Phenylketonuria: Giving treatment a second chance

Phenylketonuria (PKU) was once a common cause of intellectual disability. Children born with this metabolic condition lack phenylalanine hydroxylase (PAH), the enzyme needed to break down the amino acid phenylalanine (phe). Instead, phe builds up to levels harmful to the brain.

PKU was the original condition tested for when newborn screening was piloted in Massachusetts in 1962. In 1963, Boston Children’s Hospital opened the world’s first PKU clinic, placing children on a special phe-free diet. The diet’s impact was profound, preventing cognitive loss and enabling children to grow and develop typically.

Even children with late-treated PKU were helped. “One of the first patients I saw [in the 1970’s] lived in an institution and required a helmet because she banged herself violently in the head,” recounted Boston Children’s clinical psychologist Susan Waisbren, PhD, in a narrative published in the American Journal of Medical Genetics. “Once provided with the PKU diet, her self-abusive behaviors disappeared.”

Struggles with the PKU diet

The PKU diet, however, is restrictive and challenging. Since nearly all foods contain proteins and therefore phe, the diet for classical PKU excludes meat, eggs, dairy products, legumes, and many grains. In the early years, children with PKU could eat only fruits and measured amounts of vegetables — plus specially formulated low-protein foods and an amino acid formula that many found unpalatable.

Fran Rohr, a retired Boston Children’s dietitian of 35 years, recalls some patients being prescribed five or six 12-ounce servings of this formula per day. “I thought to myself, who could do that? I was impressed that anyone would even try.”

For many children, the PKU diet caused anxiety and social isolation. Many discontinued the diet too soon — because originally, it was believed the diet was no longer needed after age 6.

In 2001, the guidance changed to recommend adhering to the PKU diet for life. Research had found that people who had stopped the diet at age 6 had significantly lower IQ scores. Yet today, most adults with PKU no longer follow the diet and no longer attend clinic. Many don’t know about the new guidance — or that new treatment options have become available.

Now, Stephanie Sacharow, MD, director of the Harvey Levy Program for Phenylketonuria and Related Conditions at Boston Children’s, and dietitian and associate director Suzanne Hollander, LDN, are trying to bring these adults back into treatment. Their initiative is called the “Lost to PKU Clinic” study.

“Even when they’re past the age when they would sustain cognitive deficits, some people with untreated PKU experience ‘brain fog,’ reporting decreased mental clarity, anxiety, depression, and irritability,” Sacharow says. “We can reverse many of these effects if they go back on therapy.”

New treatments offer a chance at a normal diet

Several new treatments can reduce or even eliminate the need for the low-phe diet. In 2008, the FDA approved sapropterin (Kuvan), a vitamin cofactor that helps the body break down phe. People who stay on dietary therapy also have new options. One is a more palatable PKU formula made with glycomacropeptide, a byproduct of cheesemaking that can be incorporated into phe-free protein drinks. A 2016 clinical trial found that it reduces phe levels.

The most game-changing treatment has been phenylalanine ammonia lyase (PAL), a substitute enzyme that also breaks down phe. Approved in 2018 for adults, it is formulated as pegvaliase (Palynziq) and injected daily under the skin. Boston Children’s was a leading site for the Phase III trial that led to its approval.

“Pegvaliase gets blood phe levels down to normal,” says Harvey Levy, MD, a senior physician in the Division of Genetics and Genomics who has studied and treated PKU for more than four decades. “That’s something we’ve never seen in PKU.”

To date, Boston Children’s PAL clinic has treated more than 70 patients with pegvaliase. The vast majority are now eating a regular diet, enjoying foods like meat, ice cream, and peanut butter for the first time. “That is earth shattering for them,” says Sacharow. “Their focus, quality of life, functioning, and mood are much better. In some instances, people describe improved relationships, improved job performance and promotions, and increased motivation and achievement in school.”

It’s not too late: The Lost to PKU Clinic Study

As described in a recent paper, Sacharow and Hollander launched the Lost to PKU Clinic Study in 2021. Through chart reviews and other efforts, they identified 53 patients who had stopped coming to the PKU clinic. They were able to reach 27 of them. “We did lots of cold calling,” Sacharow says.

Some of those reached had been officially discharged from the clinic in childhood. Others couldn’t tolerate the low-phe diet or couldn’t get insurance coverage for the medical foods. Ages ranged from 26 to 67 years; some had been off treatment for decades.

Of the 27 people contacted, 16 met virtually with Sacharow and Hollander for interviews and education about current PKU guidelines and treatments. Six have returned to clinic; others expressed interest in returning in the future.

“Why did nobody tell me the guidelines changed?”

Not everyone approached chose to join the study. Some don’t want to revisit a painful part of their childhood or feel they are doing well enough on their own. Many are turned off by existing treatment options — including pegvaliase, which has significant side effects (injection site reactions, rashes, joint pain, and occasional anaphylaxis).

But all of those interviewed were interested in connecting with the PKU clinic and community and being contacted periodically with treatment updates.

Jeremy (not his real name), was the inspiration for the study. Diagnosed with PKU in 1965, he had stopped the diet at age 6, after his family was told that his brain was fully developed. In his mid-40s, he had what he called a nervous breakdown. “My emotions were running crazy, my anxiety was crazy,” he recounted in a published set of patient narratives. “My wife couldn’t figure out why I was crying all the time.”

Now on pegvaliase, Jeremy is experiencing improved mental health and mental clarity. He’s eating an unrestricted diet. And his blood phe levels are ideal. His question is the one that sparked the study: “Why did nobody tell me the guidelines changed?”

Adults wanting to return to PKU treatment can contact the Dr. Harvey Levy Program for Phenylketonuria and Related Conditions, within the Division of Genetics and Genomics, at 617-355-6394.