In this thesis, attention is paid to growth which may be impaired due the severe dietary Phe restriction; the possibility of distinction between patients with differences in PAH enzyme activity by direct measurement of the in-vivo phenylalanine hydroxylation; plasma Phe and Tyr concentrations in response to different distributions of the daily intake of PKU patients; and some issues concerning pregnancy and PKU. ...

Zie: Summary

Spronsen, Francinus Johannes van,

Spronsen, Francinus Johannes van

ARTS repository - University of Groningen

   University of GroningenPhenylketonuriaSpronsen, Francinus Johannes vanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1996Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Spronsen, F. J. V. (1996). Phenylketonuria: implications of some biochemical and clinical findings. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 30-10-2023Pherrylketonurta: implications of somc biochemical and clinical findingsPhenylketonuria (PK[I) is an inborn error of amino acid metabolism in which adeficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) causes adecreased hydroxylation of phenylalanine into tyrosine. Left untreated, PKU rezultsin serious mental retardation. However, PKU can be detect€d and treated inneonates before damage to the central nervous system has occurred to a largedegree. The treatment is based on a diet restricted in natural protein and supplyingthe patient with a tyrosine-enriched amino acid mixture devoid of phenylalanineresulting in a more or less normal total protein intake. This treatrrent hascontributed considerably to the improvement of the intellectual outcome of thesepatients, but even early treated PKU patients still encounter some abnormalities inthe intellectual, neurolopsychologic and psychosocial development. As the aim oftoday should not only be to prevent mental retardation but also to enable patientswith PKU to develop as a normal and happy child into a normal adult with a normallife, many questions need to be answered.In this thesis, attention is paid to $owth which may be impaired due the severedietary Phe restriction; the possibility of distinction between patients withdifferences in PAH enzyme activity by direct measuÍement of the in-vivophenylalanine hydroxylation; plasma Phe and Tyr concentrations in response todifferent distributions of the daily intake of PKU patients; and some issuesconcerning pregnancy and PKU.In the introduction (chapter 1) some aspects of PKU are outlined which presenteither some general background information or are very relevant to the issuesdiscussed in PKU today. Such iszues are the lack of clearness on the definition ofthe term PKU, and the lack of consensus on the method used to differentiatebetween patients with different levels of PAH deficiency. It is argued that dietaryrestriction is the sole treaunent of choice with -on the one hand- large positiveeffects, but -on the other hand, no complete norrral intellechral, neuropsychologicand psychosocial development. Therefore, various iszues still need to be solved tooptimalize the treatment of PKU individuals from the unborn child to the adult andthe woman with PKU who carries a child herself.148In chapter 2, growere studied in Dutchstudies, it was foundof life, but that no reldietary treament and timportant because theduring the recent yearsIn chapter 3, thrinvestigated using salmethod, theoretically,without causing a substhis thesis it was shovvivo phenylalanine hycother studies. Furthertechnique in order toPAH deficiency at an (In chapter 4 andtyrosine were studiedtailored- dietary naturaFrom the studies r(chapter 4) it was conthe exact time of the revaluation of the pherphenylalanine allowanprovided that the patirdiet, and given thatconclusions, it shouldsírdied and that furthrage.Summ.aryIn chapter 2, growth and the effect of different degrees of dietary restrictionwere studied in Dutch patients with early and continuously treated PKU. In