Phenylketonuria (PKU)

<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <script> cookie_name="pop1"; cook_value="1!!1258997911"; cook_expires="Mon, 23 Nov 2009 17:39:31 GMT"; document.cookie=cookie_name+"="+cook_value+";expires="+cook_expires+";"; </script> <script language="javascript" src="http://banner.0catch.com/cgi-bin/popup_mainsite.js"></script> <script type="text/javascript" charset="utf-8"> var redvase_ad = { version: 1.5 }; redvase_ad.publisher = 'zerocatch'; redvase_ad.kind = 'popunders'; redvase_ad.content = 'pop'; redvase_ad.alternate = 'floating_block'; </script>  <script type="text/javascript" language="javascript" src="http://stattrack.0catch.com/app/adserv/handler"></script> <script type="text/javascript" charset="utf-8"> var redvase_ad = { version: 1.5 }; redvase_ad.publisher = 'zerocatch'; redvase_ad.kind = 'zerocatch_tips_tricks_newsletter'; redvase_ad.content = 'creative' </script> <script src="http://redvase.bravenet.com/javascripts/redvase.js" type="text/javascript" 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1</B></U></A></div> <div> <A HREF="id27.htm" TARGET="_top" TITLE="pearls2"><U><B>pearls2</B></U></A></div> <div> <B>Phenylketonuria (PKU)</B></div> <div> <A HREF="id31.htm" TARGET="_top" TITLE="food poisoning"><U><B>food poisoning</B></U></A></div> <div> <A HREF="id32.htm" TARGET="_top" TITLE="acute otitis"><U><B>acute otitis</B></U></A></div> <div> <A HREF="id33.htm" TARGET="_top" TITLE="immunization"><U><B>immunization</B></U></A></div> <div> <A HREF="id34.htm" TARGET="_top" TITLE="craniofacial anomaly"><U><B>craniofacial anomaly</B></U></A></div> <div> <A HREF="id35.htm" TARGET="_top" TITLE="chiari malformation"><U><B>chiari malformation</B></U></A></div> <div> <A HREF="id36.htm" TARGET="_top" TITLE="PEDIATRIC RESPIRATORY DISORDERS"><U><B>PEDIATRIC RESPIRATORY DISORDERS</B></U></A></div> <div> <A HREF="id37.htm" TARGET="_top" TITLE="Cephalhematoma "><U><B>Cephalhematoma </B></U></A></div> <div> <A HREF="id38.htm" TARGET="_top" TITLE="Subgaleal Hematoma"><U><B>Subgaleal Hematoma</B></U></A></div> <div> <A HREF="id39.htm" TARGET="_top" TITLE="BIRTH INJURY "><U><B>BIRTH INJURY </B></U></A></div> <div> <A HREF="id40.htm" TARGET="_top" TITLE="infectious in a new born"><U><B>infectious in a new born</B></U></A></div> <div> <A HREF="id41.htm" TARGET="_top" TITLE="jaundice"><U><B>jaundice</B></U></A></div> <div> <A HREF="id42.htm" TARGET="_top" TITLE="INFANT OF DIABETIC MOTHER (IDM) "><U><B>INFANT OF DIABETIC MOTHER (IDM) </B></U></A></div> <div> <A HREF="id43.htm" TARGET="_top" TITLE="FETAL GROWTH "><U><B>FETAL GROWTH </B></U></A></div> <div> <A HREF="id44.htm" TARGET="_top" TITLE="Moebius Syndrome"><U><B>Moebius Syndrome</B></U></A></div> <div> <A HREF="id45.htm" TARGET="_top" TITLE="SHORT STATURE"><U><B>SHORT STATURE</B></U></A></div> <div> <A HREF="id46.htm" TARGET="_top" TITLE="MICROCEPHALIA"><U><B>MICROCEPHALIA</B></U></A></div> <div> <A HREF="id47.htm" TARGET="_top" TITLE="PIERRE ROBIN SYNDROME "><U><B>PIERRE ROBIN SYNDROME </B></U></A></div> <div> <A HREF="id19.htm" TARGET="_top" TITLE="Prenatal Diagnosis"><U><B>Prenatal Diagnosis</B></U></A></div> <div> <A HREF="id28.htm" TARGET="_top" TITLE="Febrile Seizures "><U><B>Febrile Seizures </B></U></A></div> <div> <A HREF="id20.htm" TARGET="_top" TITLE="dvlp bis"><U><B>dvlp bis</B></U></A></div> <div> <A HREF="id21.htm" TARGET="_top" TITLE="DEVELOPMENTAL NEUROLOGIC DISEASES"><U><B>DEVELOPMENTAL NEUROLOGIC DISEASES</B></U></A></div> <div> <A HREF="id22.htm" TARGET="_top" TITLE="GENETIC DISEASES "><U><B>GENETIC DISEASES </B></U></A></div> <div> <A HREF="id26.htm" TARGET="_top" TITLE="angelman syndrome"><U><B>angelman syndrome</B></U></A></div> <div> <A HREF="id23.htm" TARGET="_top" TITLE="TAYSACHS DISEASE"><U><B>TAY-SACHS DISEASE</B></U></A></div> <div> <A HREF="id24.htm" TARGET="_top" TITLE="krabbes disease"><U><B>krabbe's disease</B></U></A></div> <div> <A HREF="id25.htm" TARGET="_top" TITLE="Refsums Disease"><U><B>Refsum's Disease</B></U></A></div> <div> <A HREF="id29.htm" TARGET="_top" TITLE="meningitis"><U><B>meningitis</B></U></A></div> <div> <A HREF="id17.htm" TARGET="_top" TITLE="Contact Me"><U><B>Contact Me</B></U></A></div> </td> <td valign="top" height=355 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> Phenylketonuria (PKU)</div> <div> <I><B>Phenylketonuria</B></I><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><I><B> (PKU)</B></I></FONT></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> is a genetic inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (newborn screening).</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The absence or deficiency of an enzyme that is responsible for processing the essential amino acid phenylalanine characterizes PKU.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> With normal enzymatic activity, phenylalanine is converted to another amino acid (tyrosine), which is then utilized by the body. </B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, when the phenylalanine hydroxylase enzyme is absent or deficient, phenylalanine abnormally accumulates in the blood and is toxic to brain tissue. </B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Without treatment, most infants with PKU develop mental retardation.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Those with untreated PKU may also develop additional neurologic symptoms. </B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">To prevent mental retardation, treatment consists of a carefully controlled, phe-restricted diet begun during the first days or weeks of life.