Newborn Screening Method Discovered For Pediatric Disease Made Famous In 1992 Motion Picture, Lorenzo's Oil

September 26, 2006
Identification of X-linked Adrenoleukodystrophy at birth allows for early intervention, improved outcomes for males with rare genetic disorder

Baltimore, Md. - The current lack of a newborn screening method for X-linked Adrenoleukodystrophy (X-ALD) means that many boys born with the often deadly genetic disorder are not diagnosed until after symptoms develop, putting them past the window of opportunity when intervention could spare them from the disease's devastation. But a study published in the journal Molecular Genetics and Metabolism presents a discovery by researchers at the Kennedy Krieger Institute and Johns Hopkins University for utilizing tandem mass spectrometry. By "piggybacking" on this existing technology, which has made low-cost screenings for over 50 genetic disorders possible, ALD can simply be added to the states' existing newborn screening programs, allowing for the most widespread, practical diagnosis of this genetic disorder.

"The data from this study supports that a newborn screening can be added to existing screening programs, which would allow us to identify children with X-ALD and other peroxisomal disorders at birth," said Hugo Moser, M.D., Director of the Neurogenetics Research Center at the Kennedy Krieger Institute in Baltimore, Md., and senior author of the study. "Thanks to the collaborative efforts of researchers at Kennedy Krieger Institute and Johns Hopkins University, we have discovered a screening method that, if validated in larger trials, will open up a whole world of treatment options for boys who would otherwise not be diagnosed until the onset of X-ALD's dreadful symptoms."

When one considers the expanded range of treatment options that are available when X-ALD is diagnosed early, which can lead to greatly improved outcomes, the rationale for adding a newborn screening is undeniable. For one, Addison's Disease, a condition in which the adrenal glands do not function properly, occurs in 80 percent of X-ALD patients and is the sole cause of death and disability in 50 percent of these patients, yet it is completely preventable. Newborn screening will allow physicians to monitor adrenal function regularly in X-ALD patients to detect Addison's Disease before it causes symptoms, and to then treat it effectively. Furthermore, the treatment Lorenzo's Oil was proven in a 2005 study to be effective in preventing the onset of X-ALD symptoms, and newborn screening would ensure families have the information to seek out this regimen when it can help. Lastly, boys diagnosed with X-ALD at birth can be monitored on a regular basis by Magnetic Resonance Imaging (MRI) of the brain, thereby allowing physicians to identify candidates for bone marrow transplant at the stage of the illness when the procedure is most effective.

"For boys born in the future with the X-ALD gene, this study has critical implications because it signals that we have the knowledge base to begin to stamp out this disease," said study author Ann B. Moser, Research Scientist in Neurology at the Kennedy Krieger Institute. "X-ALD boys screened at birth would not only have the chance to benefit from current treatments, such as Lorenzo's Oil, they will also be the best candidates for any future treatments on the horizon, such as gene therapy and stem cell therapy, since treatments are invariably more effective before symptoms appear."

The study analyzed blood samples from 25 male patients with X-ALD, nine patients with peroxisome biogenesis disorders and 19 controls using a specific tandem mass spectrometry technique known as liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the chemical composition of the samples. Researchers found that the concentration of a specific type of lipid known as C26:0 lysophosphatidyl choline (lyso-PC) was five to 60 times greater in the samples from males with X-ALD and patients with Peroxisome Biogenesis Disorders than in the 19 controls. Lyso-PC's contain very long chains of saturated fatty acids, which accumulate in abnormally high levels in the brains of individuals with X-ALD. This is the first time lyso-PC's have been examined in diagnostic studies of X-ALD, and their profile and relative abundance appear to be very suitable for screening newborns for X-ALD.

"This finding truly underscores the tremendous scope of knowledge that can be gleaned from the application of innovative newborn screening techniques, " said Walter Hubbard, Ph.D., Associate Professor, Division of Clinical Pharmacology at Johns Hopkins University School of Medicine. "For X-ALD and a myriad other neurological disorders, newborn screenings represent the key to improved outcomes."

Dr. Moser and his co-authors feel that the preliminary results of this study are novel and sufficiently promising, but acknowledge that more extensive studies must be done before newborns are screened for X-ALD and other peroxisomal disorders using LC-MS/MS. The authors have initiated studies in collaboration with the States of Maryland and California and the Mayo Clinic that will involve hundreds of patients with peroxisomal disorders and 60,000 anonymous newborn blood samples. Although these studies will take several years to complete, researchers believe this method is a probable option for large scale screening that holds the potential to drastically change the devastating impact of X-ALD on affected boys and their families.

About X-Adrenoleukodystrophy (X-ALD) X-ALD, the most common peroxisomal disorder, causes the breakdown of myelin, a fatty substance that acts as an insulator around nerve fibers. Approximately 35 - 40 percent of affected males have the classic childhood form of the disease, which is more severe and progresses very rapidly. Symptoms normally appear between four and 10 years of age, and may include visual loss, learning disabilities, seizures, dysphagia, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, and progressive dementia, nerve deterioration, loss of verbal communication, strength and coordination and, eventually, complete breakdown of bodily function. While there is no effective therapy for this form of the disease after symptoms develop, diagnosis of X-ALD at birth would allow parents to initiate presymptomatic therapy, which studies have shown can prevent it from developing.

About Hugo Moser, M.D.

Hugo Moser, M.D. is a research scientist and Director of the Neurogenetics Research Center at the Kennedy Krieger Institute in Baltimore, Maryland. Dr. Moser is also a University Professor of Neurology and Pediatrics at Johns Hopkins University. He was previously President of the Kennedy Krieger Institute.

Dr. Moser has focused his research on genetic disorders that affect the function of the nervous system in children, particularly those that involve a part of the cell referred to as the peroxisome. Of the 15 known peroxisomal disorders that lead to mental retardation and nervous system disabilities, the most common is X-ALD. Dr. Moser helped to identify the characteristic biochemical abnormalities and the gene mutations that cause each of these disorders. He established methods of early diagnosis, counseling and worldwide programs to evaluate methods of therapy, including diet, pharmacological agents and transplantation.

About the Kennedy Krieger Institute

Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 12,000 children each year through inpatient and day treatment programs, outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop and pioneering new interventions and earlier diagnosis. For more information about Kennedy Krieger Institute, visit www.kennedykrieger.org.

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