Newborn Screening for Krabbe Disease - A Grand Experiment Changes Lives, But Cries for Oversight

Neurology Today
4 December 2008; Volume 8(23); p 4-5

FRIEDMAN, ROBERTA PHD

A pediatric neurologist calls for greater oversight and established protocols for interventions for a New York state-mandated screening program for Krabbe disease.

SANTA CLARA, CA-A New York State-mandated screening program is finding cases of Krabbe disease (also called globoid-cell leukodystrophy) and sending the children for immediate stem cell therapy at Duke University in North Carolina, but, according to a new report, physicians and families lack appropriate oversight for the treatment.

Many people view the screening program as a success, Jennifer Kwon, MD, MPH, assistant professor of neurology and pediatrics at the University of Rochester, said here at the annual meeting of the Child Neurology Society on Nov. 7. It provides an opportunity for treatment that could not otherwise be made available. However, the treatment itself is expensive, urgent, and some would argue, experimental.

She noted that safeguards - such as an independent data and safety monitoring board - are lacking to review the efficacy of the treatment. We are now screening for so many more disorders and most states screen for more than ten diseases, said Dr. Kwon, but there is no standard for clinical follow-up and often no state support for any continued medical care. She said that the Krabbe program has obtained private foundation funding to help the New York State physicians develop an approach to follow infants who have screened positive for Krabbe disease.

Krabbe disease is an autosomal recessive, lysosomal storage disorder caused by a deficiency of galactocerbrosidase (GALC), an essential enzyme for myelin metabolism. It occurs in one in 100,000 births, and approximately 85 to 95 percent have the infantile form involving extreme irritability, spasticity, and developmental delays before six months of age. The children die, on average, by 13 months. (See More About Krabbe disease.) Enzyme replacement is possible through a stem cell transplant from umbilical cord blood after bone marrow is suppressed through myeloablation, and children can survive the disease, albeit, with disabilities.

The New York State screening program was instituted in 2006 by then Governor Pataki, and since then, 600,000 newborns have been screened at birth by analysis of heel stick blood. Ninety children have tested positive for the disorder, Dr. Kwon said. Two symptomatic infants have received stem cell transplants. One died from complications of the procedure; the other child clearly has developmental delays, she added.

Banks exist for human umbilical cord blood, said Dr. Kwon, and the banked samples are matched to allow the transplants. We send blood for tissue typing, she explained. New York is only state to screen for Krabbe disease, but Illinois is about to follow, she said.

Dr. Kwon said New York now processes a thousand heel stick samples daily. The decision procedure to assign risk is complex, but in essence there is a cut off at which the GALC enzyme activity present in the heel stick sample is called either above or below normal level.

If activity falls below their cutoff, then not only is the activity re-measured, but DNA testing is done to look for GALC mutations, explained Dr Kwon in an e-mail. Using a combination of the enzyme activity and DNA testing results, the state lab determines whether to make a referral to a regional metabolic center so that the infant can be examined. The family and physicians are then notified, said Dr. Kwon.

The confirmatory test is carried out in the lab of David Wenger, PhD, director of lysosomal diseases in the neurology department of Thomas Jefferson University Hospital in Philadelphia. Dr. Wenger is one of the world's foremost experts in Krabbe disease and its diagnosis, said Dr. Kwon. His lab is renowned for its superb quality and the rapid service it has provided to the New York infants. But, she added, most newborn screening tests do not require that the confirmatory testing be done in only a single lab. This is what makes the Krabbe program so unusual and so much like a research study.

DNA testing produces a risk status, not a diagnosis, said Dr. Kwon. This risk is defined by the results of the further tests at the Wenger lab. There is no precedent for developing these risk categories based on enzyme activity from a single sample in a single lab, Dr. Kwon emphasized. These definitions have been implemented as part of clinical care, because once the state mandated the testing, physicians felt that they had no choice but to do the best they could with the information they had.

In the past two years, the state lab identified 90 infants as meriting referral to their regional metabolic centers. Six babies were deemed moderate to high risk for the disease and 20 are low risk, according to Dr. Kwon, with ongoing clinical follow up recommended for at least a few years.

