Normally, PAH is produced in the liver where it helps convert an amino acid, phenylalanine, into another amino acid called tyrosine.  Amino acids are individual components of proteins.  They arrive in the liver after the intestine absorbs them from the food we eat. To make the conversion, PAH grabs an oxygen (O) atom and transfers it to the ring at the bottom of a phenylalanine.  Afterward, a nearby hydrogen ion (H+) automatically sticks to the oxygen, completing the transformation to tyrosine. Tyrosine and any remaining phenylalanine move from the liver into the bloodstream and circulate through the body to cells in the brain and every other organ.  These cells incorporate the amino acids into the proteins they make. In people with PKU, a mutation in the PAH gene changes the shape of the PAH enzyme.  The mutation can occur in any one of the thousands of DNA bases inside the gene. Different mutations have different effects on the enzyme.  Some mutations change the shape of the enzyme so that it no longer recognizes phenylalanine anymore. Some mutations change the shape so that the enzyme works very slowly. Other mutations change the shape so that the enzyme is unstable and degrades. Whatever the underlying mutation, the end result is that PAH never converts phenylalanine to tyrosine.  If a person with PKU keeps adding phenylalanine to his body by eating protein-laden foods, like meat, cheese, and even cake, excess phenylalanine builds up in the brain and poisons the neurons. No one is sure why extra phenylalanine causes mental retardation, but one idea is it somehow slows the development of neurons inside the cerebral cortex, the part of the brain that senses the outside world and makes decisions.  If the phenylalanine level is not reduced, people with PKU will have undersized neurons that fail to make enough connections with other neurons.  Another idea is that the retardation is caused by the lower levels of dopamine found in people with untreated PKU.  Dopamine is a chemical that transmits messages from one neuron to another.  With less dopamine, the brain can't transmit messages as well, like when it tells us to move an arm, or plans future events, like finishing a term paper before its due date. Other changes may also contribute.  Deeper in the brain, underneath the cerebral cortex, people with untreated PKU have less white matter.  The white matter forms a sheath around long neurons and speeds the transmission of their messages. Other changes may also contribute.  

Deeper in the brain, underneath the cerebral cortex, people with untreated PKU have less white matter.  The white matter forms a sheath around long neurons and speeds the transmission of their messages. Finally, the brain's ability to produce its own proteins is reduced, possibly contributing to the retardation of an untreated person with PKU.  Ultimately, however, no one really knows why an excess of phenylalanine is toxic to the brain. Most babies in the United States and many other countries are screened soon after birth for high levels of phenylalanine in their blood.  In the initial step, the doctor pricks the heel or hand of the newborn and collects a few drops of blood on a piece of filter paper (a.k.a. Guthrie cards). A cut-out from the bloodspot is placed on a plate of bacteria that can't grow without phenylalanine.  When the baby has a normal level of phenylalanine, there is not enough phenylalanine to support bacterial growth, and nothing happens. When the baby has higher levels, the phenylalanine feeds the bacteria around the blood spot.  The bigger the halo of bacteria around the disk is, the more phenylalanine is present. Upon a second positive result, further blood and urine tests will determine whether the high phenylalanine level is due to a defect in the PAH enzyme, or a defect in a co-factor (BH4) that helps the PAH enzyme work. Only 2% of people with elevated phenylalanine levels have a BH4 deficiency, which is caused by a defect in one of four different enzymes. PKU is not a contagious disease, but an inherited disorder.  Inheritance of PKU starts with the parents.  Each parent has two PAH (phenylalanine hydroxylase) genes, one on each chromosome 12.  One of their genes is mutated (as represented by the red chromosome). When each parent produces sperm or eggs, only one of their two PAH genes goes into each cell.  About half the cells will contain the mutated PAH. The union of a sperm and egg that both contain a mutated PAH gene produces a child with two mutated genes.  This child has PKU. A genetic disorder like PKU is called a recessive disorder, because a person must have two mutated genes to develop symptoms.  People who only have one mutated gene do not display any symptoms of the disorder and they are called "carriers." When both parents carry a mutation in the PAH gene, every child they have has a 1 in 4 chance of inheriting PKU.  To see why, we first represent the parental genes with letters:  big P represents the normal gene, and little p represents the mutated gene. Then we set up a Punnett square by arranging each parent's genes on the outer edges of the square. Each parent donates only one of their two PAH genes to the child, so we place one of the father's genes and one of the mother's genes into each box.  Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations. Next, we count the boxes that contain a PKU-causing genotype (the pp combo).  1 out of 4 boxes contain this combo, so the chance of this couple's child developing PKU is also 1 out of 4, or 25%.The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 25% chance of developing PKU. In this family, one in four children has PKU.  Other couples with the mutation may have two, three, four, or even no children with the disorder. A man or woman with PKU has greater odds of passing on PKU, if the partner also carries a mutated PAH gene.  In the Punnett square below, the man has PKU (pp), but the results are the same if the woman had PKU instead. There are two boxes with the pp genotype, so every child of this couple has a 50% chance of inheriting PKU. If the partner does not carry a mutated PAH gene (she is PP), there is no chance any of the children will inherit PKU. A woman with PKU (pp) can also give her child a PKU-like condition during pregnancy, but this has nothing to do with what genes the child has.  The fetus will feel the effect of her mother’s phenylalanine level if it is high even when the child has a normal PAH gene (the Pp genotype). Once born, the child may have cognitive delays, heart disease, and/or a smaller than usual brain. Phenylketonuria (PKU) is a recessive disorder.  

