Prospective Data on Leukodystrophies Characterize Disease And Define Epidemiological Features
ARTICLE IN BRIEF
Among epidemiological data gleaned from an analysis of medical records from hospitals in Utah and surrounding areas, investigators reported that inherited leukodystrophies are associated with substantial morbidity and mortality in children.
Pediatric neurologists see children with inherited white matter diseases but no one knows the incidence or can easily put a name to the specific leukodystrophy. Josh L. Bonkowsky, MD, PhD, an assistant professor of pediatrics and pediatric neurology at the University of Utah designed a study to figure out whether there was a way to better provide epidemiological information about these leukodystrophies, which would pave the way to better treatments.
Inherited leukodystrophies include abnormal myelin development, hypomyelination, or degeneration of myelin, he and colleagues noted in a paper, which appeared online July 12 before the print Aug. 24 edition of Neurology. The problem with diagnosis stems in part because there is no agreed upon definition of an inherited leukodystophy. Even with better imaging technology through MRI and molecular testing, about 50 percent of patients go undiagnosed, Dr. Bonkowsky said.
There has been so much debate about the conditions that fall under the leukodystrophies that some experts estimate that it is rare (affecting two in 100,000 live births) while others think it is more common (1 in 5,000 live births.) These inherited leukodystrophies can also begin in adulthood, further making diagnosis difficult. Diagnosis has become easier since genetic tests became more readily available.
STUDY METHODS, RESULTS
Based on an analysis of medical records and data on pediatric cases from a regional hospital in Utah, Dr. Bronkowsky and his colleagues identified 664 patients with a possible leukodystrophy, of whom 122 patients met these criteria: they were younger than 19 years at their initial evaluation of symptoms that led to the diagnosis of leukodystrophy; brain MRI abnormalities showed white matter signal consistent with the diagnosis of a leukodystrophy; and MRI results were obtained prior to determination of an alternative diagnosis not typically considered a leukodystrophy (for example, Rett syndrome). Patients were excluded from the study if they had a known (past medical history) or likely reason for their leukodystrophy.
Among the most salient features they shared: 49 percent had epilepsy; 43 percent had a gastrostomy tube; 36 percent had abnormalities in the corpus callosum, and 32 percent had a history of developmental delays.
The study shows for the first time that “inherited leukodystrophies are associated with substantial morbidity and mortality in children. The incidence of these kinds of inherited white matter problems had not been assessed before,” said Dr. Bronkowsky.
They found that one in three children died, on average, at around eight years old. The severity of the disease course was linked to the development delays: only 51 percent of the children ever walked and 28 percent had no visual eye tracking.
The most common diagnoses were metachromatic leukodystrophy (8.2 percent), Pelizaceus-Merzbacher disease (4 percent), and another four percent had adrenoleukodystrophy. Fifteen percent of the children also had endocrine abnormalities and 14 percent had hypoplastic cerebellum abnormalities. But the authors noted that more than half of the cohort (122 cases) did not have a final diagnosis.
The incidence of a leukodystrophy was one in 7,663 live births. The average cost of annual treatment was $22,000. But some of the families (10 percent) spent upwards of $500,000 over the course of the study. And the total cost of this cohort over the 12 years (assessed two years beyond the decade) was $14 million. Many of the children did not even see a neurologist until they were 3 years old.
“These diseases of inherited white matter significantly contribute to disease burden in the pediatric population,” said Adeline Vanderver, MD, an assistant professor of neurology, pediatrics, integrative systems biology at Children's National Medical Center in Washington, DC, who was not involved with the study. “We don't have a case definition at this time so it is hard to really know the incidence. We need to look at a broader population with a consensus as to what the disorders actually are. This study is very important [toward that end], and it is one of many studies that need to be done.”
Dr. Vanderver added, however, that the field needs a good definition to conduct a thorough study. She noted that the Utah group included some conditions, such as Rett syndrome, that some in the field might argue is not a leukodystrophy.
Jonathan Mink, MD, PhD, chief of pediatric neurology at the University of Rochester in New York, said that identifying these children is difficult because “leukodystrophies are really a collection of disorders that have a common feature: degeneration of the white matter of the brain.” He added that the clinical signs are not specific, which makes diagnosis difficult.
Looking at this cohort retrospectively raises the possibility that current day technologies may have provided better clues to a diagnosis, Dr. Mink said. Going forward, he added, the field “needs a prospective natural history study.”
“To have interventions, you need to have a good idea of the normal progression of these diseases,” Dr. Mink said. “We can learn a lot by seeing what they have in common but there are so many different diseases, each with a different biology.”
Dr. Bronkowsky is now working to establish a national registry to expand the diversity of the population.