Eating Cheese Without Fear

A New Drug Is Allowing People With A Rare Genetic Disorder To Eat Foods That Were Forbidden Because Too Much Protein Causes Mental Retardation

by David Wahlberg, Wisconsin State Journal

Tad and Matt Martin recently ate what they had never been able to eat before: hamburgers, hot dogs, ice cream and grilled cheese sandwiches, with real cheese and regular bread.

The teenage brothers from Janesville have a rare genetic disorder called phenylketonuria, or PKU. It causes mental retardation and other neurological problems unless people maintain a strict low-protein diet.

The first drug for the condition, approved last month, is allowing many people with PKU to eat more foods. An experimental protein being studied at UW-Madison, a hub for PKU research, also could someday broaden patients’ food choices.

“It’s cool that we get to eat a lot more,” said Tad Martin, 13, who is taking the new drug and especially enjoying ice cream sandwiches. “It’s been hard for me.”

The drug, Kuvan, doesn’t help everyone. BioMarin, the California company that developed Kuvan, said it works on 30 percent to 50 percent of the at least 13,000 people with PKU in the United States.

Kuvan didn’t work for Jessica Zimmerman of Middleton. The 10-year-old has a severe form of PKU that requires her to limit her protein intake more than most patients.

Ann Zimmerman said the drug’s lack of effect was disappointing for her daughter, who has to alter her already restrictive meals if she wants a few french fries for lunch or a couple handfuls of popcorn with friends.

“She’s quietly resigned herself to it,” Ann Zimmerman said. “We’re hopeful that within her lifetime a lot of progress will be made.”


The PKU gene mutation reduces the activity of an enzyme that breaks down phenylalanine, an amino acid found in virtually all protein. Levels of phenylalanine build up in the bloodstream and damage nerve cells.

The research of Dr. Harry Waisman, the late UW-Madison pediatrician for whom the university’s Waisman Center is named, focused on PKU. The Waisman Center, next to UW Hospital, specializes in developmental and neurodegenerative disorders.

Beginning in 1956, Waisman developed animal models that showed how PKU impairs mental development and how a low-protein diet could prevent such problems.

Other scientists developed a blood test for the disease. In the mid-1960s, PKU became the first disorder for which all babies around the country were screened. Today, newborns in Wisconsin are tested for 47 conditions, using blood drawn from a prick of their heels.

Roughly one in 13,500 newborns is found to have PKU. Since screening began, babies who test positive have been immediately started on a formula free of phenylalanine. The intervention has prevented the babies from becoming mentally retarded.

Children with PKU continue to drink the formula even when they are ready for solid foods. They also start to eat fruits, vegetables and some grains. But they must avoid protein-rich foods such as meat, eggs, dairy products, nuts, beans and soy products.

Even as adults, people with PKU stay on the formula, which contains the essential amino acids except for phenylalanine. They get the tiny amount of that amino acid they need from the limited solid foods they eat.

“Their diets are basically reversed from regular diets,” said Susan Heighway, a nurse practitioner at the Waisman Center’s Biochemical Genetics Clinic. “They get the bulk of their nutrients from the liquid in their diet, not from solid foods.”


The amino-acid formula has a bitter taste, however, and the regimented diets can be difficult to maintain, especially for teenagers and young adults, said Denise Ney, a UW-Madison professor of nutrition sciences.

Patients who stray from the special diets after age six or so, when major brain growth is finished, generally won’t become mentally retarded, doctors say. But such people can develop learning disabilities, headaches, seizures, tremors, psychiatric disorders and other neurological problems.

Ney is studying the use of an alternative protein that could make PKU diets more palatable.

The protein – called glycomacropeptide, or GMP – is extracted from whey, a byproduct of making cheese. It is the only known dietary protein free of phenylalanine, Ney said.

Mark Etzel, a UW-Madison food scientist, patented a method of separating GMP from whey. The university’s Center for Dairy Research has made pudding, crackers and sports drinks using GMP. A Massachusetts company has developed a granola bar.