That is, a person gets PKU only when he or she inherits two copies of the mutated gene, one from each parent. PKU appears in about 1 in 10,000 births in Caucasians and East Asians.  Some ethnic groups have higher rates (e.g., Turks — 1 in 2,600; Irish — 1 in 4,500), and some have lower rates (e.g., Japanese — 1 in 143,000).  The disorder is exceedingly rare in Africans. Newborn babies are screened for high levels of phenylalanine in their blood.  Other blood tests must be conducted to determine if the high level is due to PKU or to a defect in another protein — BH4 — that causes the same symptoms. PKU occurs when a person inherits a genetic mutation that disrupts the function of a crucial metabolic enzyme (PAH).  Without a good PAH enzyme, a person can accumulate dangerously high phenylalanine levels in the brain.  Excess phenylalanine poisons neurons and causes mental retardation and epilepsy if the condition is not treated. Children with PKU must adhere to a low-protein diet as soon as the disorder is diagnosed, and should stay on the diet for as long as possible.  Even after 12, relaxation of the diet can change a person's behavior. Experts recommend people "diet for life." Soothing New Parents Dr. Selma Snyderman discusses parents’ initial reactions and what they can do to ensure that their children are following the special diet. Initial Diet Dr. Selma Snyderman explains the purpose of the special diet and its initial components. Doctor’s Visits At the beginning, visits to the doctor are frequent. Dr. Selma Snyderman comments on the purpose of these visits. Formulas and Solid Foods Dr. Selma Snyderman discusses the introduction of low phenylalanine formulas and regular food into the diet. Stopping the Diet Dr. Selma Snyderman comments on the possibility of stopping the diet. Returning to Diet Dr. Selma Snyderman discusses what happens if a person leaves the diet and the advantages of returning to the diet. PKU and Pregnancy Women with PKU must take additional steps to help ensure a healthy baby. Dr. Snyderman discusses the reasons behind the careful monitoring. Untreated People Dr. Selma snyderman and Pat Ryan stress the importance of the diet and what will happen if it is not followed. Aspartame High in phenylalanine, aspartame (i.e. Nutrasweet) is prevalent in diet sodas and children’s medications. Dr. Snyderman advises avoidance. Future Treatments Dr. Selma Snyderman discusses the pros and cons of possible future treatments, including gene therapy, partial liver transplant, and the use of stem cells. Advice to Paretns Erin Buckley, a college student with PKU, discusses the difficulty of the PKU diet and how parents should respond. More Advice This advice for new parents comes from Pat Ryan, a father of two 28-year-old sons with PKU. Avoiding Certain Foods Erin Buckley discusses how she felt about her limited diet as a child and how other parents and friends reacted to her avoidance of certain foods. First Memories of PKU Erin Buckley recalls her earliest memories of PKU – the recognition of the Nutrasweet symbol in the supermarket. 

Parental Guidance Erin Buckley and Dr. Selma Snyderman – the first doctor in the US to treat kids with PKU – advise parents on how to successfully teach their child to stay on the diet. Doctor Visits Erin Buckley discusses the frequency of her visits to the doctor and her blood tests. Formulas The formulas are yucky, but Pat Ryan and Erin Buckley describe how to deal with them. Cheating Erin Buckley describes what happens when she does not ake her formula, and Pat Ryan discusses the cheating temptations his sons have had to repress. Diets and Special Foods Erin Buckley and Pat Ryan discuss limited items in the diet and special foods that can fill up the stomach. Limitations Travelling with loads of formula can be a pain, but there aren’t many things a person with PKU is completely barred from. Erin Buckley names two – the military and reality TV shows. Special Expenses Dr. Selma Snyderman discusses the financial difficulties that people with PKU have despite the current laws, and Erin Buckley describes her own financial situation. School Experiences Success in school is possible. Erin Buckley discusses her junior and high school experiences. Friends and dating Pat Ryan describes his son’s social lives and the minor difficulties of dating.

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