Questions and Answers about PKU

By Virginia Schuett, MS, RD, Editor, National PKU News

I wanted to share a few of the hundreds of e-mail questions I have gotten from all over the world in the past year. The ones Iíve chosen to print are especially interesting and important. In some cases, my answers reflect my interpretation of what I have found in the medical literature. On several topics, other people may have more information than I do. I would be glad to hear of otherís experiences, or other scientific papers, especially those that relate to the controversial questions.

The following questions and answers were printed in the Fall 1997 issue of National PKU News.

PKU & ADD/ADHD*
PKU, Depression & Anorexia
Treating Older Adults
PKU & Behavior Problems

Ask The Doctor

Dr. Richard Koch, a world-renowned expert in PKU, regularly answers diverse questions from all over the globe about PKU and its treatment via his participation in our internet PKU Listserv group. He has truly become our "resident doctor for all families" and we continually benefit from his vast experience and knowledge acquired over more than 50 years of work with PKU. Here are his answers to some of the many questions posed by families.

Autism and PKU
Hyperphe, Mild or Atypical PKU and Classical PKU Clarified
PKU and Male Fertility
PKU Inheritance
PKU Carrier Determination
Incidence of PKU in Other Countries
Low Protein Diet and Hair Falling Out
PKU and Aggression
PKU and Arm Twitching
Vomiting PKU Formula
PKU Formula and Headaches
PKU and Agoraphobia
PKU and Eczema
PKU and Babies Spitting Up
PKU Diet and Fatty Acid Deficiency
PKU and ADD/ADHD*
PKU Diet and Protein Deficiency
Phenylalanine Content of Aspartame
PKU and Lack of Energy

* Also see report by Dr. Kevin Antshel under PKU Research titled ADHD and PKU, reproduced from the Winter 2008 issue

Autism and PKU
Q.  I have heard there may be a relationship between PKU and autism, but is there an increased risk of autism from childhood immunizations for children who have PKU?

A.  There has been no causal relationship established between autism and vaccinations. Earlier research that suggested such a link has been found to be unreliable. No study since then has been able to establish a correlation. However, I believe there is a relationship between autism and PKU. Prior to newborn screening, 5% of children presenting with late-diagnosed PKU were first diagnosed as autistic. There is no question in my mind that those children improved on the phe-restricted diet. I have cared for quite a few such children, who are no longer autistic. Autism is a problem that has many causes. At the moment we think that it is a metabolic problem because it comes on gradually.

Hyperphe, Mild or Atypical PKU and Classical PKU Clarified
Q.  What is the difference between hyperphe, mild PKU and atypical PKU, and classical PKU?

A.  While we now know there are over 500 different mutations in the phenylalanine hydroxylase gene causing PKU, it is still useful to roughly categorize PKU based on the amount of enzyme activity that is present, since the amount of enzyme activity influences blood level control and dietary phenylalanine tolerance.

Classification of PKU has been a difficult problem until mutations of the PKU gene were identified. Most clinicians in the field utilize mutations and tolerance to phenylalanine in the diet to identify and classify persons with PKU. Newborn screening has been practiced worldwide since the l960s so that we have many persons with PKU who have grown up and that has helped a great deal. Dr. Charles Scriver in Montreal has categorized all recently identified mutations and has published them on the internet so the information is readily available to every one.
The web site: http://www.pahdb.mcgill.ca/ is the location of this vast amount of data.

But actually, parents are more interested in the mutation that exists in their child or adult. Mutations are related to outcome and the interpretation I am going to give you is based on 50 years of experience. I use the data on mutations in the patients that I take care of to guide my therapy. Since I have been working with Drs. Savio Woo, Randy Eisensmith, and Flemming Guttler over the years (all of whom are involved in PKU mutation analysis), nearly all of my patients have had their mutations identified. The mutations that completely prevent activity of the enzyme that converts phenylalanine to tyrosine are considered severe. These patients usually have phenylalanine levels over 20 mg/dl (1200 Ķmoles/L). If each of the mutations carried by a person with PKU is severe then that person has the most severe form of PKU. These persons are considered to have "classic" PKU. Fortunately the phenylalanine restricted diet, when well managed and continued over a lifetime, protects the person from the devastating neurological damage exhibited by persons born before newborn screening.