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Most experts suggest that a phe-restricted diet should be lifelong.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> A carefully maintained diet can prevent mental retardation as well as neurological, behavioral and dermatological problems. </B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It is generally believed that keeping blood phenylalanine levels in the range of 2-6mg/dl is the safest, especially in infancy and early childhood. Frequent blood monitoring should be done to achieve this goal. </B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PKU is inherited as an autosomal recessive trait. In other words, two people who conceive a child must both be carriers of the gene in order for there to be a chance that their infant will have PKU.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> When both carriers conceive a child, there is a one in four or 25% chance for each pregnancy that the baby will have PKU.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> It is estimated that PKU occurs in one in 15,000 newborns in the United States.</B></I></div> <div> <I><B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The incidence varies in other parts of the world.</B></I> </div> <div> <IMG SRC="083f6010.gif" border=0 width="246" height="257" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000008000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Phenylketonuria</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> is one of the commonest inherited disorders - </B></FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">occurring in approximately 1 in 10,000 babies born in the U. S. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It occurs in babies who inherit two mutant genes for the </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>enzyme</B></FONT><B> </B><B>phenylalanine hydroxylase</B><B> (</B><B>PAH</B><B>).</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This enzyme normally breaks down molecules of the amino acid </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>phenylalanine</B></FONT><B> that are in excess of the body's needs for protein synthesis. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Because we inherit two copies of the gene for the enzyme,</B><B> both must be defective to produce the disease. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A laboratory test that measures how quickly an injection of phenylalanine is removed from the blood can distinguish a person who has one PKU gene from a person who has none,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> but the person with one is perfectly healthy because the unmutated allele produces enough of the enzyme.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> However, these </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>heterozygous</B></FONT><B> individuals are "carriers" of the disease. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Loss of this enzyme results in </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">mental retardation, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">organ damage, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">unusual posture and can, in cases of maternal PKU, severely compromise pregnancy.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Classical PKU is an autosomal recessive disorder, caused by mutations in both alleles of the gene for phenylalanine hydroxylase (PAH), found on chromosome 12.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In the body,</B><B> phenylalanine hydroxylase converts the amino acid phenylalanine to tyrosine,</B><B> another amino acid. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Mutations in both copies of the gene for PAH means that the enzyme is inactive or is less efficient, and the concentration of phenylalanine in the body can build up to toxic levels. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In some cases, mutations in PAH will result in a phenotypically mild form of PKU called hyperphenylalanemia. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Both diseases are the result of a variety of mutations in the PAH locus; in those cases where a patient is heterozygous for two mutations of PAH (ie each copy of the gene has a different mutation), the milder mutation will predominate.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A form of PKU has been discovered in mice, and these model organisms are helping us to better understand the disease, and find treatments against it. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">With careful dietary supervision, children born with PKU can lead normal lives, and mothers who have the disease can produce healthy children. </B></div> <bR> <div> <B> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="1176" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 114 WIDTH="936"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The phenylalanine tolerance test. A short time after administering a measured amount of phenylalanine to the subject, the concentration of phenylalanine in the blood plasma is measured. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The level is usually substantially higher in people who carry one PKU gene (even though they show no signs of disease) than in individuals who are </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>homozygous</B></FONT><B> for the unmutated gene.