Brain glycogen build-up measured by magnetic resonance spectroscopy in classic infantile Pompe disease

Classic infantile Pompe disease is caused by abnormal lysosomal glycogen accumulation in multiple tissues, including the brain due to a deficit in acid alpha-glucosidase. Although treatment with recombinant human acid alpha-glucosidase has dramatically improved survival, recombinant human acid alpha-glucosidase does not reach the brain, and surviving classic infantile Pompe patients develop progressive cognitive deficits and white matter lesions. We investigated the feasibility of measuring non-invasively glycogen build-up and other metabolic alterations in the brain of classic infantile Pompe patients. Four classic infantile patients (8-16 years old) and 4 age-matched healthy controls were scanned on a 7 T MRI scanner. We used T2-weighted MRI to assess the presence of white matter lesions as well as 1H magnetic resonance spectroscopy and magnetic resonance spectroscopy imaging to obtain the neurochemical profile and its spatial distribution, respectively. All patients had widespread white matter lesions on T2-weighted images. Magnetic resonance spectroscopy data from a single volume of interest positioned in the periventricular white matter showed a clear shift in the neurochemical profile, particularly a significant increase in glycogen (result of acid alpha-glucosidase deficiency) and decrease in N-acetyl-aspartate (marker of neuronal damage) in patients. Magnetic resonance spectroscopy imaging results were in line and showed a widespread accumulation of glycogen and a significant lower level of N-acetyl-aspartate in patients. Our results illustrate the unique potential of 1H magnetic resonance spectroscopy (imaging) to provide a non-invasive readout of the disease pathology in the brain. Further study will assess its potential to monitor disease progression and the correlation with cognitive decline. Classic infantile Pompe disease is caused by abnormal lysosomal glycogen accumulation in multiple tissues, including the brain. Current treatment does not reach the brain, and patients develop cognitive deficits and brain lesions. Najac et al. show the feasibility of using 1H magnetic resonance spectroscopy to directly measure glycogen in patients. Graphical Abstract