentration
by Guthrie method was used as the screening method.
This proved to be a good screening method, but there was
still high percentage of “recall” examinations. This caused a
prolongation of final diagnosis. At the time of diagnosis and
initiation of treatment, the average age of the child was up to
6.3 weeks.
In 1995, there was a significant change in the arrangement
of mandatory newborn screening. The screening method
was changed for a quantitative fluorometric determination
of phenylalanine concentration from dry blood drop. The
cut-off screening limit 150 µmol/l was determined for
phenylketonuria. The values ranging from 150 to 300 µmol/l
were reported as a gray zone and the values above 300
µmol/l were reported as a hot «recall» to appropriate centres
for diagnosis and treatment of phenylketonuria. The new
screening arrangement brought minimum recall values; the
positive screening was almost equal to the diagnosis; there
was a shortening in definitive diagnosis to an average of 2.3
22
weeks of the child’s age, and a single registration, coding
and collecting detection were introduced (Dluholucký
and Knapková, 2013). Since 2013, a new screening method
for the diagnosis of phenylketonuria in Slovakia has been
introduced. As in the most developed countries, in Newborn
Screening Center of the Slovak Republic in Banská Bystrica,
we have introduced a tandem mass spectrometry method,
the so-called tandem MS/MS. By this method, the newborn
screening has been extended to the detection of other
inherited metabolic diseases in the field of amino acids,
organic acids and disorders of fatty acid beta-oxidation
(Dluholucký, Knapková and Zahorcová, 2014).
TREATMENT OF PHENYLKETONURIA
(HYPERPHENYLALANINEMIA)
Phenylketonuria (hyperphenylalaninemia) belongs to the
group of inherited metabolic disorders that are successfully
treatable today. Horst Bickel, a German professor, became
a pioneer in the treatment of PKU. In 1953, as the first, he
published the work on effects of low-phenylalanine diet
on phenylalanine levels in patient’s blood. This treatment
successfully led to prevention of irreversible brain damage in
the affected child (Sarkisian and Gamez, 2005).
The treatment of phenylketonuria has progressed significantly
since that time. We already know that HPA is a heterogeneous
disease making the treatment more complicated. Because
of many mutations in the phenylalanine hydroxylase gene,
it is not easy to establish a correlation between patient’s
genotype and phenotype. Not every type of PKU can be
treated with low-protein diet with a supplementation of
amino acid mixtures without phenylalanine. This treatment is
ineffective in some cases; in other cases, it is useless.
Most patients in Slovakia suffer from hyperphenylalaninemia
(HPA) type I, i.e. classic PKU. A differentiation of this type
of HPA from others and ensuring the compliance with
treatment strategy is a responsibility of clinicians at centres.
It is necessary to find out so-called daily phenylalanine
tolerance (Phe) for a patient; choose an individual approach
in compliance with recommended needs of Phe, proteins and
energy in the diet per day according to patient´s body weight
and age; maintain blood Phe concentration of the patient in
determined limits according to national recommendations
by age; monitor blood Phe concentration regularly; and
ensure and prescribe a special dietary regimen based on lowprotein foods. The food with high content of natural proteins
is excluded from the diet; missing proteins are replaced with
special dietary products. These are amino acid mixtures
without phenylalanine. The energy in diet is supplemented
by carbohydrates and fats which are not limited in the diet;
supplements to dietary treatment include minerals, trace
elements and vitamins, which also represent a part of dietary
products. Patients with PKU require regular long-term outclinic monitoring.
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PRINCIPLES OF CURRENT MODERN TREATMENT
Current modern treatment of PKU is based on a strict lowprotein dietary treatment in combination with quality
products (amino acid mixtures) that meet the most
demanding criteria. In these products, it is mainly about exact
ratio of individual amino acids, minerals, trace elements and
vitamins needed for different age groups. They allow patients
to receive a full diet, which is variegated enough and also
meets taste requirements. Typical diet for phenylketonuria
does not contain traditional food sources of omega-3polyunsaturated fatty acids, which are essential for healthy
development of nervous system, cognitive functions, mental
health, retina development, cardiovascular functions and
other essential systems. Omega-3-polyunsaturated fatty
acids have currently become a standard part of the diet.
Strict adherence to daily dose of protein and energy is
important due to negative impact of catabolism and thus
paradoxical increase of phenylalanine concentrations in the
blood, which comes from protein degradation in the body. A
regular administration of amino acid mixtures, divided into
three to five doses per day, is very important (Burton, Grande,
Milanowski, 2007).