If the person is fortunate and born with only one severe mutation and another that permits partial activity of the enzyme that can convert phenylalanine to tyrosine, the person has a less severe form of the disorder. If the diet is discontinued, that person may live for 20 to 30 years on a normal diet, but eventually will develop one or more of the complications seen in persons off-diet, such as mental illness, IQ decline, seizures, etc. Off-diet blood phenylalanine levels usually are between 15-20 mg/dl ( 900-1200 Ķmoles/L). These persons are considered to have mild or moderate PKU.

If a person is born with two mild mutations, the blood phe levels are much lower. Off-diet, they usually range from 4-15 mg/dl. These persons often do well without dietary treatment. There is disagreement among clinicians about how to treat these individuals. Some physicians treat anyone with a phe level over 10 mg/dl (600 Ķmoles/L) and some even treat those with a level of 6 mg/dl (360 Ķmoles/L). This latter group of patients will usually be sensitive to BH4 therapy; in the future, I believe they will all be treated when the FDA approves BH4 for use in PKU. These persons have had a variety of names applied to them, such as hyperphe, variant PKU, mild PKU, etc.

PKU and Male Fertility
Q.  Is there any effect of PKU on male fertility? I am married and want to start a family and have heard that I might have decreased fertility as a result of my PKU.

A.  Seven years ago, Dr. Harvey Levy in Boston published a paper concerning fertility in PKU men and concluded that they were normal. However, Dr. Robert Fisch in Minneapolis published an article that suggested the sperm count was low in PKU men who were not on the diet. I know of no other studies that have been done in this area of research. If a PKU man is having difficulty with conception, I would suggest that diet treatment be resumed and I would bet money he would be virile.

PKU Inheritance
Q.  Can you please review how PKU is inherited?

A.  Everyone has two #12 chromosomes. Each of the #12 chromosomes has one site for the PKU gene. A carrier of PKU has a mutation on one of the #12 chromosomes. If a carrier marries another carrier (who also has a mutation on the #12 chromosome, there is a one in four chance at each pregnancy that their child will inherit two mutant PKU genes, one from each parent. There is a two in four chance at each pregnancy that the child will be a carrier for PKU and a one in four chance that the child will be completely free of the mutation. These are the mathematical probabilities only. In a real family, there may be two or three or more children with PKU. Other carriers may have children and none of their children have PKU so they never know they are carriers. As soon as a child with PKU is born, you automatically know that both parents have a mutation that the child inherited.

PKU Carrier Determination
Q.  How do you determine if a person is a carrier for PKU?

A.  The only accurate way to determine if a person is a carrier is to have a DNA analysis done to identify the mutation. This is a very expensive test, around $1000 or more, and is only done in a few places in the world. These include Montreal Childrenís Hospital in Montreal, Quebec, Canada (www.moleculargenetics.mcgill.ca); The John F. Kennedy Institute in Glostrup, Denmark (pku@kennedy.dk, the web site www.kisoe.org); and the Childrenís National Medical Center in Washington, D.C. (ulichter@cnmc.org, the web site http://www.cnmc.org). There also is a "loading" test, but it is only 90% accurate and I donít recommend it.

Incidence of PKU in Other Countries
Q.  Do you have any information regarding the incidence of PKU in other countries? My daughter is African-American and all of the doctors and medical professionals are always saying how rare it is for an African-American person to have PKU. We only know of three others.

A.   The incidence of PKU in Caucasians is about 1 in 10,000. In African Americans it is 1 in 200,000. So the doctors are correct, it is quite unusual in African Americans. In Chinese, it is 1 in 15,000, in Japan it is 1 in 100,000. In Turkey, it is 1 in 2500 due to intermarriage. In Ireland it is 1 in 4,000. In Poland, it is 1 in 7,000. You can see it varies a great deal throughout the world.

Low Protein Diet and Hair Falling Out
Q.  I am an adult female with classical PKU and have been back on my diet for about 6 months after being off for about 10 years. I have noticed in the last week that my hair is falling out in large amounts. Is this related to the diet?

A.  Your hair is falling out because your protein intake is too low (too little PKU formula). We see this commonly in patients who are not well-monitored. Have your doctor measure your blood total protein and A/G ratio. Iíll bet they are both low. See your dietitian for advice on formula.