thesestudies, it was found that growth retardation occurs during the first three yearsof life, but that no relationship exists between different degrees of the strictness ofdietary treatment and the previously described growth retardation. The last finding isimportant because the targetted phenylalanine concentrations have been decreasedduring the recent years.In chapter 3, the in-vivo hydroxylation of phenylalanine into tyrosine wasinvestigated using stable isotopically labelled phenylalanine and tyrosine. By thismethod, theoretically, the hydroxylation rate of phenylalanine can be measuredwithout causing a substantial increase of the plasma phenylalanine concentration. Inthis thesis it was shown that continuously treated PKU patients have decreased in-vivo phenylalanine hydroxylation rates. This finding is in contrast with the results ofother studies. Further studies are needed to investigate the usefulness of thistechnique in order to select between patients with differences in the degree of thePAH deficiency at an early age.In chapter 4 and 5, the daily fluctuations of both plasma phenylalanine andtyrosine were studied in relation to different distributions of the daily -individuallytailored- dietary natural protein intake.From the studies concerning the daily fluctuations of phenylalanine in plasma(chapter 4) it was concluded that the nutritional condition (fasting/postprandial) andthe exact time of the day the blood sampling is performed are not important in theevaluation of the phenylalanine intake, and that unequal distributions of the dailyphenylalanine allowance are justified in PKU patients on an occoasional baseprovided that the patient is in good clinical condition, adjusted adequately to thediet, and given that the daily allowance is not exceeded. Regarding these twoconclusions, it should be stressed that only patients older than 1 year of age werestudied and that further studies are necessary for patients younger than 1 year ofage.t49Phenylkaonuia: implications of some biochemical and clinical findingsThe studies of the daily fluctuations of tyrosine concentrations in plasma(chapter 5) showed that these fluctuations can be large resulting in veryhigh tyrosine concenfations. These studies further showed tlnt even patients withan even distribution of their protein intake may encounter both too low and too hightyrosine concentrations at the same day. It could, therefore, be concluded that asingle blood sample either taken in the overnight fasting or postprandial conditionis insufficient to detect a possible tyrosine deficiency and that a combination of apre- and postprandial blood sample on the same day may be more effective. Second,it could be concluded that strict control of plasma tyrosine is necessary when extratyrosine supplementation is considered in addition to the tyrosine-enriched aminoacid mixtures.In chapter 6, different aspects concerning PKU and pregnancy were discussed,including both the fetal condition of the PKU patient and that of the offspring of afemale patient with PKU (maternal PKI-D. It was shown that in PKU children therisk of congenital heart disease and low birth weight may be increased. In thischapter inforrration is also given on reference values of amino acid concentrations inmaternal blood which are necessary for the treafinent of maternal PKU.In the general discussion (chapter 7) the results of chapter 2 to 6 are discussed.Attention is focussed on the need of a method to distinguish between patients withdifferent PAH enzyme activity and the problems related to the method which is mostoften used (phenylalanine tolerance at 5 years of age according to GËttler). Further,difficulties in the treatment of maternal PKU are discussed. The chapter ends with ashort enumeration of aspects of treaÍnent which deserve special attention tooptimalize the intellectual and neuropsychologic outcome and to decrease thepsychosocial burdensome of the treatnent.Samenvatting voor de150

