North Carolina toddler's cerebral palsy misdiagnosed, dietary change fixes his medical condition

From The Raleigh News & Observer:

DURHAM, N.C. — The last thing Wes and Melissa Klor want to do is rein in their son when he darts around like 18-month-old toddlers are apt to do.

Just six months ago, the couple had no hope their baby would ever walk, much less run.

As an infant, John Klor failed to reach normal physical milestones and was diagnosed with cerebral palsy.

But last summer, John was instead discovered to have a rare metabolic disorder that affected his ability to process protein, creating a toxic assault on muscle and brain function.

A fairly simple dietary change, along with supplements, resulted in a swift turnaround. Within days and weeks, John went from being unable to bear weight to crawling, pulling up and walking.

"It was really unbelievable," said Wes Klor, 28.

Now doctors and scientists at Duke University Medical Center, where John is being treated, are laying the groundwork for a study to determine whether John's metabolic condition - GAMT deficiency - should be included in the battery of disorders the state screens for in its routine infant blood tests.

The state checks all newborns for 30 life-threatening metabolic and genetic disorders in a program that set national standards more than a decade ago. New disorders are periodically added, if the case can be made for the need.

"A lot of research has to be done to prove we could add this," said Dr. Dwight Koeberl, a medical geneticist at Duke and John Klor's doctor. "But it is a good candidate for screening. It causes severe conditions if it's undiagnosed, and we have a treatment."

Encouraged by John's transformation - and the suspicion that more children like him might have been misdiagnosed to a life of disability - the Duke team and the Klors said they are compelled to press forward.

John Klor had a rough arrival on May 28, 2008. His umbilical cord wrapped around his neck, causing a shortage ofoxygen to his brain. He initially didn't score well on newborn health assessments, but his numbers improved and after 24 hours on oxygen, he was fine.

For a few months, he tracked along with his peers, but then he fell behind, and even regressed. He rolled over a few times, but stopped. He laughed and cooed, and then quit. He had increasingly poor control of his head. He constantly swirled his hands in a fluid wave.

At his six-month checkup, his pediatrician confirmed the Klors' fears that John wasn't developing normally and referred them to a neurologist in Greenville. There, John was diagnosed with cerebral palsy, a broad term describing varying levels of impaired movement.

A major factor in the diagnosis was John's delivery, because oxygen deprivation often leads to brain damage.

The Klors were devastated.

"We left that office not knowing what to do," Melissa Klor said. The neurologist was so sure of the diagnosis that she didn't insist they get a brain scan for confirmation.

Melissa, 27, said she was prepared to fill her days at their home in the Carteret County coastal community with regimens to help John, while Wes, a former Marine who continues to work on Harriers as a private contractor, reevaluated the dreams he had for his first-born son.

"We were ready to have to spend a lot of time taking care of him," Wes Klor said.

But the Klors wondered about the diagnosis, especially because they hadn't gotten the brain scan, and they decided to seek a second opinion from a neurodevelopmental specialist, Dr. Karen Harum in Wilmington. Harum told them John had some classic symptoms of cerebral palsy, including the repetitive hand motions, but she wasn't convinced. She urged the Klors to get additional blood tests and the brain imaging to rule out other causes.

The brain scan, an MRI, showed little of the telltale damage to the parts of the brain that characterizes cerebral palsy. And John's serum tests, which had been sent to Duke to be read by genetic experts, were unusual.

A urine sample revealed a surprising result - a condition so rare the genetic group figured the screener had run the test incorrectly. They ran a second test and it came back identical.

John had a genetic disorder in which he wasn't processing protein properly.

"It was kind of exciting," said Jennifer Goldstein, a genetic researcher at Duke who was involved in the diagnosis. "We had been doing research on these disorders for years. It's very rare."

But it was unclear which of three protein malfunctions was the culprit: An extremely rare, but treatable form, or two others that were less rare, but had worse prognoses.

"I was like, dear God, let it be the rare one," Melissa Klor said.

The biochemical genetics lab at Duke, using tandem mass spectrometry technology and a biological procedure that Duke scientists developed, is one of two in the country that can test for the type of disorder afflicting John.

The Duke team discovered that John's condition was GAMT deficiency (short for guanidinoacetate methyltransferase deficiency).

About 40 cases have been described in the medical literature worldwide since the deficiency was identified in 1994.

The GAMT gene tells the body how to process protein into energy for muscles and the brain - a complex process involving an exact choreography of merging and diverging components of the essential nutrient.

A faulty gene can cause a major disruption in that synthesis. It's as if a dam occurs in the protein stream, so certain nutritional building blocks clog to toxic levels on one side, while other essential components aren't released on the other side.

The result is damage to the body and brain that increases over time, including developmental delays, lack of speech, seizures, movement disorder, mental retardation and autism.

"We do suspect these disorders are under diagnosed," Goldstein said.

Because no one tests for them, they aren't found, so they may actually be less rare than the literature would suggest. And that may mean some children who could be helped are, instead, diagnosed and treated for other profound disabilities - to no avail.

The Duke team hopes it can collect the data to make a case for including GAMT in the state's infant screening program, which catches an average of 230 metabolic and genetic disorders each year in infants.

The tests, using five drops of blood collected on every baby born in hospitals, began in the 1960s to catch cases of PKU, a treatable malfunction in the processing of amino acids. North Carolina was among the first in the nation to begin screenings for dozens of disorders in 1997, using mass spectrometry and a process developed at Duke.

"With many of these disorders we screen for, the effects can be mitigated by changing the diet or adding a supplement," said Leslie Wolf, director of the State Laboratory of Public Health, where the screenings are conducted. "The children become productive people with a good quality of life. That's the goal."

John Klor's treatment started immediately after the diagnosis in late June. For the rest of his life, he can eat very little protein, and instead must take a supplement that gives his body the amino acids it needs. He also requires three other supplements of essential nutritional building blocks that his body doesn't produce.

The Klors said the results were almost overnight.

"Every day we'd wake up and he was a little bit different," Wes Klor said. "It was so fast - so fast. It was like flipping a switch, and he's come out."

In late July, when John was 14 months old, he began to crawl. The next month he was pulling up. He took his first steps Oct. 19.

At Duke last week for a follow-up brain image, John explored the lobby of the Children's Hospital, and gave every appearance of being a normal 18-month-old boy. Although curious and energetic, he has language delays that will require speech therapy.

It's a miraculous outcome that keeps Melissa Klor awake at night.

"I just keep thinking, what if?" she said. "What if the geneticist wasn't in the lab that day? What if we hadn't gone to the [second] neurologist? What if we had just accepted the cerebral palsy diagnosis?"

Then John squirmed out of her arms and made a dash toward the exit, not even glancing back.