Science News: Muscle Glycogen Accumulation May Precede Damage in Late-Onset Pompe Disease

Submitted by: Ben Becker, MD

Edited by: Rebecca O'Bryan, MD

Citation: Beha GH, Stemmerik MG, Boer VO, van der Ploeg AT, van der Beek NA, Andersen H, Marsman A, Jacobsen LN, Theunissen MTM, Petersen ET, Vissing J. Quantification of muscle glycogen distribution in Pompe disease using 7 Tesla ¹³C NMR spectroscopy. J Neurol Neurosurg Psychiatry. 2026 Feb 13;97(3):201-203. doi: 10.1136/jnnp-2025-336628. PMID: 41093637.

Late-onset Pompe disease (LOPD) is a lysosomal glycogen storage disorder caused by deficiency of acid α‑glucosidase, leading to progressive limb-girdle muscle weakness and characteristic early involvement of paraspinal and hamstring muscles. The mechanisms underlying this selective pattern of muscle degeneration remain unclear. Recent advances in high field ¹³C magnetic resonance spectroscopy (MRS) allow for noninvasive quantification of muscle glycogen content and may help clarify disease pathophysiology.

This cross-sectional observational study evaluated whether elevated glycogen levels, as measured by 7-tesla ¹³C MRS, are present in muscles typically affected early in LOPD prior to overt muscle wasting or fatty infiltration. 11 minimally affected patients with genetically confirmed LOPD and 16 age-, sex-, and BMI-matched healthy controls underwent a single MRS assessment of the lumbar paraspinal muscles, hamstrings, anterior thigh, and calf.

Compared with controls, patients with LOPD demonstrated significantly increased glycogen concentrations in the hamstring, lumbar, and anterior thigh muscles, while glycogen levels in the calf muscles were similar between groups. Although three LOPD patients exhibited marked fatty replacement of the lumbar musculature, fat fraction did not correlate with glycogen levels across muscle groups. Importantly, muscles known to undergo early degeneration in LOPD showed elevated glycogen despite minimal clinical involvement.

These findings suggest that excessive glycogen accumulation precedes fatty degeneration and clinical weakness in selectively vulnerable muscles in LOPD. Elevated intramuscular glycogen may therefore play a contributory role in downstream muscle pathology, potentially through mechanical disruption of muscle architecture or autophagy-related mechanisms. While limited by its cross-sectional design and small sample size, this study supports the utility of muscle glycogen quantification by MRS as a promising noninvasive biomarker for disease staging, prognosis, and assessment of treatment response in late-onset Pompe disease.

While a small cohort study with single point of evaluation, this interesting study assessed a novel technique in MRS to assess glycogen accumulation in muscle which is thought to be a driver of symptoms. The significantly higher glycogen accumulation, as assessed on MRS, in unaffected muscles that typically found to develop weakness would be suggestive of a plausible mechanism. Serial testing to confirm fatty replacement and symptoms in these areas would be useful, but overall this shows promise for a less invasive technique for future treatment trials. 

MRS-based assessment of glycogen accumulation represents a first‑in‑class biomarker for late‑onset Pompe disease (LOPD), offering both prognostic value and potential guidance for treatment response. As a non‑invasive alternative, MRS could ultimately substitute for muscle biopsy in therapeutic trials and serve as a meaningful pharmacodynamic marker for future drug development. This approach may also have broader implications for biomarker discovery across other lysosomal storage disorders.