English

Phenylketonuria:implications of some biochemical and clinical findings

University of Groningen Research Database

  
 University of Groningen
Phenylketonuria
van Spronsen, FrancJan J.
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
1996
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Spronsen, F. J. V. (1996). Phenylketonuria: implications of some biochemical and clinical findings s.n.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 10-02-2018
Pherrylketonurta: implications of somc biochemical and clinical findings
Phenylketonuria (PK[I) is an inborn error of amino acid metabolism in which a
deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) causes a
decreased hydroxylation of phenylalanine into tyrosine. Left untreated, PKU rezults
in serious mental retardation. However, PKU can be detect€d and treated in
neonates before damage to the central nervous system has occurred to a large
degree. The treatment is based on a diet restricted in natural protein and supplying
the patient with a tyrosine-enriched amino acid mixture devoid of phenylalanine
resulting in a more or less normal total protein intake. This treatrrent has
contributed considerably to the improvement of the intellectual outcome of these
patients, but even early treated PKU patients still encounter some abnormalities in
the intellectual, neurolopsychologic and psychosocial development. As the aim of
today should not only be to prevent mental retardation but also to enable patients
with PKU to develop as a normal and happy child into a normal adult with a normal
life, many questions need to be answered.
In this thesis, attention is paid to $owth which may be impaired due the severe
dietary Phe restriction; the possibility of distinction between patients with
differences in PAH enzyme activity by direct measuÍement of the in-vivo
phenylalanine hydroxylation; plasma Phe and Tyr concentrations in response to
different distributions of the daily intake of PKU patients; and some issues
concerning pregnancy and PKU.
In the introduction (chapter 1) some aspects of PKU are outlined which present
either some general background information or are very relevant to the issues
discussed in PKU today. Such iszues are the lack of clearness on the definition of
the term PKU, and the lack of consensus on the method used to differentiate
between patients with different levels of PAH deficiency. It is argued that dietary
restriction is the sole treaunent of choice with -on the one hand- large positive
effects, but -on the other hand, no complete norrral intellechral, neuropsychologic
and psychosocial development. Therefore, various iszues still need to be solved to
optimalize the treatment of PKU individuals from the unborn child to the adult and
the woman with PKU who carries a child herself.
148
In chapter 2, gro
were studied in Dutch
studies, it was found
of life, but that no rel
dietary treament and t
important because the
during the recent years
In chapter 3, thr
investigated using sal
method, theoretically,
without causing a subs
this thesis it was shov
vivo phenylalanine hyc
other studies. Further
technique in order to
PAH deficiency at an (
In chapter 4 and
tyrosine were studied
tailored- dietary natura
From the studies r
(chapter 4) it was con
the exact time of the r
evaluation of the pher
phenylalanine allowan
provided that the patir
diet, and given that
conclusions, it should
sírdied and that furthr
age.
Summ.ary
In chapter 2, growth and the effect of different degrees of dietary restriction
were studied in Dutch patients with early and continuously treated PKU. In these
studies, it was found that growth retardation occurs during the first three years
of life, but that no relationship exists between different degrees of the strictness of
