Federal committee supports adding Pompe disease to screening panel

Decision is first step toward enabling states to screen newborns for the disorder

The federal Secretary's Discretionary Advisory Committee for Heritable Disorders in Newborns and Children (DACHDNC) has recommended adding Pompe disease to the Recommended Uniform Screening Panel (RUSP).

Following an 11–2 vote in favor of the measure by committee members last May, the U.S. Secretary of Health and Human Services (HHS) will need to approve the move before states can vote to include the test in their own screening panel. Many states are likely to adopt newborn screening for the condition over the next five years, just as many states have begun screening for Severe Combined Immunodeficiency (SCID) after HHS added it to the RUSP in 2010.

Pompe disease, a lysosomal storage disorder, is caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Mutations in the GAA gene result in either a complete or near complete absence of the enzyme. Symptoms usually begin in the first weeks and months of life, and without treatment, babies often die from cardiac or respiratory complications before their first birthday.

Age of onset and severity of Pompe disease vary and are related to the degree of enzyme deficiency. Individuals with partial GAA deficiency can develop symptoms in childhood or adulthood and represent most patients with the disease.

Advocates hail the DACHDNC recommendation as an important step toward improving timely, effective treatment to children stricken in infancy.

But Pompe disease screening implementation may not be easy for cash-strapped state public health departments or geneticists who have no information about when to treat children identified with the late-onset form of the disease.

Figure 1.

A Long Road

Priya Kishnani, MD, Division Chief for Medical Genetics at Duke University Medical Center in Durham, North Carolina, has twice nominated Pompe disease be added to RUSP, first in 2006, after the U.S. Food and Drug Administration approved the enzyme replacement therapy acid alpha-glucosidase as the first treatment for Pompe disease, and again in 2008, after data from newborn screening in Taiwan showed impressive results. The committee wanted data from the U.S. and more information about how screening could distinguish between the infantile and late-onset forms of the condition.

Last May, the DACHDNC based its approval on an evidence report by Alex R. Kemper, MD, MPH, MS, Associate Professor of Pediatrics, Duke University School of Medicine and Chair of the DACHDNC Condition Review Workgroup, which included evidence from Taiwan, U.S. epidemiologic data from the University of Washington in Seattle, and four months of Pompe screening in Missouri, currently the only state that screens newborns for the disease.

Dr. Kemper's report noted that newborn screening can improve outcomes because it can lead to earlier treatment. Data from Taiwan show that babies who received enzyme replacement therapy by six months of age reduced their risk of death by 95% and their risk of death or invasive ventilation by 87%. The treated babies' overall survival rate at 36 months of age was 72%, according to the report.

Importantly, specialists are better at treating the disease, especially in patients with infantile-onset disease who make no enzyme at all, known as being CRIM (cross-reactive immunologic material) negative, Dr. Kemper notes. These patients—who comprise about 25% of infant-onset cases—produce antibodies that neutralize the enzyme therapy.

Dr. Kishnani's own research has found that, in most cases, babies' CRIM status can be predicted from GAA mutations (Bali et al., 2012).

At Duke, geneticists can have mutations in hand within two days of getting a patient sample and can start enzyme therapy as well as a five-week course of chemotherapy, if needed, to prevent immune response in patients who are CRIM negative, says Dr. Kishnani.

Treatment with enzyme replacement therapy and low-dose chemotherapy has changed the outcome of CRIM-negative babies who usually die without therapy or become ventilator-dependent by 27.1 months of age, she adds.

While it's not possible to distinguish infantile from late-onset cases based on enzyme activity in newborn screening bloodspots, geneticists can spot infantile-onset cases upon confirmatory testing and clinical exam. “If there's heart involvement, it's the infantile form of the disease,” Dr. Kishnani notes.

Bumps in the Road

While having more states screen newborns for Pompe disease and other lysosomal storage disorders could result in life-saving care for children with the infantile form of the disorder, adding and maintaining screening for the condition has its challenges.

Prompt diagnosis of babies with both forms of the disorder might be a challenge in states that lack geneticists and specialists experienced with the conditions, says Scott M. Shone, PhD, Program Manager, Newborn Screening in the New Jersey Department of Health, Division of Public Health.

Likewise, financial issues come into play. Adding any condition to a state panel involves paying for proper equipment and reagents, time spent establishing quality assurance procedures, and staff training, Dr. Shone points out.

Another challenge is careful follow-up of children with the late onset form of the disorder. While there is good evidence that early enzyme therapy prevents muscle damage and improves outcomes for babies with infantile-onset Pompe disease, most patients with the late-onset form of the disease present with irreversible muscle damage, Dr. Kemper says, emphasizing that careful follow-up will allow researchers to figure out when to begin treatment. “You don't want to treat too early because enzyme therapy is expensive and involves a central line and infusions every two weeks,” he adds.

Drs. Shone, Kishnani, and Kemper, and Natasha Bonhomme, Vice President of Strategic Development for the Genetic Alliance in Washington, D.C., all emphasize that successful screening for Pompe disease requires cooperation between newborn screening programs and geneticists.

Geneticists not only give families accurate information and connect them to services, but play key roles in the long-term follow-up that can lead to new observations about natural history and better treatment, Bonhomme says.

Dr. Kemper urges geneticists to appropriately share information about patients with Pompe disease.

“Be a voice for collected data and make sure that newborn screening improves outcomes, as intended,” he adds. There will be lessons for other lysosomal storage disorders.”