Krabbe disease added to federal newborn screening panel

On July 1, 2024, infantile Krabbe disease (IKD) was added to the federal Recommended Uniform Screening Panel (RUSP). The RUSP is a list of disorders the Secretary of the Department of Health and Human Services (HHS) recommends states include in their newborn screening (NBS) programs. It took three nominations to the secretary from a group of medical experts — the last two nominations including Dietrich Matern, M.D., Ph.D., co-director of Mayo Clinic’s Biochemical Genetics Laboratory — in collaboration with Hunter’s Hope, an advocacy group for Krabbe disease patients and families, before the disease was accepted into the RUSP. The list now includes 38 core conditions and 26 secondary conditions.

This is only the second time in the history of the RUSP that the secretary added a condition with limited scope. Dr. Matern explains, “They added ‘Infantile Krabbe disease (low [GALC] galactocerebrosidase and psychosine ≥ 10nM)’ instead of just Krabbe disease, so it’s very specific. The first more defined condition added was spinal muscular atrophy, SMA, listed on the RUSP as ‘SMA due to homozygous deletion of exon 7.’”

About one out of every 200,000 babies is born with Krabbe disease, an inherited condition caused by two pathogenic GALC (galactocerebrosidase) gene variants. In cases of IKD, the newborn doesn’t produce functional GALC enzyme, which causes the destruction of the protective coating of nerve cells in the brain and peripheral nervous system. This results in rapidly progressing neurodegenerative disease.

“In these most severe cases of Krabbe disease, neurologic symptoms usually begin within three to six months after birth, with a life expectancy of two years, on average,” says Amy White, CGC, a genetic counselor in Mayo Clinic’s Biochemical Genetics Laboratory. “Disease symptoms include irritability, inconsolable crying, progressive loss of mental and physical abilities, leading to the inability to swallow and breathe in the late stage of disease.

“In other cases, newborns inherit two ‘milder’ pathogenic variants and can still produce a small amount of GALC enzyme, which means they appear normal and healthy over their first year of life. After that, symptoms can appear anytime between childhood and adulthood. These milder cases are known as late-onset Krabbe disease (LOKD).”

Currently, only 12 states in the country are screening for Krabbe disease, which equals 34% of newborns in the U.S. Adding IKD to the RUSP will lead more states to follow suit, so that babies with IKD can be identified and assessed for rapid treatment initiation with stem cell transplantation.

First-tier test method plagued by false positives

Previous nominations of KD to the RUSP were declined due, in large part, to concerns about false-positive screening results. The first-tier newborn screen for KD measures GALC enzyme activity in an infant’s dried blood-spot sample, collected via a heel prick at 24–48 hours of age. However, relying on GALC activity for screening has poor specificity, which means more false positives and costly, time-consuming follow-up testing.

Attempts to improve this by molecular genetic analysis of GALC also mostly failed due to the large number of variants of uncertain significance. Most states already screening for KD have therefore added measurement of psychosine (PSY), a more specific disease marker. This PSY test allows identification of KD patients with near 100% specificity. However, there had yet to be a universal approach to screening for KD, as some states added PSY analysis but do not rely on its results to determine if a screen is positive or negative.  

Dr. Matern led a recent study that addressed this inconsistency and recommended a PSY cutoff of ≥ 2 nM to avoid false positive results while identifying all patients with IKD and most with LOKD. “The goal of the paper was to survey the states that are currently screening for Krabbe disease and have been using psychosine in one way or another, for more than a year,” he says. “With the second and third nominations of Krabbe disease, the recommendation was to always make psychosine part of the screening test and to use the psychosine result as a deciding factor in whether the result is positive or negative.”  

Overall, seven states were surveyed for the study: Georgia, Illinois, Kentucky, Missouri, New York, Pennsylvania, and Tennessee.  

Dr. Matern continues, “What we found is that states don’t use the same cutoff for psychosine. Kentucky and Georgia consider psychosine less than 2 as normal. And if it’s above 2, then it’s abnormal. And if it’s greater than 10, then it’s an emergency because that’s most likely IKD. But then you have other states that use a lower cutoff for psychosine. For example, Illinois had a cutoff of 1.1, then they raised it to 1.5. Our findings show nicely that just doing that dramatically reduced their false positives, but it didn’t eliminate them.”

A two-tier strategy to eliminate false positives

After the seven states were surveyed, their screening outcomes were modeled for three different PSY cutoffs. It showed that a cutoff of 10 nM would limit detection to IKD, and a cutoff of 2 nM would eliminate false-positive results while identifying cases with later-onset forms of KD. 

“The RUSP nomination recommended that infantile Krabbe disease with the cutoff of 10 be added as a core condition on the RUSP, which it now is,” says Dr. Matern. “This cutoff is based on another paper that we wrote four years ago, the Guenzel paper, where we looked at many cases, and the lowest psychosine level in an infantile patient was 11. So we decided to go with 10 as the cutoff for infantile Krabbe disease and, with that, you basically have no false positives, which is substantiated in our recent survey paper.”
      

In short, the addition of “Infantile Krabbe Disease (low [GALC] galactocerebrosidase and psychosine ≥ 10nM)” to the RUSP dictates a two-tiered test strategy: the first-tier measures GALC enzyme activity and, if low, a second-tier PSY test is required to confirm a positive or negative result with a quick turnaround.

While the RUSP only includes IKD, this does not prevent states from screening with a lower cutoff for PSY and therefore identifying other forms of KD, which also benefit from early treatment. Because of this, Mayo Clinic’s Biochemical Genetics Laboratory, which provides PSY analysis as a second-tier test, has no intention of raising the cutoff above 2 nM unless a state were to explicitly request it.

Psychosine testing is currently only offered by a small group of laboratories, including Mayo Clinic Laboratories (Mayo ID: PSY).  

Screening facilitates timely treatment

The current gold standard for IKD treatment is a bone marrow or hematopoietic stem cell transplant, which must be done early, ideally in the first 30 days of life, before irreversible damage to the nervous system has progressed too far to make this treatment beneficial. The treatment has been controversial, as it’s an invasive procedure on such a tiny human being. Additionally, a positive outcome is not guaranteed, as it is not a cure (most patients still experience some developmental delays and may develop peripheral neuropathy), and the procedure carries a risk for potentially fatal complications. These were all concerns that contributed to earlier nominations of KD to the RUSP having failed.

The survey also summarized what types of Krabbe disease were identified in infants in these seven states and how many of those children were still alive, particularly those with IKD who received treatment versus those who did not (see Table 3). Almost every baby who received the stem cell transplant was still alive beyond the average life expectancy for the disease, while babies who did not receive treatment had died or were deteriorating. More detailed outcome data were presented at this year’s WORLD Symposium.

Both show evidence that the treatment is worthwhile and has significantly extended the lives of babies with IKD. These data further demonstrate that without newborn screening (or a positive family history of Krabbe disease), affected infants have no chance at life.

There is also gene therapy for IKD now available in a clinical trial. And there’s been some good news closer to home.  

“Here in Minnesota, working with the Department of Health (MDH) and our colleagues at a pediatric transplant center in Minnesota, we identified the first baby with IKD four weeks after screening for KD began in our state (on Feb. 26, 2024),” says Dr. Matern. “This baby was transplanted on day 26 of life at the pediatric center. As far as we know, the baby is doing well and may enter the gene therapy trial as well.”

For an inspiring story about a Kentucky baby who was saved because that state was already screening for KD (via Mayo Clinic Laboratories) even before it was added to the RUSP, click here.