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Newborn screening thwarts metabolic disease

By SARAH AVERY, Staff Writer

WILSON - The phone rang on a Friday afternoon, just 10 days after Joshua Allen was born and while the newness of him still enchanted his first-time parents, Sharon and Jimmy.

When the lady said she was calling from the hospital, Sharon's anxiety spiked. A new blood test taken after Joshua's birth indicated a problem, the lady said. There may be a metabolic disorder. "It hit me so strong," Sharon Allen said. "My cousin immediately came to mind."

Six years before, Sharon's cousin, Toni Cline, had a baby girl, Kasie, who appeared to be perfectly healthy until, at 9 months, she went to sleep and never awoke. Tests showed she died of a hidden metabolic disorder in which her body lacked an enzyme to process fat. Now here was Joshua, facing the same thing.

But thanks to a screening test days after his birth in 1997, Joshua's illness was diagnosed. And other than eating a special low-fat diet, he now lives the life of a normal 4-year-old.

Joshua was the first baby identified as part of an infant screening program that North Carolina pioneered to detect as many as 30 metabolic disorders -- genetic defects that impair the way foods are digested and absorbed. Without diagnosis, the disorders can result in mental retardation or death.

Now, after five years of screening, which uses a technology developed by scientists at Duke University, results of the statewide program have been published in the current edition of American Scientist magazine. Since 1997, 515,000 babies have been tested, and 106 have been diagnosed with metabolic disorders -- 38 of whom showed signs of the illness that threatened Joshua Allen's life and killed his cousin.

"In our family, the screening program is the difference between having a cousin or having an angel," said Sharon Allen, watching as Joshua darted around his family's home in Wilson.

At least nine other states have followed North Carolina's lead in screening infants for metabolic disorders, and two dozen more have launched pilot projects or are considering starting programs.

But despite North Carolina's success, the program fights budget constraints that threaten to dismantle it. Last year, legislators cut $2 million from the program and directed state health officials to recoup that money by billing Medicaid for the cost of screening poor children. This year, program administrators are bracing for another funding battle, as legislators again consider cuts to cover a state revenue shortfall.

"The most cost-effective thing anyone can ever support is newborn screening," said Elizabeth "Lib" Moore, unit supervisor for genetic health care with the State Laboratory of Public Health in Raleigh. "Think about what it would cost the state if a baby ended up having severe mental retardation -- all the resources at the community level the child would have to have, and the number of days the baby would spend in the intensive care nursery. Even if we identify just one baby, that practically pays for the equipment."

A variety of rare disorders

Metabolic disorders are so rare that parents have no idea they exist, and pediatricians often fail to diagnose them because the symptoms mimic those of other ailments. But there are dozens of varieties, and they share common traits. They usually result from two recessive genes, one from each parent.

When children inherit both genes, the mutation creates a breakdown of the complicated chemical process that turns food into energy and waste.

Sometimes, one or another enzyme is lacking that helps metabolize amino acids, the building blocks of proteins. The best-known metabolic disorder, phenylketonuria, or PKU, falls into this category. It afflicts an estimated one in 10,000 babies. In the 1960s, most states began screening newborns to catch it early and begin a special diet that spared children from mental retardation.

In other cases, such as Joshua's, fat isn't properly processed. His disease is called medium-chain acyl-CoA dehydrogenase deficiency.

Nationally, MCAD deficiency afflicts one in 25,000 children, but it's more prevalent in North Carolina, where the state screening program has found a rate closer to one in 10,000.

With MCAD deficiency, children can seem perfectly healthy until they don't eat for some period of time, perhaps because of a common ear infection or a stomach virus.

For most people, the body compensates for a lack of food by tapping nutrients stored in fat. But people with the enzyme deficiency lack the key to unlock that nutritional pantry. Desperate for energy, their bodies begin to shut down: they become lethargic; their muscles grow limp.

The condition can quickly progress to a dangerous level as the brain becomes increasingly starved for nutrients and triggers a seizure. Such episodes result in death in as many as 25 percent of cases, while still more children suffer permanent brain damage.

Joshua's cousin, Kasie, had several incidents that scared her parents, Toni and Mark Cline of Richmond, Va. Kasie had always been a sound sleeper, just like her dad. But there were times when the Clines became distressed when Kasie had trouble waking up, then stayed listless until she ate.

It was 1991, and MCAD had only recently been identified as a disease. Kasie's pediatrician found nothing wrong.

"He told me I have a good baby and I should stop being overprotective," Toni Cline said. On the March day that Kasie died, Toni had checked on her early in the morning, and as usual, she was sleeping heavily. An hour later, Mark went in and found her utterly limp.