A special status has the treatment of newborn with
phenylketonuria. New modern treatment products without
phenylalanine but with sufficient protein and energy content
allow a combination of dietary treatment and breastfeeding
almost in all cases. This is a significant change in the PKU
treatment strategies at which the breastfeeding was
contraindicated due to inferior products.
It should be noted that same as high phenylalanine
concentrations in patient’s serum cause damage of the central
nervous system (CNS), and low values of phenylalanine also
pose a risk for an organism. They cause a dystrophy of a child,
growth failure, delay in bone maturation and formation of
bone itself, and anemia and aminoaciduria due to catabolism.
A sudden death has also been described in the literature.
Opinions on duration of dietary treatment have been also
resolved. Phenylketonuria is considered as a lifelong disease.
Treatment shall not be discontinued and is life-long. Currently,
a particular attention is devoted especially to female patients
with phenylketonuria. Education of female patients with PKU
and their parents about risks of uncontrolled pregnancy,
importance of choosing partner and right upbringing,
leading to a family planning education, is very important
(Singh, Douglas and Quirk, 2011).
Thanks to introduction of full-area screening (in Slovakia since
1972) of patients already in neonatal age and quality dietary
treatment of PKU, a generation of “healthy” female patients
with phenylketonuria, who can live a fulfilling life in all areas,
is growing up.
It was proven that increased phenylalanine (Phe)
concentration in mother’s blood during pregnancy adversely
affects foetal development. The causes of potential foetal
harm include unintended pregnancy, diet breach before
conception, incorrect dietary products or unrecognized
and thus untreated hyperphenylalaninemia. The most risky
period for maternal phenylketonuria is the first trimester of
pregnancy. Each female patient with PKU requires special
individual treatment regimen in advance of planned
pregnancy. Required low blood phenylalanine levels in
patients can be achieved only with very strict measures and
arrangements of dietary meal. It was found out that also slightly
elevated phenylalanine levels may damage a developing
fetus. Abortus, malformations (facial dysmorphia), CNS
damage with subsequent mental retardation, microcephaly,
congenital heart defects and low birth weight occur the most
often. Mothers with maternal form of PKU, who had elevated
blood phenylalanine concentrations during pregnancy, have
affected children in up to 90% of cases.
STRATEGY OF DIETARY TREATMENT
Nowadays, the strategy of phenylketonuria treatment
consists of
-
balanced intake of amino acid mixtures (so-called dietary
products),
- low-protein dietary treatment with precisely calculated
content of phenylalanine in the diet,
- sufficient energy intake and
- regular monitoring of patient´s serum phenylalanine
concentrations.
AMINO ACID MIXTURES
Amino acid mixtures, the so-called basic products, represent
a basic treatment of phenylketonuria. Their administration
provides an adequate supply of amino acids without
phenylalanine and, therefore, compensation of reduced
protein intake in low-protein dietary regimen. Several
years ago, preparations produced on the basis of casein
hydrolysates represented a basis of the treatment but they are
not used anymore because of their lack of amino acid content
and certain amount of phenylalanine. In the production of
currently used amino acid mixtures, an exact weighting of
particular amino acids without phenylalanine, which meets
the needs of the organism according to particular age
periods, is essential. Amino acids are produced by genetic
engineering methods. A corresponding amount of minerals,
trace elements and vitamins for a specific age group is also the
part of their content. Despite their high quality, they also have
certain shortcomings such as smell, taste and solubility. The
amino acid mixtures are the basis for treatment of this disease
and are fully or partially covered by health insurance. They are
given by a prescription to patients with phenylketonuria and
belong to the group of foods on special medical purposes.
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Acta Fac. Pharm. Univ. Comen. LXII, 2015 (Suppl XI): 21-26.
A current view of the diagnostics and treatment of phenylketonuria in Slovakia
DISTRIBUTION OF AMINO ACID MIXTURES
Recently, a relatively large development in PKU treatment
happened. New formulations that partially eliminate negative
taste characteristics of basic products were introduced in the
market. Nowadays, the amino acid mixtures can be divided
into:
- basic products (different types depending on patient’s
age),
- supplementary products – powder and other forms and
- supplementary products – liquid forms
BASIC PRODUCTS
The above-mentioned method represents the basis of
phenylketonuria treatment. Almost all products of this group
are fully covered by health insurance. They are usually packed
in cans of 500 grams. Their dosage is individual and depends
on patient’s age and weight. Younger children usually take
20–50 grams, and older children 60–100 grams per day. Their
disadvantages include difficult preparation, poor solubility
and already mentioned taste and odour properties. An
advantage is zero surcharge at the pharmacy at relatively
financially demanding dietary treatment.
