Pompe Disease, DMD: Newborn Screening Proposed

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Proposals exploring the feasibility and advisability of implementating newborn screening for two disorders in MDA's program — Duchenne muscular dystrophy and Pompe disease — were presented to a federal advisory committee in a "virtual" meeting Jan. 31 and Feb. 1, 2013.

The audio and slide presentations of these two proposals are now available online without charge. Below are summaries of both the Pompe and Duchenne muscular dystrophy (DMD) proposals to the newborn screening advisory committee.

What is newborn screening?

In the United States, newborns are screened for a variety of diseases that can be detected at birth and for which early treatment — before obvious symptoms appear — is available and judged to be beneficial.

Each individual state decides which disorders it will screen for based on recommendations from the U.S. Department of Health and Human Services (HHS).

HHS recommendations are based in large part on the advice of the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) — the committee that heard the Pompe and DMD screening proposals outlined below.

Pompe newborn screening: ‘A question of days’

Pompe disease symptoms can begin at birth, or during childhood or adulthood, and can cause profound weakness of the skeletal and cardiac muscles. In the infantile form, the disease is often fatal within the first few months or years of life because of cardiac or respiratory muscle impairment. The late-onset form causes weakness of arms, legs, trunk and respiratory muscles.

Pompe, also known as acid maltase deficiency, is caused by a deficiency of the GAA (acid maltase) enzyme, leading to an accumulation of glycogen in cellular structures called lysosomes. Lifesaving enzyme replacement therapy (Myozyme) has been available for Pompe disease since 2006.

Pediatrician Alex Kemper from Duke University gave the Pompe disease presentation at the SACHDNC meeting on Jan. 31, 2013.

In addition to Kemper, Priya Kishnani, a pediatrician and medical geneticist at Duke University who has a special interest in Pompe disease and has received MDA funding to study it, also testified in favor of newborn screening so that treatment with enzyme replacement therapy can be started as early as possible.

"In the past, even for the infantile-form of the disease, we always took that starting babies [on enzyme replacement therapy] under 6 months of age was a good thing to do," Kishnani said. "It is true that the outcome was changed in the first months and years. But now we know that even this is too late. Some children are not doing as well as they should have done. In infantile Pompe disease, the need for treatment is not a question of weeks or months; it's a question of days. There's a difference between three days after diagnosis and eight days after diagnosis."

Summary of Pompe newborn screening proposal

Kemper made the following points in his presentation:

• Pompe-causing mutations are present in about one in 40,000 newborns.
• The infantile-onset form of the disease affects about one in 133,000 infants. The late-onset form of the disease affects from one in 57,000 people, to one in 26,466 people.
• The median age for diagnosis of infantile Pompe disease is 4.7 months. Without treatment, the median age of death in infantile Pompe disease is 8.7 months.
• Diagnosis involves detecting reduced GAA enzyme activity in white blood cells, skin cells or muscle cells; activity of less than 1 percent of normal is associated with infantile-onset Pompe disease.
• In a newborn screening program for Pompe disease conducted in Taiwan, 31 babies were identified as having GAA enzyme abnormalities, out of 473,738 newborns screened.
• The Taiwan experience shows a dramatic improvement in survival rates for babies with Pompe disease born in the post-treatment era compared to those born in the pre-treatment era.
• Early detection of Pompe disease improves outcomes.
• The psychosocial implications for parents of early identification of late-onset Pompe disease are unclear.
• It remains unclear whether all patients receiving an early diagnosis of Pompe disease would be assured access to enzyme replacement therapy.

The SACHDNC may make a decision about whether to add Pompe disease to the list of conditions for which screening is recommended either prior to or after the next meeting of the committee, tentatively scheduled for May 2013.

Two-step DMD screening proposal

Neurologist Jerry Mendell, a longtime MDA research grantee and co-director of the MDA Clinic at Nationwide Children's Hospital in Columbus, Ohio, gave the DMD presentation at the second day of the SACHDNC meeting, Feb. 1, 2013.

Mendell has a strong interest in newborn screening for DMD. In January 2012, he and several colleagues published a paper describing a plan for large-scale implementation of a two-stage newborn screening process for DMD.

The two-step process involves screening all newborn babies for markedly elevated levels of blood creatine kinase (CK), an enzyme that leaks out of damaged muscle cell. In the first step, a dried blood spot (obtained by pricking the infant’s heel) would be tested for CK. If the infant has a very high CK level, the same dried blood spot would be used to conduct DNA testing for DMD-causing mutations in the dystrophin gene.

At an MDA symposium on newborn screening last fall, Mendell presented more details about his proposed plan to a blue-ribbon panel of physicians and researchers, patient advocacy groups, federal agencies, and others, including members of the SACHDNC.

Summary of DMD proposal for newborn screening

Mendell made the following points in his presentation to the SACHDNC in February:

• DMD is caused by the absence of the dystrophin protein in muscle tissue, which results in scar formation and loss of muscle.
• Prior to the use of corticosteroid medications to treat DMD — the "pre-steroid era" — boys with the disorder were expected to lose the ability to walk between 9.5 and 10 years, to develop a spinal curvature by age 12 and to die at an average of 19 years of age.
• The mean age of diagnosis of DMD is 4 years, 9 months.
• Corticosteroids — also known as glucocorticoids — are now an established standard of care for DMD.
• In a 14-year study, treatment of DMD with corticosteroids starting as early as 2.4 years of age permitted walking beyond age 16, while untreated patients lost ambulation by age 10.
• Experimental molecular therapies are now in the pipeline that may effectively treat specific DMD dystrophin mutations, and it is likely that individuals with DMD would benefit from early treatment with these.
• The two-tier system of assessing CK level and then performing DNA testing only on those with markedly elevated CK appears to be a highly sensitive and specific method of screening for DMD.
• Early treatment with corticosteroids is effective in prolonging walking and delaying spinal curvature development (scoliosis).
• Early diagnosis would help DMD-affected families avoid the "diagnostic odyssey" — visiting multiple physicians and facilities over months to years — that frequently occurs with this disorder.

Mendell said the goal of his presentation was to promote discussion of DMD newborn screening, and that he would like to come back to the SACHDNC at a later time to make a "formal nomination" to add DMD to the list of conditions recommended for newborn screening.

The committee was receptive to this idea.

Audio and slide presentations

Audio of both Kemper’s and Mendell’s presentations, plus the slides they showed the committee, can be accessed on the SACHDNC site (select Twenty-Ninth Meeting and then Audio Archives and Transcripts).

The Pompe presentation can be found in the afternoon session of Day 1 (Jan. 31, 2013) at about two minutes into the meeting.

The DMD presentation can be found on Day 2 (Feb. 1, 2013).

Next steps

The next (30th) meeting of the SACHDNC is tentatively scheduled for May 16-17, 2013. The 31st meeting is tentatively scheduled for Sept. 19-20, 2013.