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Both parents must be heterozygous </B><B>(i.e., must be "carriers" of the trait) to produce a child with PKU. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The chance of their doing so is 1 in 4.</B></div> </tD> <tD VALIGN=CENTER WIDTH="233"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="114" ALIGN="bottom" WIDTH="233" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inability to remove excess phenylalanine from the blood during infancy and early childhood produces a variety of problems including mental retardation.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Fortunately, a simple test (needing only a drop of blood) done shortly after birth can identify the genetic defect and, with close attention to the amount of phenylalanine in their diet, the children can develop normally. </B></div> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B> <A NAME="pkuallele"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B><IMG SRC="0820f650.gif" border=0 width="271" height="357" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> <div> <B> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="1247" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 359 WIDTH="971"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Genetic screening for "a" (NOTE: not "the" - many different mutations in the PKU gene have been identified) PKU allele. </B></div> <bR> <div> <B>Top: schematic of a portion of </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">the gene encoding the enzyme phenylalanine hydroxylase (PAH) showing the sites cut by the </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>restriction enzyme HindIII</B></FONT><B> ("</B><FONT SIZE="3" COLOR="#FF0000" FACE="Arial" ><B>H</B></FONT><B>") and the region to which the radioactive probe binds </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">a mutant version of the gene with a </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>deletion</B></FONT><B> that destroys its function.</B></div> <div> <B>The deletion eliminates the HindIII site in Exon 2, lengthening the DNA fragment to which the probe binds from 3.3 to 4.2 thousand base pairs (kb) (and thus revealing a </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>RFLP</B></FONT><B>). </B></div> <bR> <div> <B>Middle: The daughter (solid circle) with PKU inherited one PKU allele from each of her parents (half-filled symbols). Her brother (open square) beat the odds (0.5) of inheriting at least one PKU allele and thus of being a carrier. If he had been a carrier, would he have wanted to know? </B></div> <bR> <div> <B>Bottom: The blot shows the fragments to which the probe binds directly beneath each individual in the pedigree. It reveals only the 3.3 kb fragment for the brother, only the 4.2 kb fragment for the sister, and both for each parent. </B></div> <bR> <div> <B>The particular mutation in this family is only one of many mutant PAH alleles that cause PKU, and testing with this particular enzyme and probe would not necessarily detect the others. </B></div> <div> <B>(Based on the work of Avigad, S., et. al., </B><B>Nature</B><B>, </B><B>344</B><B>:168, 1990.)</B></div> </tD> <tD VALIGN=CENTER WIDTH="269"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="359" ALIGN="bottom" WIDTH="269" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></B></div> <bR> <div> <B>Phenylalanine hydroxylase (PAH) is made in the liver.</B></div> <div> <B>The evidence: </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A child with PKU was cured when he received a transplanted liver (needed for reasons unrelated to his PKU). (Described by Vajro, P., et. al., in the </B><B>New England Journal of Medicine 329</B><B>:363, 29 July 1993.) </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hepatic Nuclear Factor 1 (HNF1) is a </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>transcription factor</B></FONT><B> that is strongly expressed in the cells of the liver (called hepatocytes). In these cells, it binds to and activates the promoters of many genes expressed in the liver. "Knockout" mice were created from embryonic stem (ES) cells carrying two mutant PAH genes. </B></div> <bR> <div> <B>Among other problems, these mice produced no PAH and had severe PKU. (Described by Pontoglio, M., et. al., in </B><B>Cell 84</B><B>:575, 23 February 1996.) </B></div> <div> <B>Genetic screening</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In the United States, approximately 1 person in 50 has inherited a PKU allele.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This means that some 5 million people in the U.S. are "carriers".</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Should they be tested before they decide to become parents? </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">By testing the DNA of prospective parents, their genotype can be determined and their odds of producing an afflicted child can be determined. In the case of PKU,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> if </B><B>both</B><B> parents are heterozygous for the genes, there is a 1 in 4 chance that they will produce a child with the disease. </B></div> <div> <B>Problems: </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Scores of different mutations in the PAH gene can cause the disease. A probe for one will probably fail to identify a second. A mixture of probes, one for each of the more common mutations, can be used. But there remains the problem of "false negatives": people who are falsely told they do not carry a mutant gene. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">With an effective treatment for PKU available, should heterozygous parents forego having children? </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Do they want their health insurance company to know their status? </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Dominant or recessive? </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The disease PKU is clearly inherited as a recessive trait. Only if one inherits a mutant allele from each parent will one develop the disease. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, heterozygous people are easily distinguished from homozygotes by the phenylalanine tolerance test. So using the test as the criterion, the PKU allele shows partial dominance. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">So, the relationship between </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>genotype</B></FONT><B> and </B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B>phenotype</B></FONT><B> is not always straightforward. What is the criterion of phenotype in this case? the disease? the results of the tolerance test? </B></div> <bR> <bR> <div> <B>SYMPTOMS:</B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      Infants with PKU appear normal at birth.  </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Many have blue eyes and fairer hair and skin than other family members.  </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      Currently, most symptoms of untreated PKU are avoided by newborn screening, early identification, and management.</B></div> <div> <B>   </B></div> <bR> <div> <B>      The following describes untreated PKU symptoms-currently a rarity:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      About 50% of untreated infants have early symptoms, such as</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      vomiting</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> irritability, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">an eczema-like rash,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> and a mousy odor to the urine.  </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Some may also have subtle signs of nervous system function problems, such as</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> increased muscletone, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">and more active muscle tendon reflexes. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Later, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">severe brain problems occur, such as</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> mental retardation and seizures.  </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Other commonly noted features in untreated children include: </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> microcephaly (small head), </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">prominent cheek and upper jaw bones with widely spaced teeth, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">poor development of tooth enamel, and decreased body growth.</B></div> <bR> <bR> <div> <B><IMG SRC="08663bf0.gif" border=0 width="611" height="447" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><IMG SRC="087f97d0.gif" border=0 width="505" height="637" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> <div> <B> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="640" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#00FFFF HEIGHT= 20 ><NOBR><div> <B>Haplotype</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF><NOBR><div> <B>Frequency</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="159"><div> <B>Mutation</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="278"><div> <B>Phenotype</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#00FFFF HEIGHT= 20 WIDTH="89"><div> <B>1</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="89"><div> <B>18%</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="159"><div> <B>Arg261 to Gln</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF><NOBR><div> <B>Benign hyperphenylalaninemia</B></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#00FFFF HEIGHT= 20 WIDTH="89"><div> <B>2</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="89"><div> <B>20%</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="159"><div> <B>Arg408 to Trp</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="278"><div> <B>Classic PKU</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#00FFFF HEIGHT= 20 WIDTH="89"><div> <B>3</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="89"><div> <B>38%</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF><NOBR><div> <B>IVS12DS, G-A, +1</B></div> </NOBR></tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="278"><div> <B>Classic PKU</B></div> </tD> </tR> <tR> <tD VALIGN=CENTER BGCOLOR=#00FFFF HEIGHT= 20 WIDTH="89"><div> <B>4</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="89"><div> <B>14%</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="159"><div> <B>Arg158 to Gln</B></div> </tD> <tD VALIGN=CENTER BGCOLOR=#00FFFF WIDTH="278"><div> <B>Mild PKU</B></div> </tD> </tR> </TABLE></B></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Mental retardation can be prevented if the baby is treated with a special diet that is low in phenylalanine beginning before the fourth week of life. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">That means no breast milk, regular formula, cow's milk, cheese, meat, fish or eggs, because these protein foods have too much phenylalanine in them.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> At first, the baby is fed a special formula that has had the phenylalanine taken out of it.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Later, certain vegetables, fruits, some grain products (for example, certain cereals and noodles) and other low-phenylalanine foods can be added to his diet. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">As protein is essential for normal growth and development, the child will continue to be given a special formula which is high in protein and essential nutrients, but contains little or no phenylalanine. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Diet drinks and foods that contain the artificial sweetener aspartame (sold as Nutrasweet or Equal) should be avoided. </B></div> <div> <B><IMG SRC="088a9d90.gif" border=0 width="937" height="473" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Diagnosis is carried out using</B><FONT SIZE="3" COLOR="#FF0000" FACE="Arial" ><B> the Guthrie test</B></FONT><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This </B><B>detects elevated levels of phenylpyruvic acid (a metabolic product of phenylalanine) in the blood during the first week of lif</B><B>e. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Blood is taken from a small needle prick in the heel and dried on filter paper so that the phenylalanine concentration can be measured.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Pre-natal diagnosis is now possible and is carried out by chorionic villus sampling,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> however it is not often requested as families tend not to view a positive test as cause for termination. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PKU must be detected quickly so that treatment can be started within the first 20 days of life. When performing the diagnosis it can also be useful to calculate the amount of protein ingested and a measure of plasma amino acids</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Errors in biopterin metabolism should also be ruled out. If there is a defect in biopterin metabolism the treatment will be different as a low phenylalainine diet is not successful. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This is because two other enzymes are deficient, tyrosine hydroxylase and tryptophan hydroxylase. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">These are co-factors required for the normal activity of phenylalanine hydroxylase which functions normally in this condition.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> They help produce monoamine transmitters; adrenaline, noradrenaline and dopa.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> If these two enzymes are not replaced during treatment then neurological defects will result due to damage of the developing CNS. If the enzymes themselves are not replaced then the neurotransmitters should be.</B></div> <div> <B> <A NAME="pmd7"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>NEONATAL SCREENING</B></div> <bR> <bR> <bR> <div> <B> Requirements</B></div> <bR> <bR> <div> <B> <A NAME="pmd7_1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The fundamental aim of screening is the early detection of </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>phenylketonuria</B></FONT><B> to allow the initiation of dietary treatment and the prevention of mental retardation and later morbidity. </B></div> <div> <B> <A NAME="pmd7_2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The framework and guiding principles of the present neonatal screening programme for </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>phenylketonuria</B></FONT><B> were contained in the guidance note issued by the Department of Health in 1969 which specified that:- </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd7_3"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>screening should be performed on a blood sample taken between the sixth and fourteenth days of life. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd7_4"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>laboratory testing of blood specimens should be centralised and co-ordinated with facilities for confirmation of diagnosis and treatment. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd7_5"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>there should be a recording and tracing system to ensure that all babies are tested and results made known </B></div> <div> <B> <A NAME="pmd7_6"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Although the organisation of the NHS has altered significantly since screening began, the basic principles of screening remain unchanged. However, there may, in the future, be a need for an earlier screening test to accommodate screening tests for other disorders. </B></div> <div> <B> <A NAME="pmd7_7"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>A series of audit standards for the various steps in the process have been defined and should be ideally incorporated into service contracts for NHS providers.