They rushed her to the hospital, but doctors could not revive her. Toni knew that the cause of death was something other than SIDS, even though that diagnosis was listed on the death certificate.

Several months later, after one of Kasie's doctors read an article about MCAD, the Clines had additional tests run on Kasie's tissues, which had been saved after the autopsy. The tests, conducted at Duke, revealed the disorder.

In the decade since Kasie died, the Clines have urged Virginia officials to institute newborn screenings for metabolic disorders. They have not succeeded, and frustration has compounded grief.

"You can't explain to anyone what it's like to lose a child unless you've been through it," Toni Cline said. "Imagine what it would be like if your child died. You can't. You can't even go there. And you're fortunate that you can't."

Finding a solution

In the 1980s, a single baby, suffering from a failure to process amino acids, prompted North Carolina scientists to develop the technology to screen for metabolic disorders. The child was being treated at Duke University, and the baby's doctor approached David Millington, who holds a Ph.D. in organic chemistry, to find a way to prove that a dietary treatment had corrected the metabolic imbalance.

"I said, 'I know there is technology we can use for this,' " Millington said. As a chemist, Millington had often used mass spectrometry to determine the chemical makeup of complex compounds. The technology essentially breaks molecules into fragments, and from the pattern of those fragments, the chemical structure can be identified.

Millington applied the technology to the clinical process, and to broaden the work, he used two mass analyzers in tandem, allowing him to separate the molecules and analyze them at once. Additional developments enabled the machines to analyze whole blood and plasma.

"We were given some blood spots from normal babies and from babies known to be subsequently affected by metabolic disease," Millington said.

He said one family that benefitted from the early analysis lost two children to a metabolic disorder. The second child died, in fact, as the mother was giving birth to another. The Duke team was able to determine that the newborn also had the disease, avoiding a third death.

"We found we were able to pick up the diseases," Millington said. "We were doing detective work, and we found it quite convincing."

By the early 1990s, Millington secured a grant from the state to begin using tandem mass spectrometry on a large scale, so that as many as 500 samples could be processed in a day.

In August 1997 -- the month before Joshua Allen was born -- the state began screening all newborns by taking blood samples of infants. At first, a private company ran the tandem mass spectrometers and analyzed the results as part of a pilot program. In 1999, the State Laboratory of Public Health in Raleigh took over.

Moore, at the state lab, said it costs less than $3 to run one baby's test. When the results come back showing an abnormality, the state lab notifies the hospital where the baby was born, which then directs the parents to doctors.

Each of the state's four medical centers has experts in metabolic disorders, as do regional medical centers in Charlotte and Asheville.

Dr. Joseph Muenzer, an associate professor of genetics and metabolism at the University of North Carolina at Chapel Hill and chairman of the state's newborn screening committee, said the program has added to an already-heavy workload at the state lab. Still, he said, since the program began in 1997, no babies identified as having metabolic disorders have died as a result of their conditions.

"There's no question the program has been a success," Muenzer said. "We've clearly saved infant lives in this state."

Life-saving instructions

Now that Joshua is 4, the Allens are less stressed about when and what he eats. But in that first year, when most parents rejoice as their babies learn to sleep through the night, the Allens set the alarm clock to ring every four hours so they could get up and feed Joshua.

Everywhere they could think of -- in the glove box of every car in the family, in the homes of every person in the family, in the diaper bags, in purses, in wallets, in kitchen drawers, on the shelves, at work -- they kept copies of Joshua's diagnosis and treatment requirements.

"We had them all over the place," Sharon Allen said, "in case something happened and we needed to rush him to the hospital. They told doctors what Joshua had, and what they needed to do."

They had only one emergency, when Joshua was 16 months old: His blood sugars dropped, he was throwing up and lethargy was setting in, so the Allens rushed him to Wilson Memorial Hospital. They presented the treatment protocol that called for an immediate infusion of calories, which doctors followed.

But the doctors also ordered a battery of tests. None had ever treated anyone with MCAD deficiency.

One doctor told Sharon Allen that if she hadn't seen the treatment protocol, she would have sent Joshua home because his symptoms seemed innocuous.

"This condition," Sharon Allen said, "can go from something that seems minor to something that is serious quickly."

Joshua stayed in the hospital for two days, but has had no other incidents. Now he plays baseball in the front yard with his folks, and is gearing up for kindergarten in the fall. For the rest of his life, he'll have to eschew french fries, pizza buffets and ice cream sundaes. Endurance sports are out. And he'll have to heed even the faintest tinges of hunger.

It's a small price for life, Jimmy Allen said.

"Knowledge is very powerful," he said. "If you know about this, you can prevent a death. It's not hard to prevent. And your child can live a normal life."

Staff writer Sarah Avery can be reached at 829-4882 or savery@newsobserver.com.

ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.