The Brown family at the Grand Tetons (2019). Clockwise from left, Christine, Kevin, Keagan, Connor, and Kellen.
But Christine Brown knew none of this when the hospital called saying that standard newborn screening of her son Connor had come back positive for PKU. It was urgent that they visit a special metabolic clinic the next day, which was about a three-hour drive away.
“I was told not to go on the Internet,” Christine recalls, “So when somebody tells you not to go on the Internet, what do you do? Even back in 2005, right.” What she saw were the worst examples of retardation, which was a common outcome from PKU before newborn screening became routine. “We were just in complete shell shock, our whole world just kind of shattered and went into a tail spin.”
“I remember feeding him the night before our clinic visit and almost feeling like I was feeding him poison because I knew that breast milk must have protein in it,” she says.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods.'"
Over the next few days the dedicated staff of the metabolic clinic at the Waisman Center at the University of Wisconsin Madison began to walk she and husband Kevin back from that nightmare. They learned that a simple blood test to screen newborns had been developed in the early 1960s to detect PKU and that the condition could be managed with stringent food restrictions and vigilant monitoring of Phe levels.
Everything in Your Mouth Counts
PKU can be successfully managed with a severely restricted diet. That simple statement is factually true, but practically impossible to follow, as it requires slashing protein consumption by about 90 percent. To compensate for the missing protein, several times a day PKU patients take a medical formula – commonly referred to simply as formula – containing forms of proteins that are digestible to their bodies. Several manufacturers now add vitamins and minerals and offer a variety of formats and tastes to make it more consumer friendly, but that wasn't always the case.
“When I was a kid, it tasted horrible, was the consistency of house paint. I didn't think about it, I just drank it. I didn't like it but you get used to it after a while,” recalls Jeff Wolf, the twang of Appalachia still strong in his voice. Now age 50, he grew up in Ashland, Kentucky and was part of the first wave of persons with PKU who were identified at birth as newborn screening was rolled out across the US. He says the options of taste and consistency have improved tremendously over the years.
Some people with PKU are restricted to as little as 8 grams of protein a day from food. That's a handful of almonds or a single hard-boiled egg; a skimpy 4-ounce hamburger and slice of cheese adds up to half of their weekly protein ration. Anything above that daily allowance is more than the body can handle and toxic levels of Phe begin to accumulate in the brain.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods,’” recalls Les Clark. He has never eaten a hamburger, steak, or ribs, practically a sacrilege for someone raised in Stanton, a small town in northeastern Nebraska, a state where the number of cattle and hogs are several-fold those of people.
His grandmother learned how to make low protein bread, but it looked and tasted different. His mom struggled making birthday cakes. “I learned some bad words at a very young age” as mom struggled applying icing that would pull the cake apart or a slice would collapse into a heap of crumbs, Les recalls.
Les Clark with a birthday cake.
Courtesy Clark
Controlling the diet “is not so bad when you are a baby” because that's all you know, says Jerry Vockley, Director of the Center for Rare Disease Therapy at Children's Hospital of Pittsburgh. “But after a while, as you get older and you start tasting other things and you say, Well, gee, this stuff tastes way better than what you're giving me. What's the deal? It becomes harder to maintain the diet.”
First is the lure of forbidden foods as children venture into the community away from the watchful eyes of parents. The support system weakens further when they leave home for college or work. “Pizza was mighty tasty,” Wolf' says of his first slice.
Vockley estimates that about 90 percent of adults with PKU are off of treatment. Moving might mean finding a new metabolic clinic that treats PKU. A lapse in insurance coverage can be a factor. Finally there is plain fatigue from multiple daily dosing of barely tolerable formula, monitoring protein intake, and simply being different in terms of food restrictions. Most people want to fit in and not be defined by their medical condition.
Jeff Wolf was one of those who dropped out in his twenties and thirties. He stopped going to clinic, monitoring his Phe levels, and counting protein. But the earlier experience of living with PKU never completely left the back of his mind; he listened to his body whenever eating too much protein left him with the “fuzzy brain" of a protein hangover. About a decade ago he reconnected with a metabolic clinic, began taking formula and watching his protein intake. He still may go over his allotment for a single day but he tries to compensate on subsequent days so that his Phe levels come back into balance.
Jeff Wolf on a boat.
Courtesy Wolf
One of the trickiest parts of trying to manage phenylalanine intake is the artificial sweetener aspartame. The chemical is ubiquitous in diet and lite foods and drinks. Gum too, you don't even have to swallow to receive a toxic dose of Phe. Most PKUers say it is easier to simply avoid these products entirely rather than try to count their Phe content.
Treatments
Most rare diseases have no treatment. There are two drugs for PKU that provide some benefit to some portion of patients but those drugs often have their own burdens.
