INSTRUCTIONS
1. BEGIN reading the Scenario.
SCENARIO
Stacy and Paul Chance are referred to the genetics center because their newborn daughter, Michelle, had elevated phenylalanine levels as determined by newborn screening. The diagnosis of phenylketonuria (PKU) is made.
2. DISPLAY and discuss pedigree. Use overhead 1-A or draw on board.
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"P" in the pedigree indicates the proband - the first affected family member coming to medical attention. |
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The inheritance shown is recessive. Both parents carry one recessive gene for PKU, but neither has the disorder. With each pregnancy, there is a 25% (1 out of 4) chance that the offspring will receive both recessive genes. In the Chance family, Michelle has received the two recessive genes and has PKU. Other genetic conditions inherited in the same manner include cystic fibrosis (see Scene X), sickle-cell anemia and thalassemia (see Scene IX). |
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Many people think that the term "pedigree" originated with the science of animal husbandry. In fact, the term is a corruption of the phrase "pie de grue" - French for "crane's foot". Early pedigrees showed lines of descent dropping down from parents to their offspring in a manner that resembled the claws of a large bird. Hence, "pie de grue". |
3. CONTINUE reading Scenario.
The couple wonders why their child was tested. They have two other children, Alan (age 6) and Frank (12) who are apparently healthy, active, intelligent boys. The couple couldn't remember any special testing that either boy had at birth. State mandated newborn screening is explained to them. A description of PKU and its inheritance is provided, and dietary management is discussed.
PROCEDURE: NEWBORN METABOLIC SCREENING FOR PKU
OBJECTIVE: Early detection of phenylketonuria
INDICATIONS: All newborns
WHEN PERFORMED: Around day 2
SPECIMEN(S) NEEDED: Blood obtained from a heel-stick applied to filter paper and dried
METHOD: Blood spots are punched out of filter paper and applied to gels that contain bacteria. Each gel is incubated under conditions that would prompt bacterial growth only if there were an excess of phenylalanine in the blood sample. A few laboratories use a fluorometric method for detection of phenylalanine.
ANALYSIS: Each gel is examined for bacterial growth. The presence of bacteria around a blood spot indicates the presence of an excess amount of phenylalanine in the blood spot.
OTHER: Once the identification has been made, follow-up confirmatory blood testing is performed. When a diagnosis has been confirmed, therapy (dietary or drug) can be immediately started. Failure to start therapy early can result in long term developmental disabilities. Newborn screening is an inexpensive process (generally under $5.00 per condition tested) mandated by many state legislatures. Prior to the initiation of newborn screening in the early 1960s, infants born with recessive metabolic disorders were likely to be severely mentally retarded and ultimately institutionalized.
The success of screening programs has reduced the immediate effect of recessive metabolic diseases, but it increases the prevalence of the PKU gene in the gene pool since all affected fertile individuals must pass a PKU gene on to each child.
4. DISCUSS newborn metabolic screening for PKU.
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Prior to the availability of this test, a common way to test for PKU was to add ferric chloride to urine-soaked diapers. The pyruvic acid in the urine of infants with PKU would react with the ferric chloride creating a distinctive green color. |
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A few laboratories are using a fluorometric test, in which phenylalanine is tagged with a marker that lights up - fluoresces - under special laboratory conditions. The amount of fluorescence in a sample is correlated with the amount of phenylalanine present. |
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Dr. Robert Guthrie, the developer of the assay that bears his name, had a niece diagnosed with previously undetected PKU at 15 months of age, prior to the widespread acceptance of newborn screening for this disorder. |
5. DISPLAY and discuss overhead 1-B or draw flow chart of the Guthrie test on board.
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If they are available, display samples of materials used in Guthrie test (filter paper, agar plate, etc.). |
6. CONTINUE discussing newborn screening for PKU.
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Even though PKU screening may seem expensive for the actual number of PKU cases diagnosed, it is considerably less expensive than the cost of a lifetime of institutional care for the few who have the disease and can't care for themselves. |
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Most states mandate screening programs for certain inherited inborn errors of metabolism and test for two disorders: PKU and congenital hypothyroidism. Some states require testing for up to six other disorders. |
CONDITION: PHENYLKETONURIA (PKU)
CLINICAL SYMPTOMS: Children born with PKU may appear to be normal for the first few months. Untreated, at three to five months they begin to lose interest in their surroundings, and by the time they are one year old, they are mentally retarded. Children with PKU often are irritable, restless and destructive. They may have a musty odor about them, and they often have dry skin or rashes. Some have seizures; however, they are physically well developed. They may have lighter coloring than their relatives.