PKU and Aggression
Q.  Is there a relationship between PKU and aggressive tendencies? I am a teen who has a problem with becoming extremely angry and aggressive, almost violent at times. Is this common, or is it just me?

A.  This behavior suggests to me that you are either off the diet, or if you are on the diet that your blood phe levels are too high. PKU patients who are off diet or whose levels are too high are often aggressive and less stable.

PKU and Arm Twitching
Q.  Recently I have been noticing that my upper right arm twitches. For awhile I didnít pay attention to it much, but now it is almost constant, very annoying. What is going on? I am not on the diet.

A.  I am almost certain that your neurological symptoms are due to phenylalanine toxicity because of your high levels. You should resume diet treatment before the symptoms get worse. A PKU clinic needs to give you guidance.

Vomiting PKU Formula
Q.  Sometimes after my 5 year-old son drinks his formula, he vomits it right back up. It doesnít happen daily, but enough that now he doesnít get upset, just asks for the bucket, bring what appears to be all of it back up and runs off to play. We donít give him his milk with meals or if we know he has a full tummy, and we encourage him to take his time drinking it. Is this normal? It only happens when he drinks his milk.

A.  The reason for the regurgitation is usually due to taking the product on an empty stomach. It is more therapeutic to give smaller amounts of the formula more frequently, with meals and snacks.

PKU Formula and Headaches
Q.  My adult son experiences headaches after drinking his formula that he describes as being "like the top of my head is congested." They only last a short while, but only occur right after drinking formula. Why should this happen?

A.  This usually occurs if the person drinks the formula on an empty stomach. Have your son take the formula with a meal or snack and see if that doesnít stop the problem.

PKU and Agoraphobia
Q.  I am an adult, age 30, who has been off the diet since age 14. I now have severe agoraphobia and depression, and suffer from anxiety and panic attacks. My existence is mostly pure torture. Are these related to having PKU and what should I do?

A.  The high phenylalanine in your blood is blocking the transport of tyrosine and tryptophan into your brain. This results in a deficiency of dopamine and serotonin in your brain, causing your agoraphobia, depression, and panic attackes. Psychotropic drugs will help, but the therapeutic approach is to resume the phenylalanine-restricted diet.

PKU and Eczema
Q.  My son has what appears to be an itchy eczema on his face at times. Is this related to PKU? His blood phe levels is usually but not always in good control.

A.  When the phe level is elevated, the child is more likely to have eczema. The phenylacetic acid that is formed from the breakdown of phenylalanine is irritating to the skin. Eczema is a very common problem in untreated PKU and almost always disappears when the diet is started.

PKU and Babies Spitting Up
Q.  I have heard that PKU babies tend to spit up more than other babies. My nine-month-old usually does this two or three times a week (not just a little bit, but she just boils over, completely soaking herself and everything within a three-foot radius!). Some days she will do it two or three times, and up to five times. I am just getting so fed up. Is this common for PKU? If so, when does it go away? Iíve heard that the formula on an empty stomach can make some people throw up, but all she eats is formula mixed with Enfamil, and rice cereal!.

A.  Your baby has pyloriospasm. This is not an unusual pediatric disorder and it is not associated with PKU. In actuality, it is easily diagnosed by an upper GI series. You are doing the right thing by consulting your doctor.

PKU Diet and Fatty Acid Deficiency
Q.  A couple of years ago I started developing little bumps under my eyes. My doctor recently told me that these bumps are actually cholesterol deposits and that I should have my cholesterol checked. I found this hard to believe since my diet is very very low in cholesterol. After doing a search on the internet, I found that cholesterol deposits under the eys are often caused by a deficiency of essential oils in the diet. The article continues to discuss omega-3 and omega-6 fatty acids and linolenic acid. This made me realize the bumps under my eyes have appeared and intensified since I switched formulas from Phenyl-Free to Phlexy-10 several years ago. I now realize that the Phlexy-10 system doesnít contain the same essential vitamins and fatty acids as some other formulas. Can you suggest a good source of the essential oils that I should take to get an adequate intake?