A 2005 paper in the New England Journal of Medicine (NEJM) by Maria L. Escolar, MD, of the University of North Carolina, and colleagues reported on the use of stem cell transplants in 11 asymptomatic newborns (siblings of children born with the disease) and 14 symptomatic children. Infants who underwent transplantation before symptoms developed had progressive central myelination and gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function, according to the report. And children who had the stem cell transplants after the onset of symptoms had minimal neurological improvement.

One of the NEJM study authors, Karen Richards, MD, a child neurologist at Dell Children's Medical Center of Central Texas in Austin, commented after Dr. Kwon's presentation that just a ten week delay in transplanting has an enormous difference in outcome.

It is incontrovertible, Dr. Richards said, that transplant changes the disease. The kids transplanted early are worlds better off than those transplanted later, and are completely different from children who are not transplanted. Those children die within two years in a vegetative state.

What is in question are the more subtle issues of when to transplant, and what to do about children who are identified without a family history, said Dr. Richards, where the course of a previously affected sibling gives some clue about the expected time course of the disease in subsequent siblings.

Figure. DR. JENNIFER KWON: Many people view the screening program as a success. It provides an opportunity for treatment that could not otherwise be made available. However, the treatment itself is expensive, urgent, and some would argue, experimental.

[ Click here to enlarge ]

Dr. Richards noted that there was controversy about which children to include in the NEJM report. I think the developmental picture for the paper is positively slanted, said Dr. Richards.

These deficits are truly and accurately reported in the paper, but it's more dramatic when you actually see the children, Dr. Richards said in an e-mailed comment to Neurology Today. The nature of graphs is that close to normal looks pretty darn good, but when you see the patient the deficit is obvious.

Most of the deficits are in motor function, said Dr. Richards, especially ambulation, but fine motor function is affected, too. She predicts cognitive changes probably will be more evident as time passes and the children enter school and get to an age where these issues are more reliably tested.

Dr. Richards noted that a similar dilemma exists for screening for adrenoleukodystrophy (ADL), a more common disease in which many more patients have undergone transplantation. Family members with risk for developing ADL are often identified in a pre-symptomatic phase, when it is still unclear if the neurologic form of the condition will develop.

ADL could be screened universally just like the Krabbe program in New York state, noted Dr. Richard, and it would raise the same questions. There are at least several dozen diseases that could become a subject of universal screening, and what will we do when faced with all these pre-symptomatic children?

I would promote (the umbilical cord blood stem cells) for treatment of any neonate with infantile Krabbe disease when it's clear that infantile onset is at hand, said Dr. Richards. But I share Dr. Kwon's reservations about what to do in children whose time course is unpredictable - and as the New York program demonstrates, this proves to be the majority of all identified cases.

Dr. Kwon questioned whether the costs and public health benefits of the screening program were being considered. The cost of the laboratory program is half a million dollars a year, and the transplant costs $1 million, said Dr. Kwon, and then there is the cost of living with a chronic disability.

While acknowledging the costs of a large screening program, Nigel Bamford, MD, assistant professor of neurology and pediatrics at the University of Washington in Seattle and Children's Hospital and Regional Medical Center - who was a moderator at the session - told Neurology Today that he supported the screening for orphan diseases. We could start screening for a lot more, he said.

Figure. DR. KAREN RICHARDS: What is in question are the more subtle issues of when to transplant, and what to do about children who are identified without a family history, where the course of a previously affected sibling gives some clue about the expected time course of the disease in subsequent siblings.

[ Click here to enlarge ]

There is always a cost consideration, but there is a humanity component as well, Dr. Bamford said. If you can rescue a child with a stem cell transplant or other therapies, what a difference that would make to that particular baby and family.

We are facing a new era of newborn screening, said Dr. Kwon, and other states are going to be pressured to add similar rare disorders with similarly expensive treatments to their panels. She added: All of us will be facing these issues in the future. •

Krabbe disease is one of a group of genetic disorders called the leukodystrophies. These disorders impair the growth or development of the myelin sheath, and cause severe degeneration of mental and motor skills.

Krabbe disease most often affects infants, with onset before age six months, but can occur in adolescence or adulthood. Symptoms include irritability, unexplained fever, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, and blindness.

Infantile Krabbe disease is generally fatal before age 2. Those with juvenile- or adult-onset cases of Krabbe disease generally have a milder course of the disease and live longer.

For more on Krabbe disease, see the Gene Reviews summary at: www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe .

• Escolar ML, Poe MD, Kurtzberg J, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.