PATHOLOGY: Phenylalanine hydroxylase (PAH) is reduced or absent, leading to the presence of excess phenylalanine, which interferes with the normal development of the brain, and, in particular, with the development of myelin, a protective covering for nerves. In about 1-3% of cases, a coenzyme vital to the normal function of PAH is deficient.
PROGNOSIS: Without treatment, PKU generally leads to severe mental retardation. Children whose blood phenylalanine levels are under strict control from the first few months of life develop normally with no symptoms of PKU. Children whose blood phenylalanine levels are less strictly controlled develop intellectual deficits.
INHERITANCE: autosomal recessive
PREVALENCE: 1:10,000 to 1:15,000
RELEVANT TESTING: Newborn babies can be tested for PKU when only two days old. The baby's heel is pricked and a few drops of blood are taken. The blood is sent to a state or regional screening laboratory to find out if it has an increased amount of phenylalanine. The gene for PAH is located near the end of the long arm of chromosome 12 (12q24.1).
DNA testing is available for prenatal diagnosis and for carrier testing. Because there are so many mutations and the DNA test is expensive ($500-$1,000), DNA testing is not suitable for population screening. In couples in which one member has PKU or is a sibling of a person with PKU and the other has the population risk for being a carrier, the couple may prefer to use biochemical studies for preliminary testing before incurring the expense of DNA studies.
TREATMENT: The baby is put on a low phenylalanine diet. No regular cow's milk formula or meat are allowed because these protein foods have too much phenylalanine in them. At first, the baby is fed a protein formula milk that contains only the amount of phenylalanine required for normal development. Later, certain vegetables and other foods that are low in phenylalanine are added. The affected family incurs a cost of about $10,000 per child per year for formula and low protein food. In many states, the cost of formula is covered by health insurance. In addition, some states have mandated insurance coverage for special low protein foods.
As the child grows, blood samples are tested regularly because the diet has to be changed if the amount of phenylalanine becomes either too high or too low. Children should stay on a low phenylalanine diet as long as possible. In school-age children, a slightly higher blood phenylalanine level than in infancy is probably acceptable.
Researchers have identified a number of different mutations that result in PKU. It may someday be possible to replace the mutant PAH gene in cells in the liver, where the gene is active, using retroviruses to insert the normal gene.
When a woman who has untreated PKU becomes pregnant, her baby is likely to be born mentally retarded and may have congenital heart disease. This situation, known as maternal PKU, has become a great problem because many girls who were treated for PKU and grew up normally are now having babies.Their infants rarely inherit PKU but are likely to be brain-damaged as a result of having been exposed in the womb to their mothers' altered phenylalanine metabolism.
There is hope that the fetal damage may be prevented by treatment of the mother during pregnancy with the special low phenylalanine diet. It seems that the best results are obtained when the woman with PKU attains strict control of her blood phenylalanine level before she becomes pregnant and maintains it throughout the pregnancy. It has been estimated that the cost of special formula to sustain a woman throughout a pregnancy is about $11,000.
An alternative approach to prevent maternal PKU would be in vitro fertilization using egg and sperm from the parents, followed by implantation in a surrogate mother who does not have PKU.
7. DISCUSS phenylketonuria (PKU).
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PKU was first diagnosed in 1934, by the biochemist Folling when a Norwegian mother noted that her two retarded children always smelled funny despite her efforts to keep them clean. The unusual musty odor was traced to phenyl ketones (an abnormal breakdown product of phenylalanine) excreted in urine. |
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PKU is most common in persons of Celtic (England, Ireland, Scotland) origin. It is also common among Israeli Jews from Yemen. Twenty-two Yemenite Jewish families, descended from seventeenth century residents of San'a, the Yemen capital, have been shown to be missing an identical section of the gene for phenylalanine hydroxylase. It is probable that a mutation occurred in a single ancestor of these families. |
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Recent studies of the PKU gene seem to show that there are several different ways the gene can be defective. Defects in some parts of the gene may cause mild effects while defects on other parts may cause major mental retardation. Some day doctors may be able to examine the gene for the type of defect and order a specific tailor-made treatment for a particular defect. |
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Nobel Prize winning author Pearl S. Buck's only natural child, Carol, was born with phenylketonuria in 1921. She was mentally deficient and was institutionalized in New Jersey. |
