Early treatment for Pompe disease helps girls walk and have healthy hearts

According to researchers who used a start combination enzyme replacement therapy (ERT) and immunotherapy.

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

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

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The report, “A favorable outcome in an infant-onset Pompe patient with negative cross-reactive immunological material (CRIM) disease with high-dose enzyme replacement therapy and adjusted immunomodulationwas 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 protein isn’t built properly, it doesn’t do its job as well or at all, and glycogen builds up inside cells. Too much glycogen causes problems, especially with the heart and other types of muscles.

Enzyme replacement therapy for Pump

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

ERT – in which the missing enzyme is delivered into a person’s bloodstream – may help patients with infantile Pompe disease live longer, healthier lives. It works by providing patients with the GAA they lack. But some people can develop antibodies in response to ERT. Antibodies block artificial GAA and can make therapy less effective.

This is particularly concerning for patients who produce no functional GAAs – a condition called negative CRIM. These people are more likely to develop antibodies. However, certain drugs can dampen this immune response to ERT.

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

She and her twin sister were born early (prematurely) to two first cousins. The infant developed respiratory distress syndrome, which occurs when the lungs had not fully developed at birth, and needed supplemental oxygen to help him breathe until he was 5 weeks old.

When she was 4 months old, she was admitted to hospital with fever, cough and difficulty breathing and eating. A physical exam revealed weak muscle tone and a heart murmur, an unusual sound that blood can make as it travels through the heart.

Further examination of the heart revealed hypertrophic cardiomyopathy, which occurs when the muscular wall of the heart becomes overgrown, making it harder for blood to pump from the heart to the body.

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

A blood test showed elevated levels of liver transaminases, which indicated liver damage, and creatine kinase, which meant heart and muscle damage.

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

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Testing revealed a pathogenic c.2560C>T mutation in both copies of the GAA embarrassed. The mutation results in no GAA being made and no GAA enzyme activity being detected.

It should be noted that the child’s twin sister was also tested. She turned out 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

This baby was diagnosed with infantile-onset Pompe disease, and the girl was put on ERT at 20 milligrams per kilogram (mg/kg) every two weeks. 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 lower the number of certain immune cells. In addition, she received intravenous immunoglobulins (IVIg) to allow her to fight infections until the immune cell pool is restored after treatment. The combination has been found to help dampen the immune response to ERT.

“She showed gradual improvement in motor skills, began to eat well and gained weight normally,” the scientists wrote. When she was 10 months old, her heart seemed healthy and she stopped taking propranolol.

When she was 1 year old, she was given off-label albuterol to make ERT even more effective by increasing muscle uptake of GAA.

Every month, his blood was tested for the presence of anti-GAA antibodies. They were absent for the first four months of ERT, but peaked about a month later. To reduce antibody production, she received bortezomib and continued the combination of rituximab, methotrexate and IVIG on a monthly basis.

When antibody levels dropped, immunotherapy was stopped. Her blood creatine kinase levels also dropped and she started walking at 20 months. When she was last seen, at 30 months old, she could walk on her own, run — albeit with some clumsiness, the researchers said — and climb stairs with help.

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

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