In a recent study, 10 people with PKU who ate the GMP foods for several days at UW Hospital said the products were tasty, and they experienced no side effects. Ney is applying for a grant to expand the research to about 60 patients at five sites around the country.

The GMP products could someday replace the amino acid formula and expand the variety of foods people with PKU can eat, Ney said.



The drug Kuvan is making life more normal for Tad and Matt Martin, who play football and like math and science.

Since birth, their days have been measured in “exchanges” – the term people with PKU use to count each 15 milligrams of phenylalanine they consume.

An apple or a Graham cracker each are one exchange. Half a cup of most cereals is three exchanges. A McDonald’s hamburger is 41.

People with PKU are supposed to eat a set number of exchanges each day – no more or no less.

Before Kuvan, 13-year-old Tad was supposed to have 26 exchanges a day. Matt, who is 14, was supposed to have 28. With each snack and meal, patients must keep track of the numbers, which are based on how poorly they metabolize phenylalanine.

Now that the Martins are on Kuvan, Tad should have 71 exchanges a day and Matt should have 56 (Tad’s body responds better to the drug). The drug, taken in several pills once a day, is a synthetic version of a natural chemical that assists the enzyme that breaks down phenylalanine.

Kuvan is expensive – about $57,000 a year, according to BioMarin. The company is covering the cost for the Martins for now through a special program, and the family hopes their insurance will eventually pay for it.

Most insurance plans have agreed to cover the drug, said BioMarin spokeswoman Susan Berg. The company says the fee is high because Kuvan is an “orphan drug” – for a rare disease, with few patients to absorb the costs of developing the drug.

Tad and Matt still must drink their formula three times a day, but now they’re able to try foods that were previously forbidden.

Not that they like all of them.

They gave the two tiny hamburgers they’ve each eaten mixed reviews. Matt stopped eating a hot dog after two bites. Tad spit out his one bite.

Such reactions are typical among people with PKU because they’ve been trained to think of protein-rich foods as bad, said Heighway, the Waisman Center nurse practitioner.

The Martins have enjoyed eating breakfast sausages, ice cream and grilled cheese sandwiches.

A big reason Cristal Martin, their mother, is happy about their expanded diet is that they can now eat regular bread, she said. For years, she has had to bake low-protein bread.



Jessica Zimmerman, a fifth-grader at Northside Elementary School in Middleton, still must abide by her strict diet of 13 exchanges a day. After she tried Kuvan for a few weeks, it was clear it had no effect, her mother said.

That means Jessica, a student council member and sports enthusiast, still can’t eat regular bread and other store-bought baked goods because of their modest protein levels, in addition to avoiding protein-rich foods.

Her mainstays for lunch are low-protein pasta or low-protein bread, along with applesauce, grapes or carrot and celery sticks. For dinner, she often has broccoli or a salad with a grilled cheese sandwich made with low-protein bread and imitation cheese.

When her friends bring cookies to gymnastics events or go to McDonald’s after a soccer game, she can’t eat what they eat – although she can occasionally have a bite or two if she plans ahead.

“Spontaneity is very difficult,” said Ann Zimmerman. “And that stuff is very tempting.”

But Ann Zimmerman knows what can happen if people with PKU eat too much protein, especially when they are young. Her aunt and uncle, who are in their 60s, are severely mentally retarded because of the disorder.

When Ann got married, her husband, Scott, said his family had no history of PKU. Their other child, Danny, 13, doesn’t have it.

It turns out that Ann and Scott Zimmerman are both carriers of the gene mutation, so each of their children would have a one in four chance of having PKU.

Tad and Matt Martin’s siblings, Holly, 9, and Dylan, 8, don’t have PKU.

Jessica Zimmerman has done some taste testing of the GMP products developed at UW-Madison and hopes they’ll be available soon, her mother said. She rarely complains about her condition and is used to her routine.

“Other people look at us and say, ‘How can you do that?'” Ann Zimmerman said. “But it’s so much a part of our life, I don’t even think about it anymore.”