8. DISPLAY and discuss overhead 1-C or draw metabolic pathway of phenylalanine on board.
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This illustration shows the normal metabolism of phenylalanine. Phenylalanine is an amino acid found in many proteins. It is changed by the enzyme phenylalanine hydroxylase into tyrosine which is a precursor to several other compounds including melanin, a skin pigment. In PKU this enzyme is reduced or missing. Therefore the reactions beyond the point where phenylalanine is changed to tyrosine are blocked. This causes a buildup of phenylalanine in the blood. Because of the interference with melanin synthesis, people with PKU tend to have light skin, blond hair, and blue eyes. |
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The idea that genes carry information that codes for proteins was formulated using PKU. Dr. Archibald Garrod, a British physician, first suggested that PKU was the result of a missing enzyme that should be produced in a person if the person had the correct genes for it. Garrod also first suggested that the disorder was inherited as a Mendelian trait. |
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Carriers of PKU can be detected with a DNA probe. In this procedure, a short strand of radioactively -labeled DNA is synthesized with a nucleotide sequence that is complementary to that of a defective gene. The synthetic DNA is mixed with DNA taken from a suspected carrier subject. If the subject's DNA is defective, the complementary probe will pair with it, making the subject's DNA radioactive. Other carrier states that can be detected in this way include cystic fibrosis (see Scene X), Duchenne's muscular dystrophy, hemophilia (See Scene II), and sickle cell anemia. |
9. CONTINUE discussing PKU.
10. DISPLAY and discuss some foods that are unacceptable and some that are acceptable on a PKU diet, if available. Use overhead 1-D.
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Examples: the special formula milk, diet soft drinks or a label showing the warning notice for phenylketonurics, other products containing "NutraSweet," etc. Why is the label there? (Answer: Some diet drinks are sweetened with the artificial sweetener, aspartame, a dipeptide consisting of aspartic acid and phenylalanine. A phenylketonuric consuming the drink would risk a chemical overload of phenylalanine.) |
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A suggested fast-food meal: salad, small french fries, and a non-diet soda |
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The cost of special low phenylalanine foods is high. To provide some relief to families who must accommodate such a diet, some state legislatures have mandated that these materials be dispensed by prescription only, qualifying them for reimbursement plans. Alternatively, state legislatures may mandate that third-party insurers cover the cost of these special foods. |
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Some suggestions for sandwich fillings (on Low Phe bread of course): margarine and jelly or jam, sliced cucumbers and tomato, raisins, shredded carrots, apple butter, cinnamon and mayonnaise |
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There is disagreement about whether PKU may limit fertility in men. There is no evidence that the children of men with PKU have a higher incidence of birth defects or mental retardation. |
11. CONTINUE reading Scenario.
Paul denies his contribution to his daughter's condition. He is a successful businessman, proud of his healthful lifestyle. He doesn't smoke, he jogs six miles a day and he enjoys a healthy diet. He attributes Michelle's condition to a "weakness on Stacy's side of the family" and refuses to believe that he has any "bad genes." The genetic counselor mentions that everyone carries an estimated 6-10 "unusual" recessive genes which cause no clinical problems in the carriers, but if two carriers of the same unusual recessive gene were to have children together, each child would have a 1 in 4 chance of inheriting the recessive condition for which the genes were responsible.
12. DISPLAY and discuss overhead 1-E. Ask students to complete Punnett square to determine chance of Alan carrying a PKU gene.
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What is the likelihood that Alan is a carrier of the gene for PKU? Don't be surprised if most students incorrectly guess 1/2 or 50%. Ask students to complete the Punnett square in overhead 1-E. Remind the students that Alan is an "apparently healthy" 6 year old. This "clue" should help students to eliminate nn as a possibility, since this represents affected with PKU. Therefore, of the three remaining possible combinations - NN, Nn, and nN - there is a 2/3, or 66%, chance that Alan inherited one gene for PKU, making him a carrier. |
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Genetic counseling is provided within a suitable context for each situation; that is, consideration must be given to the counselee's language, level of understanding, culture, and other challenges (i.e. hearing or vision impairment) etc. Skilled counselors will identify quickly the needs of their counselees and modify the session to meet those needs. |
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Most people think that genetic disorders are quite uncommon. Though the number of people with any one of the more than 3000 known genetic diseases is low, the total number afflicted with all genetic diseases is comparatively high. Between 12 and 15 million Americans have some kind of genetic disorder, and 20 million Americans are carriers of genetic disorders. One out of 250 newborn babies has a genetic defect and one-third of hospital admissions of young children and babies are due to some genetic problem. |
13. FINISH reading Scenario.
Paul is relieved to know that being a carrier neither reflects negatively on his manhood nor does it isolate him from his peers. He quickly turns the situation to his advantage and states, "Well, if we're all carriers of some bad genes, I guess I'm better off than most of you. At least I know what one of my unusual genes is." Stacy does not try to defend herself against Paul's earlier accusations but is relieved at his acceptance of the cause of Michelle's condition.
The further complication of maternal PKU is mentioned. Paul and Stacy are scheduled to meet with a nutritionist, and follow-up appointments for monitoring blood phenylalanine levels are made.
Upon leaving, Stacy thanks the genetics staff and says, "Well I guess we won't be seeing you again for a long time."
Little does she know...