Diffusion tensor imaging of the brain in Pompe disease

Abstract

Enzyme replacement therapy has drastically changed prospects of patients with Pompe disease, a progressive metabolic myopathy. As classic infantile patients survive due to treatment, they exhibit progressive white matter abnormalities, while brain involvement in late-onset patients is not fully elucidated. To study the underlying microstructure of white matter, we acquired structural (T1, T2, FLAIR) and diffusion tensor imaging (DTI) of the brain in 12 classic infantile patients (age 5–20 years) and 18 late-onset Pompe patients (age 11–56 years). Structural images were scored according to a rating scale for classic infantile patients. Fractional anisotropy (FA) and mean diffusivity (MD) from classic infantile patients were compared to a reference population, using a Wilcoxon signed-rank, one sample test. Effect sizes (Hedges’ G) were used to compare DTI metrics across different tracts. For late-onset patients, results were compared to (reported) tractography data on normal aging. In classic infantile patients, we found a significant lower FA and higher MD (p < 0.01) compared to the reference population. Large-association fibers were most severely affected. Classic infantile patients with advanced white matter abnormalities on structural MRI showed the largest deviations from the reference population. FA and MD were similar for younger and older late-onset patients in large WM-association fibers. We conclude that, while no deviations from typical neurodevelopment were found in late-onset patients, classic infantile Pompe patients showed quantifiable, substantially altered white matter microstructure, which corresponded with disease stage on structural MRI. DTI holds promise to monitor therapy response in future therapies targeting the brain.

Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning

“…9 Cognition, specifically performance IQ and processing speed are a measure of connectivity and cooperation between different areas of the brain. A recent study that used diffusion tensor imaging (DTI) to quantify white matter abnormalities in Pompe disease showed 45 that large WM-association tracts connecting the frontal, parietal, temporal, and occipital lobes were the most severely affected tracts and that further progression of abnormalities through different areas of the brain (i.e., a higher score on the 12-point rating scale) is related to further damage of early affected white matter fibers, specifically association tracts, which connect different areas of the cortex. We therefore hypothesize that progressive damage of large association tracts leads to the increasingly slow information processing, reflected by the significant decrease of processing speed found in this study.…”

Gene therapy for glycogen storage diseases

“…Immunomodulation strategies have since been employed to induce immune tolerance to ERT in affected individuals who are cross‐reactive immunologic material (CRIM)‐negative and would otherwise develop an IgG antibody immune response to the ERT, leading to a deeper understanding of the natural history of CRIM‐negative individuals that otherwise would have succumbed to the disease despite ERT 88 . ERT for Pompe disease has drastically improved the survival rates in affected individuals, 89–93 resulting in the emergence of new phenotypes, including variable central nervous system involvement in children with IOPD 94–101 and progression of disease in individuals with LOPD treated with ERT, including respiratory function and functional outcomes 89,102,103 . Furthermore, the addition of Pompe disease to newborn screening (NBS) programs in Taiwan in 2005 104 and the United States Recommended Uniform Screening Panel in 2015 has permitted early diagnosis of patients with IOPD, as well as those with LOPD who otherwise appear healthy 105 .…”

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“…Combining therapies may also be considered for optimal outcomes, such as using next-generation ERTs for peripheral symptoms and intrathecal administration of gene therapy for neuronal aspects. Continual development of more effective therapies is necessary to properly manage Pompe disease and provide treatment options for patients [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57].…”