A.  Your research pointed you in the right direction. The bumps under your eyes could be caused by a lack of long chain fatty acids. You should try to always use oil in cooking and in salad dressings. Canola oil is the best source of the essential fatty acids, particularly omega-3 and omega-6 fatty acids. Two tablespoons a day of canola oil is all you need. You also can take fish oil capsules, which may contain flax oil, another source of essential fatty acids. You can purchase these at local drug stores. Besides Phlexy-10, the amino acid blends and formula bars also do not contain essential fatty acids and they must be supplemented with dietary sources. Bumps under the eyes can also be a symptom of a more serious problem with cholesterol metabolism and people with such bumps should be seen by a doctor.

PKU and ADD/ADHD
Q.  Do you think it is possible that a larger number of children with PKU are diagnosed to have ADD/ADHD due to their blood phe levels being high? Would this be a misdiagnosis? At one point, my daughter started absolutelyu bouncing off the walls, sleeping less, and being a hyperactive munchkin. It wasnít normal for her, and I even mentioned it to the dietitian. Her levels are normally around 4 mg/dl, but when she was hyper, it came back at a 20. After it came back down, within a couple of weeks she was acting normally again. Do you think some kids with PKU are misdiagnosed as ADD/ADHD when they actually just have high phe levels?

A.  Yes, I agree. It is certainly possible. Furthermore, I think ADD is uncommon in well-treated PKU patients.

PKU Diet and Protein Deficiency
Q.  My teenaged daughter has had inadequate formula intake for the last few weeks and Iíve noticed it seems she has caught more colds this year than ever before. Iíve been telling her she needs to drink all of her formula so her body can fight off sicknesses. Am I right? Isnít it harder for the body to fight off colds when nutrition is inadequate?

A.  You are correct. Your daughter should take all of her prescribed formula. She could develop a protein deficiency otherwise. Also, allergies are much more common in PKU people who are not taking adequate formula.

Phenylalanine Content of Aspartame
Q.  How much phenylalanine is in aspartame?

A.  One gram of aspartame equals 1,000 milligrams aspartame. Approximately half of the aspartame molecule is phenylalanine. Therefore, an estimate is that one gram aspartame would contain approximately 500 milligrams of phenylalanine. If a label states the amount of aspartame, you can do estimates based on this formula. Of course, people with PKU on the diet should try to avoid eating foods and consuming medicines that contain aspartame.

PKU and Lack of Energy
Q.  Our 7 year-old son seems to run out of energy rather quickly on the soccer field. His blood phe levels are good and his weight is normal. We have tried giving him different food before a game, with the same result. We know he doesnít get enough exercise, but he gets as much or more as his friends do and they donítí seem to have the problem. We are wondering if this has something to do with PKU.

A.  Is your son taking a daily vitamin/mineral supplement? If his blood phe levels are between 2 and 6 mg/dl and his caloric intake is adequate for normal weight, a lack of vitamins and minerals (such as iron) is usually the reason for lack of energy.

PKU & ADD/ADHD
Q.  Our seven-year-old was just diagnosed with ADHD after an evaluation by a Neuropsychologist, information from her teacher, other parents and the referral of her PKU clinic physician. I have heard there may be a connection with PKU. Do you have any references or resources related to PKU and ADHD/ADD? My daughterís phe levels are usually under 10 mg/dl (600 Ķmol/L).

A.  Some parents and professionals have believed for a long time that there is a relationship between elevated phe levels and ADHD (Attention and Hyperactivity Disorder) and ADD (Attention Deficit Disorder), based on their own experience. At a parents meeting several years ago, I remember a question was asked of the audience about how many parents had children diagnosed with ADD or ADHD. More people raised their hands than we would have expected in that size population. Several newer papers in the medical literature do seem to suggest there is an increased incidence of attention problems in children with PKU. For example:

  • Kalverboer, et al, Social behavior and task orientation in early-treated PKU, ACTA Paed.Scan.Suppl. 407:104-105, 1994. A Dutch study showed more "negative task orientation" in PKU children than matched controls (a characteristic similar to children with ADHD), but not an increase in "negative social behavior" that is also typical of ADHD.


  • Weglage, et al., Deficits in selective and sustained attention processes in early treated children with PKU, Eur.J.Ped. 155 (3), 200-204, 1996. Group comparisons with matched controls showed that children with PKU had more specific deficits in selective and sustained attention. These were strongly correlated to serum phe levels at the time of testing. The authors conclude that even early treated children with PKU can suffer from impaired attention control mechanisms despite a normal I.Q.