KUVAN® (sapropterin dihydrochloride) is a pill or powder that helps correct a protein folding error so that food proteins can be digested. It is approved for most types of PKU in adults and children one month and older, and often is used along with a protein-restricted diet.
“The problem is that it doesn't work for every [patient's genetic] mutation, and there are hundreds of mutations that have been identified with PKU. Two to three percent of patients will have a very dramatic response and if you're one of those small number of patients, it's great,” says Vockley. “If you have one of the other mutation, chances are pretty good you still are going to end up on a restricted diet.”
PALYNZIQ® (pegvaliase-pqpz) “has the potential to lower the Phe to normal levels, it's a real breakthrough in the field,” says Vockley. “But is a very hard drug to use. Most folks have to take either one or two 2ml injections a day of something that is basically a gel, and some individuals have to take three.”
Many PKUers have reactions at the site of the injection and some develop anaphylaxis, a severe potentially life-threatening allergic reaction that can happen within seconds and can occur at any time, even after long term use. Many patients using Palynziq carry an EpiPen, a self-injection devise containing a form of adrenaline that can reverse some of the symptoms of anaphylaxis.
Then there is the cost. With the Kuvan dosing for an adult, “you're talking between $100,000 and $200,000 a year. And Palynziq is three times that,” says Vockley. Insurance coverage through a private plan or a state program is essential. Some state programs provide generous coverage while others are skimpy. Most large insurance company plans cover the drugs, sometimes with significant copays, but companies that are self-insured are under no legal obligation to provide coverage.
Les Clark found that out the hard way when the company he worked for was sold. The new owner was self-insured and declined to continue covering his drugs. Almost immediately he was out of pocket an additional $1500 a month for formula, and that was with a substantial discount through the manufacturer's patient support program. He says, “If you don't have an insurance policy that will cover the formula, it's completely unaffordable.” He quickly began to look for a new job.
Hope
It's easy to see why PKUers are eager for advances that will make managing their condition more effect, easier, and perhaps more affordable. Synlogic's efforts have drawn their attention and raised hopes.
Just before Thanksgiving Jerry Vockley presented the latest data to a metabolism conference meeting in Australia. There were only 8 patients in this group of a phase 2 trial using the original version of the company's lead E. coli product, SYNB1618, but they were intensely studied. Each was given the probiotic and then a challenge meal. Vockley saw a 40% reduction in Phe absorption and later a 20% reduction in mean fasting Phe levels in the blood. The product was easy to use and tolerate.
The company also presented early results for SYNB1934, a follow on version that further genetically tweaked the E. coli to roughly double the capacity to chop up the target proteins. Synlogic is recruiting patients for studies to determine the best dosing, which they are planning for next year.
“It's an exciting approach,” says Lex Cowsert, Director of Research Development at the National PKU Alliance, a nonprofit that supports the patient, family, and research communities involved with PKU. “Every patient is different, every patient has a different tolerance for the type of therapy that they are willing to pursue,” and if it pans out, it will be a welcome addition, either alone or in combination with other approaches, to living with PKU.
Author's Note: Reporting this story was made possible by generous support from the National Press Foundation and the Fondation Ipsen. Thanks to the people who so generously shared their time and stories in speaking with me.
In today's podcast episode, law professor Gaia Bernstein talks about the challenges of keeping control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
Gaia’s book is called Unwired: Gaining Control Over Addictive Technologies. It’s fascinating and I had a chance to talk with her about it for today’s podcast. At its heart, our conversation is really about how and whether we can maintain control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
We discuss the idea that, in certain situations, maybe it's not reasonable to expect that we’ll be able to enjoy personal freedom and autonomy. We also talk about how to be a good parent when it sometimes seems like our kids prefer to be raised by their iPads; so-called educational video games that actually don’t have anything to do with education; the root causes of tech addictions for people of all ages; and what kinds of changes we should be supporting.
Gaia is Seton’s Hall’s Technology, Privacy and Policy Professor of Law, as well as Co-Director of the Institute for Privacy Protection, and Co-Director of the Gibbons Institute of Law Science and Technology. She’s the founding director of the Institute for Privacy Protection. She created and spearheaded the Institute’s nationally recognized Outreach Program, which educated parents and students about technology overuse and privacy.
Professor Bernstein's scholarship has been published in leading law reviews including the law reviews of Vanderbilt, Boston College, Boston University, and U.C. Davis. Her work has been selected to the Stanford-Yale Junior Faculty Forum and received extensive media coverage. Gaia joined Seton Hall's faculty in 2004. Before that, she was a fellow at the Engelberg Center of Innovation Law & Policy and at the Information Law Institute of the New York University School of Law. She holds a J.S.D. from the New York University School of Law, an LL.M. from Harvard Law School, and a J.D. from Boston University.
Gaia’s work on this topic is groundbreaking I hope you’ll listen to the conversation and then consider pre-ordering her new book. It comes out on March 28.