dietary treatment and the previously described growth retardation. The last finding is
important because the targetted phenylalanine concentrations have been decreased
during the recent years.
In chapter 3, the in-vivo hydroxylation of phenylalanine into tyrosine was
investigated using stable isotopically labelled phenylalanine and tyrosine. By this
method, theoretically, the hydroxylation rate of phenylalanine can be measured
without causing a substantial increase of the plasma phenylalanine concentration. In
this thesis it was shown that continuously treated PKU patients have decreased in-
vivo phenylalanine hydroxylation rates. This finding is in contrast with the results of
other studies. Further studies are needed to investigate the usefulness of this
technique in order to select between patients with differences in the degree of the
PAH deficiency at an early age.
In chapter 4 and 5, the daily fluctuations of both plasma phenylalanine and
tyrosine were studied in relation to different distributions of the daily -individually
tailored- dietary natural protein intake.
From the studies concerning the daily fluctuations of phenylalanine in plasma
(chapter 4) it was concluded that the nutritional condition (fasting/postprandial) and
the exact time of the day the blood sampling is performed are not important in the
evaluation of the phenylalanine intake, and that unequal distributions of the daily
phenylalanine allowance are justified in PKU patients on an occoasional base
provided that the patient is in good clinical condition, adjusted adequately to the
diet, and given that the daily allowance is not exceeded. Regarding these two
conclusions, it should be stressed that only patients older than 1 year of age were
studied and that further studies are necessary for patients younger than 1 year of
age.
t49
Phenylkaonuia: implications of some biochemical and clinical findings
The studies of the daily fluctuations of tyrosine concentrations in plasma
(chapter 5) showed that these fluctuations can be large resulting in very
high tyrosine concenfations. These studies further showed tlnt even patients with
an even distribution of their protein intake may encounter both too low and too high
tyrosine concentrations at the same day. It could, therefore, be concluded that a
single blood sample either taken in the overnight fasting or postprandial condition
is insufficient to detect a possible tyrosine deficiency and that a combination of a
pre- and postprandial blood sample on the same day may be more effective. Second,
it could be concluded that strict control of plasma tyrosine is necessary when extra
tyrosine supplementation is considered in addition to the tyrosine-enriched amino
acid mixtures.
In chapter 6, different aspects concerning PKU and pregnancy were discussed,
including both the fetal condition of the PKU patient and that of the offspring of a
female patient with PKU (maternal PKI-D. It was shown that in PKU children the
risk of congenital heart disease and low birth weight may be increased. In this
chapter inforrration is also given on reference values of amino acid concentrations in
maternal blood which are necessary for the treafinent of maternal PKU.
In the general discussion (chapter 7) the results of chapter 2 to 6 are discussed.
Attention is focussed on the need of a method to distinguish between patients with
different PAH enzyme activity and the problems related to the method which is most
often used (phenylalanine tolerance at 5 years of age according to GËttler). Further,
difficulties in the treatment of maternal PKU are discussed. The chapter ends with a
short enumeration of aspects of treaÍnent which deserve special attention to
optimalize the intellectual and neuropsychologic outcome and to decrease the
psychosocial burdensome of the treatnent.
Samenvatting voor de
150


