Late onset Pompe disease revealed by newborn screening

Geneticists seek to replicate results of Taiwan-based research in U.S.

Newborn screening prompts early detection of later-onset Pompe disease (PD) and allows monitoring and enzyme replacement therapy (ERT) before irreversible muscle damage occurs in older infants, Taiwanese researchers recently reported. Meanwhile, U.S.-based researchers are conducting their own pilot-based screening programs in hopes that the data collected from these efforts will convince policy makers to add PD to newborn screening panels.

In a paper posted online Jan. 14 in The Journal of Pediatrics, researchers led by Yin-Hsiu Chien, MD, PhD, a geneticist and pediatrician at the National Taiwan University Hospital, show that although newborn screening cannot differentiate between the most serious form of the disease and the later onset version, screening does detect infants with identified mutations and allow regular follow-up that catches the earliest manifestations of later-onset PD [Chien et al, 2011]. This process enables early ERT that maintains normal motor function.

Also known as glycogen storage disease type II or acid maltase deficiency, PD is a sometimes fatal lysosomal storage disorder with a wide spectrum of pheno-types. The rapidly progressive infantile onset form, which involves a thickening of heart muscle, is the most severe. Other forms cause muscle weakness and have been diagnosed at ages ranging from less than 1 year to 78 years.

Screening Success

The researchers screened 344,056 new-borns and identified 13 with later-onset PD, defined as deficient skin fibroblast GAA and 2 GAA gene mutations and no cardiomyopathy. The researchers monitored these infants' motor development and serum creatine kinase (CK) levels every 3 to 6 months.

During a follow-up period of up to 4 years, 4 patients with identified PD received treatment for hypotonia, muscle weakness, delayed developmental milestones/motor skills, or elevated creatine kinase levels starting at the ages of 1.5,14,34, and 36 months, respectively. Muscle biopsies from these patients revealed increased storage of glycogen and lipids.

According to the researchers, it may be possible to omit the later-onset subtypes during newborn screening by excluding those new-borns who do not have cardiomyopathy, but this strategy might miss patients who might benefit from treatment early in life.

Treatment Can Come Too Late

Dr. Chien and colleagues began studying PD screening because they had seen infants for whom ERT came too late to reverse cardiac muscle damage. “It is very difficult to detect Pompe disease before patients reach 3 to 4 months of age,” Dr. Chien says. A 2008 paper “proved our concept and showed that early diagnosis does improve the outcome of patients,” Dr. Chien adds.

Compared with the affected new-borns who were identified by newborn screening, older babies who started enzyme replacement therapy at 2.9 to 5 months had more severe symptoms, including cardiomegaly, left ventricular hypertrophy, and congestive heart failure, the 2008 paper shows. The researchers' analysis found that cases could have been detected by screening at the time of birth [Chien et al, 2008].

U.S. Screening

Before Chien's 2008 paper, clinicians thought diagnosing PD in children before the age of 6 months or before need for a ventilator was enough. “The 2008 paper and our clinical experience tells us that's too late,” says Priya S. Kishnani, MD, Chief of Medical Genetics at Duke University Medical Center.

The paper in part prompted Dr. Kishnani to nominate PD for recommendation by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) for addition to state newborn screening panels. The committee, however, did not recommend PD. An SACHDNC subcommittee's 2008 evidence review calls for more data on prevalence of infantile versus later onset forms of PD, the benefits and harms of detecting later onset disease during the newborn period, cost-effectiveness, ability of other labs to perform screening. It also calls for more data relating to false positives, which occurred at a relatively high rate in the 2008 study but not in the more recent one. The committee also told Dr. Kishnani it wanted data on screening within the U.S.

original image

U.S.-based researchers are conducting their own pilot-based screening programs for Pompe disease.

Noting that SACHDNC was set up in response to politically driven newborn screening decisions by states, Benjamin Wilfond, MD, Director of the Treuman Katz Center for Pediatric Bioethics at Seattle Children's Hospital, says lack of Pompe screening data from the U.S. may be significant because of the nation's unique healthcare system. “Something that gives benefit in 1 setting might not do so in another with a different structure,” he says. State data about newborn screening for PD might be more useful, he adds.

Homegrown Data

C. Ronald Scott, MD, Director of the University of Washington's Biochemical Genetics Clinic, is now running a pilot study of newborn screening for PD, Fabry disease, and MPS that he hopes will convince his state's newborn screening committee to add these disorders to its panel and perhaps provide data to sway the federal committee. The study has thus far tested bloodspots from 40,000 newborns.

In addition, since November 1, 2010, researchers involved in an Illinois pilot program have been screening newborns for PD and collecting data at the University of Chicago Medical Center and Northwestern Memorial Hospital. The program will expand statewide in June 2011, according to Claudia Nash, the state's administrator of genetics and newborn screening follow-up programs. State law mandates screening for PD and for Krabbe, Niemann-Pick, Fabry, and Gaucher diseases.

New state laws are prompting Missouri and New Mexico's preparations for PD, Krabbe, Gaucher, Niemann-Pick, and Fabry diseases in newborns. New York state, which currently screens newborns for Krabbe disease, is reportedly considering PD testing.

Whole genome sequencing, which many predict will become a newborn screening technology, will change debate over whether to test for particular disorder, Wilfond predicts. “When you can get all of a baby's genetic data at birth, the question will become what information to reveal to parents, and when,” he says.