Special basic products are available for treatment of newborns
identified with phenylketonuria. These products look like
conventional formula preparations enriched with optimal
fatty acid composition and ensure adequate development of
the CNS.
SUPPLEMENTARY PRODUCTS (POWDER AND
OTHER FORMS)
New products were introduced in order to compensate for
the negative characteristics of basic products and generally
make life easier for patients with PKU. Mostly, it is a modified
basic product in practical 20–30 grams pack. Many times, it
is already flavoured with better solubility. These products are
also divided by age groups. They can be used as a beverage or
soup. Sticks, capsules or tablets are other forms of amino acid
mixtures. A patient surcharge is their disadvantage; however
it is adequate. Adding of essential fatty acids with optimal
composition for the youngest age group was relatively
significant change in this product group. They support
optimal development of CNS and sight.
SUPPLEMENTARY PRODUCTS (LIQUID FORMS)
The introduction of liquid forms was something new for
patients. These products significantly make dietary regimen
easier for many patients with phenylketonuria in adolescence
and adulthood. They are amino acid mixtures in a liquid form
practically in 125 or 250 ml packs. All products of this group
24
are flavoured (forest fruit, tropical fruit, citrus, orange, etc.).
Their practical feature is that no preparation is needed and,
therefore, they are suitable for use especially at school, work,
trips, entertainment and so on. The disadvantage of this
group is currently the surcharge and limited prescribing to
maximum of 20 pieces per month. This is the reason why it is
necessary to combine the treatment of PKU patient with basic
or other supplementary products.
LOW-PROTEIN DIETARY TREATMENT
A special low-protein diet regimen is the second most
important part of a comprehensive treatment of patients
with phenylketonuria. It is an exactly calculated dose of
phenylalanine in patient’s diet, which is strictly individual
according to so-called phenylalanine tolerance. The
phenylalanine tolerance is different in each patient
according to the PKU type. Determination of the amount
of phenylalanine received in the diet changes and adjusts
according to serum Phe concentrations, which must be in
acceptably safe levels.
The basis of patient’s diet is a low-protein diet. Recently, its
offer has been greatly improved and is also a part of the list
of dietary foods covered by health insurance. These products,
like amino acid mixtures, are prescribed by a physician
from the centre for diagnosis and treatment of PKU. Mostly
it is low-protein flour, pasta and other foods with reduced
phenylalanine content.
A compilation of menu card for patients is managed by
available cookbooks for patients with phenylketonuria.
They include recipes and food tables with exact content of
sugars, fat, proteins, phenylalanine and energy. The so-called
allowed food includes fruit, vegetables and other foods with
low content of protein and phenylalanine. Sugars and fats
are not limited in the diet. From the above-mentioned food,
a daily (weekly) menu with exact phenylalanine content will
be compiled and this menu may not exceed calculated daily
dose of Phe. The menu is compiled by a doctor or dietitian.
Other low-protein diets can be ensured for patients by
procuring items from specialized stores, delivery services or
online stores.
SUFFICIENT ENERGY INTAKE
The adherence to sufficient energy intake is also very
important due to negative impact of catabolism and thus
paradoxical increase of phenylalanine concentrations in the
blood, which arises as a result of protein degradation in the
body. In some cases, we are forced to check and also increase
the energy intake according to an individual load of the
patients and their needs. Although we do not limit sugars
and fats in diet meals, control Phe values in the blood often
improve after adding special oligosaccharides (maltodextrin).
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MONITORING OF SERUM PHENYLALANINE
CONCENTRATIONS
A regular monitoring of phenylalanine concentrations in
patient’s blood is closely related to dietary treatment. From
obtained results, the tolerance of organism to phenylalanine
is determined and the diet regimen is regulated. In practice,
determination of phenylalanine is carried out directly
from the serum, or from the dry drop and also by complex
examination of amino acids in the serum and urine at regular
intervals, depending on the age and diet compliance.
Patient monitoring in each diagnostic and treatment centre
in Slovakia is governed by national guidelines, which are in
compliance with international recommendations.
UP-TO-DATE KNOWLEDGE
In recent years, new information about treatment options of
certain types of phenylketonuria with other preparations or
drugs became available. Some of them have already been
used sporadically also in everyday practice. However, clinical
studies are still ongoing in some of them.
