ERT Fails to Prevent Long-Term Effects of Infantile Pompe Disease to Brain, Study Shows

ERT Fails to Prevent Long-Term Effects of Infantile Pompe Disease to Brain, Study Shows

Treatment with enzyme replacement therapy can help children with classic infantile Pompe disease reach adulthood. However, it fails to prevent the long-term effects of the disease in the brain and consequent   development of intellectual disabilities, a study shows.

The study titled “Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain,” was published in the journal Developmental Medicine & Child Neurology.

Pompe disease is characterized by genetic mutations in the GAA gene, which lead to defective production of the alpha-glucosidase enzyme and consequent accumulation of glycogen, a complex sugar molecule, in cells.

Enzyme replacement therapy (ERT) significantly improves survival, cardiac, and motor outcomes for  infantile Pompe patients. However, ERTs cannot pass the blood-brain-barrier and effectively prevent the accumulation of glycogen in the central nervous system.

A team led by researchers at Erasmus Medical Center evaluated the long-term impact of ERT treatment in the neuropsychological development of older patients with classic infantile Pompe disease.

They reviewed the clinical records of 11 patients who started ERT at ages from three days to eight months. Three of the patients died at the respective ages of 4 years 4 months, 4 years 5 months, and 15 years 7 months. The remaining patients were alive at the time of the study, with ages ranging from 7 years 7 months to 17 years 8 months.

Analysis of brain structures through magnetic resonance imaging (MRI) revealed that all patients had some abnormalities. The first changes were reported by the age of 2 years 8 months, and additional white-matter abnormalities were reported after the age of 8 years 10 months, which were found to progress in follow-up scans.

“Although there seemed to be a characteristic pattern of [brain] involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development,” the researchers wrote.

The patients were given intelligence tests, which revealed that during the time period covered by the study the patients had IQ scores from less than 45 to 121. While some patients’s tests confirmed stable, normal intelligence, others were found to have mild developmental delay to intellectual disability. Patients who had additional white-matter abnormalities had poorer performance in IQ tests.

“It seems the brain is now becoming the next puzzle in the treatment,” the researchers said.

“We advise expansion of follow-up programs to capture central nervous system/brain involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment,” they wrote. Also, the team suggests the “inclusion of the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease.”

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