Genetics and Genomics | Metabolic disease

by Michelle F. Pflumm, PhD
When President John F. Kennedy said that we can do better, he had much more in mind than landing a man on the moon. "Most of the major diseases of the body are beginning to give ground in man's increasing struggle to find their cause and cure," he said in 1963. "But the public understanding, treatment and prevention of mental disabilities have not made comparable progress since the earliest days of modern history."

The mental health initiatives President Kennedy launched included sweeping nationwide newborn screening programs that helped make some intellectual disabilities preventable. Today, newborn screening is powered by cutting-edge tandem mass spectrometry technologies that can detect at least 30 biochemical imbalances that affect the brain. But it all began with a single landmark disease, phenylketonuria (PKU), an enzyme deficiency that causes toxic accumulations of phenylalanine.

"Test every newborn for PKU"

It was all there in the January 1962 edition of Life magazine: the Guthrie test, a simple blood test that could detect PKU, and a prescribed diet that could prevent the build-up of phenylalanine and actually prevent intellectual disability.

The Guthrie Test

Blood phenylalanine levels are estimated by the level of growth of a special kind of bacteria. Here, a baby (row 1) tests positive for PKU as determined by the size of the bacterial 'halo' (compare rows 1 and 4).

With President Kennedy's influence, the Children's Bureau of the United States launched a pilot newborn screening program for PKU that spanned 29 states. The goal was to screen 400,000 children nationwide. But in Massachusetts, Bob MacCready, director of the Public Health Diagnostic Laboratory, was not satisfied with testing only a few children. He made phone calls to hospitals throughout the state, and soon almost every newborn in Massachusetts was tested. With the first few cases identified, the state legislature put mandatory, universal screening in place.

"The object was to identify each and every baby with PKU--as soon as you could," recalls Harvey Levy, MD, now a senior physician in the Division of Genetics at Boston Children's Hospital, "so that you could start them on the diet within the first few days of life."

The first PKU clinic opens

In 1963, Boston Children's became the first hospital in the world to open a clinic devoted solely to PKU, prescribing the diet and helping families manage their child's nutritional needs. PKU patients and families were released from a life sentence of intellectual disability. "It is astonishing to see the change in one of these children if he is taken off the special diet," said director Ellen Kang, MD, in the hospital's newsletter. "He may develop symptoms of irritability within hours after his first off-diet meal."

Neonatologist Joe Kennedy, MD took over the clinic in 1964. He quickly realized that not all children with PKU needed such a strict diet. Based on a groundbreaking follow-up study, he subsequently established a dietary regimen for PKU newborns that could be adjusted due to the severity of the disease.

BH4: A welcome relief from the restrictive diet

Still, many PKU patients and families find themselves on life-long parole: phenylalanine levels have to be tightly monitored and food intake strictly controlled. The diet, which excludes meat, dairy products and many fruits and vegetables, can be especially challenging for parents of rebelling adolescents or for those who can't easily afford the nutritional supplements and special low-protein foods.

In 1975, Seymour Kaufman of the National Institute of Mental Health suggested that patients with a mild form of PKU might have a better option: BH4. An essential cofactor of the enzyme deficient in PKU patients, BH4 could boost the enzyme's existing activity, reducing the amount of phenylalanine in the bloodstream to a tolerable level.

"People began thinking about the idea," says Levy, "but you couldn't get large enough quantities of BH4 to treat people."

With that problem later solved, in 2005, Levy got the opportunity to test Kaufman's idea. In an international phase III clinical trial, Levy's team found that phenylalanine dropped to normal levels in 44 percent of patients, and that in patients with certain genetic forms of PKU, a less restrictive diet sufficed. BH4, approved in 2008, is the first and only drug available to specifically treat PKU.

"What we are doing is genotyping all people with PKU--right off the bat--when they are babies," says Levy, "to predict the degree of PKU and whether or not the baby is likely to be responsive to BH4."

One clinic, many diseases

With the success of PKU screening, newborn screening laboratories added modified versions of the Guthrie test to identify other inborn errors of metabolism, including galactosemia, homocysteinuria and maple syrup urine disease. If untreated, these metabolic diseases also cause intellectual disability.

"Physicians did not know a thing about these diseases," recalls Levy, "so they sent them to the PKU clinic; after all, PKU is a metabolic disease."

By the time Levy took over as director in 1978, the PKU clinic had become a metabolic clinic: the place to refer any child in the Northeast identified by newborn screening as probably having a metabolic disease. Today, it is known as the Metabolism Program.

A fight for expansion

In the early 1990s, the advent of tandem mass spectrometry (MS/MS) gave scientists the ability, with just one drop of blood, to test for 30 metabolic disorders--many of which could not be reliably diagnosed with existing tests, and many of which, untreated, cause brain damage or cognitive difficulties.

Levy, at that time also chief of Biochemical Genetics in the state Newborn Screening Program, pushed hard to get the MS/MS technology adopted throughout Massachusetts. However, skeptics saw the technology as impractical, unreliable or just too expensive. Levy found himself stonewalled--buried in red tape.

"I could see this was going to be a memos and meetings business," says Levy. "We weren't going to get it done."

So Levy started his own newborn screening advocacy group, sparking a conversation that led Massachusetts to develop one of the most comprehensive screening programs in the U.S. Now, 30 diseases are not merely detectable; the potential severity of each disease can be predicted.

"This put newborn screening at a whole new level," says Levy. "It makes newborn screening not just screening but a diagnostic tool."

Looking ahead

Without a doubt, the newborn screening programs put in place by President Kennedy spared thousands of children from intellectual disability. The application of cutting-edge MS/MS technology promises to boost this number to many tens of thousands.

However, challenges remain. There are diseases that still cannot be reliably detected and diseases that diet alone cannot keep at bay. Gerard Berry, MD, the current director of the Metabolism Program, is focusing his efforts on galactosemia, a disease in which the body cannot metabolize galactose, a lactose byproduct found in breast milk and dairy products. His team has most recently developed an MS/MS-based follow-up test to more carefully diagnose galactosemia. In the future, in collaboration with George Daley MD, PhD, of Children's Stem Cell Program, he hopes to develop a gene therapy-based treatment to prevent intellectual disability from developing in these children.

"Much of the world's population still struggles for mere survival; others for domination," said President Kennedy in 1961. "Our aim is individual and national dignity. Our fortune is scientific and technological ability. Our obligation is to search for the secrets of the human mind and share our knowledge throughout the world."

Related Stories:

• The discovery of PKU
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• Galactosemia study launches at Boston Children's
  The Boston Globe features an ongoing national observational study led by Gerard Berry, MD, to better predict the outcomes of patients with galactosemia.
• A Boston area family's fight against galactosemia
  WBZ4 features a local Boston family's struggle to find a cure for 5-year-old Kyleigh Lydon, a Boston Children's Hospital patient with galactosemia. Gerard Berry, MD, whose research the Lydon's fundraisers support is interviewed.
• A better test for galactosemia
  Gerard Berry, MD, introduces a more sensitive test for galactosemia that can be used for routine newborn screening.