Infantile Pompe brain changes may begin long before signs appear
Study findings highlight need for therapies targeting central nervous system
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Changes in the brain and spinal cord may begin early in children with classic infantile-onset Pompe disease, years before they become apparent on brain scans, blood tests, or cognitive assessments, according to a review of data from published studies.
Researchers found widespread buildup of glycogen — the complex sugar that accumulates in Pompe disease, particularly in skeletal and heart muscle — and other abnormalities across the central nervous system (CNS), which comprises the brain and spinal cord, in children who died at a very early age. CNS abnormalities were also found in a small number of children who had received enzyme replacement therapy (ERT), the standard treatment for Pompe disease.
Yet signs of CNS involvement detectable through brain scans, blood biomarkers, and cognitive assessments tend to emerge only years later among children living with Pompe disease, researchers noted.
“These observations underscore the need for systematic, longitudinal monitoring of affected patients, including neurological examination, cognitive assessment, brain MRI, and the development of reliable biomarkers of CNS disease,” researchers wrote. “Future therapies will need to target not only skeletal muscle but also the … nervous system.”
The study, “Central nervous system histopathological findings in classic infantile Pompe disease: a systematic review with clinical relevance,” was published in the Journal of Neurology.
CNS involvement in infantile Pompe largely unaddressed
Pompe disease is caused by genetic mutations that result in little or no functional acid alpha-glucosidase (GAA), an enzyme needed to break down glycogen inside cells. Without enough GAA, glycogen accumulates to toxic levels in tissues throughout the body, particularly in skeletal and heart muscle.
Classic infantile-onset Pompe disease is the most severe form of the disease. Symptoms, including progressive, generalized muscle weakness and cardiomyopathy, or disease of the heart muscle, usually emerge during the first months of life. Without treatment, it typically leads to premature death within the first year of life.
ERT, which provides the body with a working version of the GAA enzyme, has dramatically improved survival. However, the treatment does not meaningfully cross the blood-brain barrier, a protective membrane that regulates which substances can pass from the bloodstream into the brain, leaving CNS involvement largely unaddressed.
As new therapies that may cross the blood-brain barrier are being developed, researchers in the Netherlands sought to better understand which regions and cell types of the CNS are affected in classic infantile-onset Pompe disease.
They systematically reviewed published studies up to December 2025 that examined brain and spinal cord tissue collected from children who had died from the disease.
The final analysis included 39 studies comprising 49 children, only seven of whom had received ERT. The median age at death was 6 months among untreated children and 12 months among those treated with ERT.
Abnormalities found throughout central nervous system
Overall, tissue abnormalities were found throughout the CNS, although their severity varied considerably depending on the brain region and type of cell involved.
The cerebral and cerebellar white matter, which contains nerve fibers that allow different parts of the nervous system to communicate, and the globus pallidus and dentate nucleus — brain regions involved in controlling and coordinating movement — were among the most frequently affected areas.
Motor nuclei in the brainstem and nerve cells (neurons) in the anterior horn of the spinal cord were also commonly affected. These neurons help control movement by sending signals to muscles that make them contract.
The abnormalities largely involved glycogen buildup within neurons and glial cells, which support and protect neurons. Among the glial cells, astrocytes were particularly affected, especially in the white matter. Glycogen accumulation was sometimes accompanied by cell swelling or damage and gliosis, a reactive change in glial cells in response to damage.
[The findings indicate] that glycogen accumulation in classic infantile Pompe disease affects the CNS in a region- and cell-specific manner.
Similar CNS abnormalities were also found in the seven children who had received ERT. However, the researchers cautioned against drawing firm conclusions about ERT’s effects on CNS involvement because of the small number of treated children and their relatively young age at death.
Together, the findings indicate “that glycogen accumulation in classic infantile Pompe disease affects the CNS in a region- and cell-specific manner,” the researchers wrote.
When the researchers compared these tissue findings with measures of CNS involvement in people living with Pompe disease, they found a striking difference in timing. Tissue abnormalities were already present during early infancy, while signs of CNS involvement generally became detectable on brain imaging, in blood biomarkers, and through cognitive assessments only years later.
Brain MRI abnormalities typically emerge around ages 2 to 3, followed by changes in blood biomarkers associated with nervous system damage from around age 5. Cognitive problems, including slower processing speed and progressive cognitive decline, generally become measurable around ages 8 to 10.
Despite the study’s limitations, the findings suggest that CNS involvement may evolve for years before becoming detectable with current clinical tools, supporting the need for long-term neurological monitoring, better biomarkers of CNS disease, and treatments capable of addressing disease beyond skeletal and heart muscle.
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