Early Treatment in Infantile Pompe Helps Girl Walk, Have Healthy Heart

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A toddler girl with infantile-onset Pompe disease is able to walk independently and lives with a healthy heart after receiving treatment as a baby, according to researchers who used a combination of early enzyme replacement therapy (ERT) and immunotherapy.

Immunotherapy helped tone down the body’s immune response to ERT in the little girl, who now shows normal cardiac function, the team said.

“There is still an urgent need for better and more potent therapies for Pompe disease patients especially those with … infantile onset. … In the meantime, we describe a personalized approach aiming to better exploit more fully the current treatments,” they wrote.

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The report, “A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation,” was published in the journal Molecular Genetics and Metabolism Reports.

Pompe disease occurs when there is a mutation in the gene that contains the instructions to make alpha-glucosidase (GAA), a protein that breaks down a large sugar molecule called glycogen into smaller units. When the protein is not built correctly, it does not get its job done as well or at all, and glycogen builds up inside cells. Too much glycogen causes problems, especially in the heart and other kinds of muscle.

Enzyme replacement therapy for Pompe

In patients with infantile-onset Pompe, the disease symptoms begin in early infancy, usually around 4 months of age — hence its name. Babies typically experience muscle weakness that can make it hard to feed, and grow slowly. They also develop breathing and heart problems.

ERT — in which the missing enzyme is administered into a person’s bloodstream — can help patients with infant-onset Pompe disease live longer, healthier lives. It works by providing patients with the GAA they are lacking. But some individuals may develop antibodies in response to ERT. The antibodies block the man-made GAA and may make the therapy less effective.

This is particularly worrying for those patients who do not make any working GAA at all — a condition called CRIM negative. These people are more likely to develop antibodies. However, some medications may ease this immune response to ERT.

Now, a team of scientists in the U.S. and Israel reported the case of a baby girl with infantile-onset Pompe disease who received early ERT (alglucosidase alfa, marketed in the U.S. as Lumizyme) plus immunotherapy.

She and her twin sister were born early (prematurely) to two first-degree cousins. The infant developed respiratory distress syndrome, which occurs when the lungs have not developed fully at birth, and required supplemental oxygen to help with breathing until she turned 5 weeks.

At the age of 4 months, she was admitted to the hospital with a fever, cough, and difficulties breathing and feeding. A physical examination revealed low muscle tone and a heart murmur, an unusual sound that the blood can make as it flows through the heart.

A closer look at the heart revealed hypertrophic cardiomyopathy, which occurs when the heart’s muscle wall becomes overgrown, making it harder to pump blood from the heart out to the body.

She was placed on supplemental oxygen and fed via a nasogastric tube to carry food through the nose directly to the stomach. She also was started on propranolol, a beta-blocker used to treat heart disease.

A blood test revealed high levels of liver transaminases, which indicated damage to the liver, and creatine kinase, which meant damage to the heart and muscles.

Based on these findings, doctors suspected infantile-onset Pompe disease and ordered a genetic test to look for mutations in the GAA gene.

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The testing revealed a disease-causing c.2560C>T mutation in both copies of the GAA gene. The mutation results in no GAA being made and no GAA enzyme activity being detected.

Of note, the child’s twin sister also was tested. She was found to have the same mutation in one of the two copies of the GAA gene, but she had normal enzyme activity.

Early, and personalized, treatment

A diagnosis of infantile-onset Pompe disease was made for this baby, and the girl was started on ERT at 20 milligrams per kilogram (mg/kg) every other week. Then, within a month, the dosage was increased to 40 mg/kg every week.

For the first five weeks, she also received rituximab and methotrexate to bring down the numbers of certain immune cells. In addition, she received intravenous immunoglobulin (IVIG) to provide the ability to fight off infections until the pool of immune cells was restored after therapy. The combination has been found to help tone down the immune response to ERT.

“She displayed gradual improvement of motor abilities, began feeding well, and gained weight normally,” the scientists wrote. At the age of 10 months, her heart looked healthy and she stopped taking propranolol.

When she turned 1, she was given off-label albuterol to make ERT even more effective by increasing the uptake of GAA by muscles.

Every month, her blood was tested to look for the presence of antibodies against GAA. They were absent during the first four months of ERT, but peaked about one month later. To lower the production of antibodies, she was given bortezomib and continued with the combination of rituximab, methotrexate, and IVIG on a monthly basis. 

As the antibody levels dropped, immunotherapy was stopped. Her blood levels of creatine kinase also dropped, and she started to walk at 20 months. At her last visit, at the age of 30 months, she could walk alone, run — though with some clumsiness, according to researchers — and climb stairs with help.

The use of high-dose ERT along with immunotherapy “was safe and effective in our CRIM-negative IOPD patient resulting in a favorable outcome,” the team concluded.