University of Groningen

   University of GroningenPhenylketonuriaSpronsen, Francinus Johannes vanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1996Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Spronsen, F. J. V. (1996). Phenylketonuria: implications of some biochemical and clinical findings. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Pherrylketonurta: implications of somc biochemical and clinical findingsPhenylketonuria (PK[I) is an inborn error of amino acid metabolism in which adeficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) causes adecreased hydroxylation of phenylalanine into tyrosine. Left untreated, PKU rezultsin serious mental retardation. However, PKU can be detect€d and treated inneonates before damage to the central nervous system has occurred to a largedegree. The treatment is based on a diet restricted in natural protein and supplyingthe patient with a tyrosine-enriched amino acid mixture devoid of phenylalanineresulting in a more or less normal total protein intake. This treatrrent hascontributed considerably to the improvement of the intellectual outcome of thesepatients, but even early treated PKU patients still encounter some abnormalities inthe intellectual, neurolopsychologic and psychosocial development. As the aim oftoday should not only be to prevent mental retardation but also to enable patientswith PKU to develop as a normal and happy child into a normal adult with a normallife, many questions need to be answered.In this thesis, attention is paid to $owth which may be impaired due the severedietary Phe restriction; the possibility of distinction between patients withdifferences in PAH enzyme activity by direct measuÍement of the in-vivophenylalanine hydroxylation; plasma Phe and Tyr concentrations in response todifferent distributions of the daily intake of PKU patients; and some issuesconcerning pregnancy and PKU.In the introduction (chapter 1) some aspects of PKU are outlined which presenteither some general background information or are very relevant to the issuesdiscussed in PKU today. Such iszues are the lack of clearness on the definition ofthe term PKU, and the lack of consensus on the method used to differentiatebetween patients with different levels of PAH deficiency. It is argued that dietaryrestriction is the sole treaunent of choice with -on the one hand- large positiveeffects, but -on the other hand, no complete norrral intellechral, neuropsychologicand psychosocial development. Therefore, various iszues still need to be solved tooptimalize the treatment of PKU individuals from the unborn child to the adult andthe woman with PKU who carries a child herself.148In chapter 2, growere studied in Dutchstudies, it was foundof life, but that no reldietary treament and timportant because theduring the recent yearsIn chapter 3, thrinvestigated using salmethod, theoretically,without causing a substhis thesis it was shovvivo phenylalanine hycother studies. Furthertechnique in order toPAH deficiency at an (In chapter 4 andtyrosine were studiedtailored- dietary naturaFrom the studies r(chapter 4) it was conthe exact time of the revaluation of the pherphenylalanine allowanprovided that the patirdiet, and given thatconclusions, it shouldsírdied and that furthrage.Summ.aryIn chapter 2, growth and the effect of different degrees of dietary restrictionwere studied in Dutch patients with early and continuously treated PKU. In thesestudies, it was found that growth retardation occurs during the first three yearsof life, but that no relationship exists between different degrees of the strictness ofdietary treatment and the previously described growth retardation. The last finding isimportant because the targetted phenylalanine concentrations have been decreasedduring the recent years.In chapter 3, the in-vivo hydroxylation of phenylalanine into tyrosine wasinvestigated using stable isotopically labelled phenylalanine and tyrosine. By thismethod, theoretically, the hydroxylation rate of phenylalanine can be measuredwithout causing a substantial increase of the plasma phenylalanine concentration. Inthis thesis it was shown that continuously treated PKU patients have decreased in-vivo phenylalanine hydroxylation rates. This finding is in contrast with the results ofother studies. Further studies are needed to investigate the usefulness of thistechnique in order to select between patients with differences in the degree of thePAH deficiency at an early age.In chapter 4 and 5, the daily fluctuations of both plasma phenylalanine andtyrosine were studied in relation to different distributions of the daily -individuallytailored- dietary natural protein intake.From the studies concerning the daily fluctuations of phenylalanine in plasma(chapter 4) it was concluded that the nutritional condition (fasting/postprandial) andthe exact time of the day the blood sampling is performed are not important in theevaluation of the phenylalanine intake, and that unequal distributions of the dailyphenylalanine allowance are justified in PKU patients on an occoasional baseprovided that the patient is in good clinical condition, adjusted adequately to thediet, and given that the daily allowance is not exceeded. Regarding these twoconclusions, it should be stressed that only patients older than 1 year of age werestudied and that further studies are necessary for patients younger than 1 year ofage.t49Phenylkaonuia: implications of some biochemical and clinical findingsThe studies of the daily fluctuations of tyrosine concentrations in plasma(chapter 5) showed that these fluctuations can be large resulting in veryhigh tyrosine concenfations. These studies further showed tlnt even patients withan even distribution of their protein intake may encounter both too low and too hightyrosine concentrations at the same day. It could, therefore, be concluded that asingle blood sample either taken in the overnight fasting or postprandial conditionis insufficient to detect a possible tyrosine deficiency and that a combination of apre- and postprandial blood sample on the same day may be more effective. Second,it could be concluded that strict control of plasma tyrosine is necessary when extratyrosine supplementation is considered in addition to the tyrosine-enriched aminoacid mixtures.In chapter 6, different aspects concerning PKU and pregnancy were discussed,including both the fetal condition of the PKU patient and that of the offspring of afemale patient with PKU (maternal PKI-D. It was shown that in PKU children therisk of congenital heart disease and low birth weight may be increased. In thischapter inforrration is also given on reference values of amino acid concentrations inmaternal blood which are necessary for the treafinent of maternal PKU.In the general discussion (chapter 7) the results of chapter 2 to 6 are discussed.Attention is focussed on the need of a method to distinguish between patients withdifferent PAH enzyme activity and the problems related to the method which is mostoften used (phenylalanine tolerance at 5 years of age according to GËttler). Further,difficulties in the treatment of maternal PKU are discussed. The chapter ends with ashort enumeration of aspects of treaÍnent which deserve special attention tooptimalize the intellectual and neuropsychologic outcome and to decrease thepsychosocial burdensome of the treatnent.Samenvatting voor de150