We do know that persons with untreated PKU tend to be very hyperactive, restless people unable to focus on tasks. For early treated children with PKU, the evidence for increased incidence of attention problems is still sketchy and an area for further research. But the little we do know about this again strongly suggests that consistently low blood phe levels are the most prudent.

PKU, Depression & Anorexia

Q.  I found your home page on the Internet. Iím the only child in an Irish family of four who was not born with PKU. I have a brother, 30, and two sisters, 32 and 21. My younger sister (who is off-diet) has recently developed anorexia and depression. Do you have any idea if there is a connection between PKU and these problems?

A.  There are several reports in the medical literature that suggest a relationship between high phe levels and depression. For example:

  • Fisch, R.O., et al. Phenylketonuric patients decades after diet, J.Inher.Metab.Dis. 18:347-353, 1995. Two out of 19 off-diet patients were diagnosed with depression.


  • Battistini, S. Unexpected white matter changes in an early treated PKU case and improvement after diet treatment, Func.Neurol. 6 (2): 177-180, 1991. An 18 year-old off-diet woman is described who developed "anxious-depressive symptoms."


  • Waisbren, SE and Zaff, J., Personality disorder in young women with treated phenylketonuria, J.Inher.Metab.Dis. 17:584-592, 1994. Depression is not described per se, but a variety of thought disorders and mood disturbances were associated with being off the diet.


  • Pietz, et al, Psychiatric disorders in adult patients with early-treated phenylketonuria, Ped. 99 (3): 345-350, 1997. This study found that depressive psychiatric problems were more predominant in PKU adults than a control population; depression was more frequent in women with PKU than men.

It is known that high phe levels decrease production of a key neurotransmitter important for mood maintenance, serotonin. Many antidepressant drugs act by elevating serotonin. It is thus natural to suspect that depression could be a consequence of high phe levels. There is only one reported case of PKU and anorexia, although the relationship between the two, if any, is unclear (Clarke, D.J., and Yapa, P., J. Mental Defic. Res. 35: 165-170, 1991.) This is the case of a girl with late-treated PKU and mild mental retardation who developed severe behavior disorders and anorexia in her teens. Her anorexic symptoms did not respond to the usual management strategies, but did respond to a reduction of serum phe after the introduction of a low protein diet. Although her phe levels were never lowered to a good control range on a modified low protein diet (she refused a low phe diet that included the PKU medical food), this suggests a connection between high serum phe levels and the development of anorexia.

So in your sisterís case, anorexia may be another sign of disturbed mental processes caused by high blood phe levels.

Treating Older Adults
Q.  I am looking for information on older adults, between 50-60 years of age. Are there any treatments that benefit this age group? Three brothers in our care are exhibiting increasingly challenging behavior and losing previously acquired skills at a rapid rate.

A.  To answer this and the many similar inquiries I get regarding previously untreated adults: I believe that diet treatment is always worth a try in older adults, if the facilities and support are available. It has been shown often that lowering blood phe levels can led to improvements in behavior, eczema, and a variety of other problems. While the diet cannot undo the brain damage that has been done, it can allow the adult to learn more easily due to better and more focused behavior. Please see the Diet Intervention Guidelines for Adults with Previously Untreated PKU in the Adults with PKU section of the Web site. These are practical guidelines for diet treatment based on experiences with several adults who were placed on diet for the first time in their 50's.

PKU & Behavior Problems
Q.  My daughter is three years old and I was wondering: if her levels are high for a short period of time (between blood tests) can that cause intermittent episodes of behavior problems or is she just being a three-year-old?

A.  Based on reports I have heard from families, I do think it is possible that intermittent higher levels can cause behavior changes. It seems that some children are more sensitive to higher phe levels than others. But for any one child, it is hard to say. The important thing is to try to control her diet very consistently, whether before a blood test or not, and to get frequent blood tests done. When the phe level comes back, you can then presume that for most of the interim time, her level was in the general vicinity of that number. (This is a valid assumption unless of course she is sick, or unless something else unusual is going on with her growth or other factors that would significantly affect her phe level.) If the phe level is low (in the range of 2-6 mg/dl), you are probably just experiencing a very normal three-year old.

 


Last update: February 2008
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org