Jerry Vockley, MD, PhD, is chief of medical genetics and director of the Center for Rare Disease Therapy at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh. Vockley, who's been at UPMC since 2004, is also a professor of pediatrics at the University of Pittsburgh School of Medicine and a professor of human genetics at the Pitt Graduate School of Public Health.
Phenylketonuria (PKU) is a rare disorder that you're born with. It happens because of changes to a gene that helps break down the amino acid phenylalanine (Phe). People with PKU lack the enzyme needed to process Phe, so it can build up in the blood. That can slow development and cause other health problems. To have PKU, you need to inherit two copies of the changed gene, one from each parent.
Phe is one of many amino acids that form proteins. It's found in many foods, especially high-protein foods like meat, fish, milk, and eggs, as well as the artificial sweetener aspartame. There's no cure for PKU, but you can manage it by limiting how much protein you eat. Medicines for PKU are also available. If they work for you, then you may be able to eat more protein.
PKU is "the most common" of the rare disorders that Vockley treats. The Center for Rare Disease Therapy routinely sees about 200 PKU patients, about half of whom are children under age 18. "The younger they are, the more frequently we see them," he said.
Below, Vockley answers other common questions you might have about PKU.
Q: All babies born in the U.S. are now tested for PKU. What prompted that?
"PKU was actually the reason a newborn screening was started. There was a recognition — after PKU was first identified in patients with very severe neurodevelopmental delay — that when the next child was born, if you treated them early, you could avoid that. And by treating early, it meant a phenylalanine-restricted diet. As frequent as the disease is, it prompted several investigators in the field to look into the possibility of trying to screen for it in babies, rather than waiting for the first baby in the family to show symptoms. That was Robert Guthrie, back in the 1960s, who developed the technology.
"After two or three state-based programs to test whether it could be implemented on a large scale, it became clear that it could. Slowly, over the next few years, the rest of the states started adding it as a test for all babies born. This was the first disease identified by newborn screening and prompted PKU to become the first new disease screened for, and ultimately everything on current newborn screens, which is more like 50 diseases that were added over time."
Q: When PKU is detected in a newborn, what symptoms appear?
"For the most part, it's nothing. And that's a good thing, because what it means is we're getting them before they become symptomatic. If you talk to some parents, what they'll tell you is that when you take the baby off a normal diet and put them on a phenylalanine-reduced diet, maybe they become a little bit more alert, if there was some early indication of what we view as phenylalanine intoxication. But for all intents and purposes, the babies look completely healthy."
Q: Do treatments for PKU change throughout life? How are newborns treated versus adults?
"In babies, giving them a low-phenylalanine formula that can incorporate breast milk gives them the minimum amount of protein to grow and provides the rest of their calories by individual amino acids that exclude phenylalanine. As kids get older, they start eating solid foods, and the phenylalanine restriction follows. The families learn how much phenylalanine is present in various foods. They learn how to count that, and they learn how to deliver the amount that's prescribed for their baby. Then the rest of their calories are made up of either low-protein foods, low-phenylalanine foods, or a more palatable metabolic formula that's designed to be for older children and all through adulthood.
"For decades, the only treatment we had was reducing phenylalanine in the diet. There are now, finally, some medications that have been approved. If they work, then you see where the patients' phenylalanine levels fall, and then you can start adding back some Phe into the diet to make their life a little bit more normal.
"There are two drugs that are pills or powders, one called sapropterin (Kuvan), another called sepiapterin (Sephience). Both help increase the activity of the phenylalanine hydroxylase protein and can provide patients with the ability to metabolize a little bit more phenylalanine. Usually in the United States, we try medications as children are starting to transition over to solid foods.
"There's another drug called pegvaliase (Palynziq) that has a different mechanism of action. Individuals take a daily injection one, two, or three times a day. It gives them a completely new enzyme floating around in their bloodstream that will digest the phenylalanine. It's approved for people with PKUI who are age 12 and older."
Q: What treatments do your patients best respond to? Are there some treatments that your patients have been able to tolerate better than others?
"Sapropterin and sepiapterin are usually most effective in individuals who have milder disease, because they already have some stable protein and this helps make more of it. But they're tried in really any baby diagnosed with PKU. Pegvaliase is a completely new enzyme, and the advantage is that it can theoretically work in anybody regardless of how severe your case of PKU is. A clinical trial just finished to test it in adolescents. FDA approval now extends to adolescents ages 12 to 17.
"It's a lot easier to take a pill, and so if that pill works, that's our first choice. The pegvaliase injections are difficult. They're 2 milliliters. That's almost a half a teaspoon that you're injecting subcutaneously daily. It can get old very quickly, especially if you have to do two or three different injections. It also can generate some allergic reactions that some folks have difficulty tolerating, and can even generate anaphylaxis, a severe allergic reaction that can require emergency room or hospitalization therapy."
Q: How do you know when it's time to do more?
"The simplest way is you start seeing phenylalanine levels creep up. That means you're not being effective in managing that. So you try other things. From the standpoint of patients who are off therapy but are still coming in for an occasional visit, what you start finding is a deficit in executive function. Executive function is how you go through your day, how you plan your life. And we'll see that in our patients. You can get it from talking to them. You get it from talking to their friends, their families. The problem is, they don't always recognize it in themselves. If you can get them on therapy and drop their phenylalanine, suddenly it's like a cloud lifts. They go, 'Oh my gosh, I can't believe how much better I feel now.' It's a sort of constant battle to help them recognize the problem, understand it, and be able to treat it."
Q: How well are adults (who were diagnosed 20-50 years ago as newborns) living with PKU today?
"It depends. When it was first recognized that reducing Phe in the diet would prevent the worst neurologic symptoms, the thought was that brain development was done by age 2 or 3, so those kids could come off diet and they would be OK. Well, that turned out not to be right. Over the next couple of decades, [the recommendation] changed to treatment for life. Basically, the better controlled you have been throughout your life, the less of these chronic symptoms you have as you get older.
"The first PKU patients who were identified by newborn screening are starting to hit 60. We still take care of patients who had neurologic damage prior to the onset of newborn screening. Mostly, they're in care facilities, because they're very difficult to manage in a home setting. We have some 50- and 60- and 70-year olds who are falling into that category. And as our newborn screening population ages, we continue to follow them."
Q: How do you counsel women with PKU who want to get pregnant?
"Now we recognize that the sooner a woman who has PKU gets her phenylalanine level down to recommended treatment levels, the better their baby will do. We start talking to kids with PKU as soon as they're old enough, certainly adolescents, to say, 'When you start thinking about having a family, if your blood Phe levels are out of the treatment range, there are risks to your baby.'
"Most women will work with their metabolic team to try to get this under control before they start their pregnancy. But if someone comes to you and says, 'I wasn't planning it, but now I'm pregnant,' the sooner you get [their Phe levels] under control, the better. The outcome is OK."
Q: Are there clinical trials looking for new PKU treatments? Are researchers working on anything that you think is exciting for PKU patients? What treatments do you see on the horizon?
"There are multiple clinical trials for new medications for PKU currently underway, including gene therapy and new oral medications. The latter are particularly intriguing, as they could potentially be used in combination with other oral meds to bring patient Phe levels into the recommended treatment range without diet. Development of a handheld Phe meter is also in clinical trials and would provide a major benefit for patients by enabling at-home monitoring."
Q: How strong is the support network for patients and advocacy for PKU research?
"The support network for PKU patients and families is incredibly strong, led by the National PKU Alliance. They host annual national scientific and family-oriented conferences, organize local community activities, and fund research."