   University of GroningenPhenylketonuriaSpronsen, Francinus Johannes vanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1996Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Spronsen, F. J. V. (1996). Phenylketonuria: implications of some biochemical and clinical findings. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 16-07-2023Pherrylketonurta: implications of somc biochemical and clinical findingsPhenylketonuria (PK[I) is an inborn error of amino acid metabolism in which adeficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) causes adecreased hydroxylation of phenylalanine into tyrosine. Left untreated, PKU rezultsin serious mental retardation. However, PKU can be detect€d and treated inneonates before damage to the central nervous system has occurred to a largedegree. The treatment is based on a diet restricted in natural protein and supplyingthe patient with a tyrosine-enriched amino acid mixture devoid of phenylalanineresulting in a more or less normal total protein intake. This treatrrent hascontributed considerably to the improvement of the intellectual outcome of thesepatients, but even early treated PKU patients still encounter some abnormalities inthe intellectual, neurolopsychologic and psychosocial development. As the aim oftoday should not only be to prevent mental retardation but also to enable patientswith PKU to develop as a normal and happy child into a normal adult with a normallife, many questions need to be answered.In this thesis, attention is paid to $owth which may be impaired due the severedietary Phe restriction; the possibility of distinction between patients withdifferences in PAH enzyme activity by direct measuÍement of the in-vivophenylalanine hydroxylation; plasma Phe and Tyr concentrations in response todifferent distributions of the daily intake of PKU patients; and some issuesconcerning pregnancy and PKU.In the introduction (chapter 1) some aspects of PKU are outlined which presenteither some general background information or are very relevant to the issuesdiscussed in PKU today. Such iszues are the lack of clearness on the definition ofthe term PKU, and the lack of consensus on the method used to differentiatebetween patients with different levels of PAH deficiency. It is argued that dietaryrestriction is the sole treaunent of choice with -on the one hand- large positiveeffects, but -on the other hand, no complete norrral intellechral, neuropsychologicand psychosocial development. Therefore, various iszues still need to be solved tooptimalize the treatment of PKU individuals from the unborn child to the adult andthe woman with PKU who carries a child herself.148In chapter 2, growere studied in Dutchstudies, it was foundof life, but that no reldietary treament and timportant because theduring the recent yearsIn chapter 3, thrinvestigated using salmethod, theoretically,without causing a substhis thesis it was shovvivo phenylalanine hycother studies. Furthertechnique in order toPAH deficiency at an (In chapter 4 andtyrosine were studiedtailored- dietary naturaFrom the studies r(chapter 4) it was conthe exact time of the revaluation of the pherphenylalanine allowanprovided that the patirdiet, and given thatconclusions, it shouldsírdied and that furthrage.Summ.aryIn chapter 2, growth and the effect of different degrees of dietary restrictionwere studied in Dutch patients with early and continuously treated PKU. In thesestudies, it was found that growth retardation occurs during the first three yearsof life, but that no relationship exists between different degrees of the strictness ofdietary treatment and the previously described growth retardation. The last finding isimportant because the targetted phenylalanine concentrations have been decreasedduring the recent years.In chapter 3, the in-vivo hydroxylation of phenylalanine into tyrosine wasinvestigated using stable isotopically labelled phenylalanine and tyrosine. By thismethod, theoretically, the hydroxylation rate of phenylalanine can be measuredwithout causing a substantial increase of the plasma phenylalanine concentration. Inthis thesis it was shown that continuously treated PKU patients have decreased in-vivo phenylalanine hydroxylation rates. This finding is in contrast with the results ofother studies. Further studies are needed to investigate the usefulness of thistechnique in order to select between patients with differences in the degree of thePAH deficiency at an early age.In chapter 4 and 5, the daily fluctuations of both plasma phenylalanine andtyrosine were studied in relation to different distributions of the daily -individuallytailored- dietary natural protein intake.From the studies concerning the daily fluctuations of phenylalanine in plasma(chapter 4) it was concluded that the nutritional condition (fasting/postprandial) andthe exact time of the day the blood sampling is performed are not important in theevaluation of the phenylalanine intake, and that unequal distributions of the dailyphenylalanine allowance are justified in PKU patients on an occoasional baseprovided that the patient is in good clinical condition, adjusted adequately to thediet, and given that the daily allowance is not exceeded. Regarding these twoconclusions, it should be stressed that only patients older than 1 year of age werestudied and that further studies are necessary for patients younger than 1 year ofage.t49Phenylkaonuia: implications of some biochemical and clinical findingsThe studies of the daily fluctuations of tyrosine concentrations in plasma(chapter 5) showed that these fluctuations can be large resulting in veryhigh tyrosine concenfations. These studies further showed tlnt even patients withan even distribution of their protein intake may encounter both too low and too hightyrosine concentrations at the same day. It could, therefore, be concluded that asingle blood sample either taken in the overnight fasting or postprandial conditionis insufficient to detect a possible tyrosine deficiency and that a combination of apre- and postprandial blood sample on the same day may be more effective. Second,it could be concluded that strict control of plasma tyrosine is necessary when extratyrosine supplementation is considered in addition to the tyrosine-enriched aminoacid mixtures.In chapter 6, different aspects concerning PKU and pregnancy were discussed,including both the fetal condition of the PKU patient and that of the offspring of afemale patient with PKU (maternal PKI-D. It was shown that in PKU children therisk of congenital heart disease and low birth weight may be increased. In thischapter inforrration is also given on reference values of amino acid concentrations inmaternal blood which are necessary for the treafinent of maternal PKU.In the general discussion (chapter 7) the results of chapter 2 to 6 are discussed.Attention is focussed on the need of a method to distinguish between patients withdifferent PAH enzyme activity and the problems related to the method which is mostoften used (phenylalanine tolerance at 5 years of age according to GËttler). Further,difficulties in the treatment of maternal PKU are discussed. The chapter ends with ashort enumeration of aspects of treaÍnent which deserve special attention tooptimalize the intellectual and neuropsychologic outcome and to decrease thepsychosocial burdensome of the treatnent.Samenvatting voor de150

Phenylketonuria: implications of some biochemical and clinical findings

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