TETRAHYDROBIOPTERIN BH4 (SAPROPTERIN)
It is a synthetic cofactor of phenylalanine hydroxylase
enzyme. BH4 increases thermal stability and protection
against proteolytic degradation and oxidative inactivation
of the mutant protein, the so-called chaperone-like effect.
The present results of BH4 use suggest that mainly patients
with at least partially retained phenylalanine hydroxylase
enzyme activity, which is directly responsible for disease
development, respond to treatment. It is mostly mild or
light form of phenylketonuria. The classic form with severe
deficiency of the enzyme activity is mostly resistant to
treatment. As expected, some patients may respond to
treatment with sapropterin, allowing them a gradual relieving
(not dropping) of the diet with low content of phenylalanine.
Patient selection is carried out by stress tests with BH4. A
patient with a decrease in the phenylalanine concentration by
30% of the original value after administration of sapropterin
is considered as an appropriate respondent.
protocols and tests are used for this purpose. The so-called
long test (4 weeks) is used in Slovakia; the dose of BH4 is 10–20
mg/kg of body weight, recommended initial phenylalanine
concentration shall be 400 µmol/l. From 2012 until now,
approximately 30 patients have been tested for treatment
with Kuvan and approximately 50% of them have continued
with treatment. In regard to type of mutation and HPA type,
others did not react to treatment.
PHENYLALANINE AMMONIUM LYASE (PAL)
The use of phenylalanine ammonium lyase (PAL) enzyme in
microcapsules could be another prospective option of PKU
treatment.
It is a bacterial enzyme that transforms a part of phenylalanine
taken in diet to less toxic metabolites – trans-cinnamon acid
and ammonia (enzyme replacement therapy) in the digestive
tract. Therefore, the amount of phenylalanine that gets into
the blood decreases.
The problem was its inactivation by digestive enzymes. In
animal experiment (mice), a recombinant phenylalanine
ammonia lyase chemically conjugated with polyethylene
glycol PEG-PAL was used. Clinical trials in human subjects are
still ongoing.
AMINO ACID MIXTURES OF LARGE NEUTRAL
AMINO ACIDS
(LNAAs = Large Neutral Amino Acids)
Amino acid mixtures of large neutral amino acids (LNAAs
= large neutral amino acids) might be the last prospective
product. Phenylalanine and other large neutral amino acids
(tyrosine, tryptophan, leucine, isoleucine, valine, methionine)
are transported through the blood–brain barrier by the l-type
amino acid transporter.
Their effect is explained by a competition between
phenylalanine and neutral and branched-chain amino acids
for the transport through the blood–brain barrier. When
blood phenylalanine concentration is high, it wins the
competition for a transport mechanism and reaches the
brain at the expense of other amino acids. Increased intake of
LNAAs gives their transport an advantage over phenylalanine
and it will result in reduction of cerebral phenylalanine
concentrations in the brain.
FIRST EXPERIENCES WITH THE TREATMENT BY
TETRAHYDROBIOPTERIN BH4 (SAPROPTERIN)
IN SLOVAKIA
GENE THERAPY
Since 2009, sapropterin has been registered as Kuvan
in Slovakia. It is the first pharmacological treatment for
PKU. In pharmacological doses, it increases stability and,
consequently, the activity of phenylalanine hydroxylase
enzyme in BH4-responsive individuals.
First of all, a determination whether the patient responds
to treatment with Kuvan is the basis of treatment. Several
The gene therapy will be probably a final treatment option
for patients with phenylketonuria. Currently, a cloned gene
animal model exists and “carriers” of genetic information,
the so-called viral vectors, are tested. Short treatment effect,
safety and immune response problem remain outstanding
issues. The gene is “corrected” very slowly, and the repair is
now only for a limited time. In addition to technical problems,
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Acta Fac. Pharm. Univ. Comen. LXII, 2015 (Suppl XI): 21-26.
A current view of the diagnostics and treatment of phenylketonuria in Slovakia
specific aspects of the disease itself exist. Resolving these
problems will mean revolutionary changes in treatment of
PKU as well as other metabolic disorders.
CONCLUSION
Phenylketonuria is a lifelong disease. Current modern
treatment of this disease enables all patients to live a fulfilling
life. Nowadays, no discontinuation of dietary treatment in
patients with phenylketonuria can be taken for granted.
Thanks to new therapeutic procedures, we can see that the
treatment is fully accepted by patients, and it allows them to
achieve the highest level of education as well as live a full life.
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