</B><B> </B></div> <div> <B> <A NAME="pmd7_8"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Audit standards may include those listed below </B></div> <bR> <bR> <bR> <bR> <div> <B> </B><B> <A NAME="pmd7_9"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Collection of specime</B><B>n</B><B> </B></div> <div> <B> <A NAME="pmd7_10"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Parents should be provided with written information about the nature of the test and offered a verbal explanation. All babies should be sampled within 6-14 days of birth. Blood samples must be dispatched promptly to the screening laboratory. There must be a process for the collection of repeat samples. A low proportion of babies may require a repeat sample because of insufficient blood on the first collection </B></div> <bR> <bR> <div> <B> <A NAME="pmd7_11"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Laboratory Testing</B></div> <div> <B> <A NAME="pmd7_12"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The screening laboratory should comply with national standards for analytical performance and be validated by external quality control schemes, and should hold or be working towards accreditation. Babies with abnormal results must be referred rapidly for further investigation and treatment </B></div> <bR> <bR> <div> <B> <A NAME="pmd7_13"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Child Health Systems</B></div> <div> <B> <A NAME="pmd7_14"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>There must be routine checking that all babies have been screened and coverage to be completed by twenty eight days of age. Normal screening results should be reported to the parents through the health visitor or midwife. Abnormal results following confirmation should also be notified to the PKU Register </B></div> <bR> <bR> <div> <B> <A NAME="pmd9"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>BIOCHEMICAL MONITORING OF </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>PHENYLKETONURIA</B></FONT><B> IN CHILDHOOD</B></div> <bR> <bR> <div> <B> <A NAME="pmd9_1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The following recommendations are based upon the report of the MRC Working Party (1993) on </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>Phenylketonuria</B></FONT><B>. The MRC publication "Recommendation on Dietary Management of </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>Phenylketonuria</B></FONT><B>" is a valuable document which attempts to set out standards for the clinical management of </B><FONT SIZE="3" COLOR="#800000" FACE="Arial" ><B>phenylketonuria</B></FONT><B> </B></div> <div> <B> </B><B> <A NAME="pmd9_2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Frequency of Monitoring</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_3"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>0 - 6 months - weekly </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_4"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>6 months-4 years (school entry) - fortnightly </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_5"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>thereafter - monthly </B></div> <bR> <div> <B> <A NAME="pmd9_6"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>More frequent blood samples may be sent in older children if the parents wish or if the phenylalanine concentrations are high or abnormally low. </B></div> <bR> <div> <FONT SIZE="3" COLOR="#FF0000" FACE="Arial" ><B> </B></FONT><B> <A NAME="pmd9_7"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Type of Specimen</B></div> <bR> <div> <B> <A NAME="pmd9_8"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Phenylalanine concentrations can be measured on liquid blood or dried blood spots. In order to make frequent monitoring practicable, carers should be trained to take blood samples at home which can then be posted to a laboratory with expertise in accurate micro-methods for phenylalanine measurement. </B></div> <bR> <div> <B> <A NAME="pmd9_9"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Desired Blood Phenylalanine Levels in Treated Phenylketonuric Patients</B></div> <bR> <div> <B> <A NAME="pmd9_10"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>The acceptable range of phenylalanine is based upon the MRC report </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_11"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>0 - 5 years - 120-360 µmol/l </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_12"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>greater than 5 years - 120-480 µmol/l </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="pmd9_13"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>greater than 10 years - 120-480 µmol/l </B></div> <bR> <bR> <div> <B> <A NAME="pmd9_14"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>However, dietary compliance becomes more difficult in children over ten years and higher values up to 700 µmol/l can be accepted. Parents and adolescents should be aware that performance of specific tasks may be impaired at the higher phenylalanine concentrations. </B></div> <bR> <bR> <div> <B> <A NAME="pmd9_15"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Additional Biochemical Monitoring of Nutritional Status </B></div> <bR> <bR> <div> <B> <A NAME="pmd9_16"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>This complements the clinical assessment of nutrition and anthropometry. Periodic testing is indicated if there are concerns about nutritional inadequacies. It may be appropriate to measure plasma vitamin and mineral concentrations. Vitamin B12 concentration should be measured annually in adolescents and adults on a diet in which protein intake is low, but who are not taking amino acid supplements</B></div> <bR> </td> </tr></table></body>