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Abstract

Lafora disease is a fatal teenage-onset progressive myoclonus-epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease. Mouse work, however, has not yet revealed the mechanisms of polyglucosan generation, and few in vivo human studies have been performed. Here, non-invasive in vivo magnetic resonance spectroscopy (1H and 31P) was applied to test scan feasibility, and assess neurotransmitter balance and energy metabolism in Lafora disease toward a better understanding of pathogenesis. Macromolecule-suppressed GABA-edited 1H magnetic resonance spectroscopy and 31P magnetic resonance spectroscopy at 3 Tesla and 7 Tesla, respectively, were performed in 4 Lafora disease patients and a total of 21 healthy controls (12 for the 1H- magnetic resonance spectroscopy and 9 for the 31P-magnetic resonance spectroscopy). Spectra were processed using in-house software and fit to extract metabolite concentrations. From the 1H spectra, we found 33% lower GABA concentrations (p = 0.013), 34% higher glutamate + glutamine concentrations (p = 0.011), and 24% lower N-acetylaspartate concentrations (p = 0.0043) in Lafora disease patients compared to controls. From the 31P spectra, we found 34% higher phosphoethanolamine concentrations (p = 0.016), 23% lower nicotinamide adenine dinucleotide concentrations (p = 0.003), 50% higher uridine diphosphate glucose concentrations (p = 0.004) and 225% higher glucose 6-phosphate concentrations in Lafora disease patients versus controls (p = 0.004). Uridine diphosphate glucose is the substrate of glycogen synthase and glucose 6-phosphate is its extremely potent allosteric activator. The observed elevated uridine diphosphate glucose and glucose 6-phosphate levels are expected to hyperactivate glycogen synthase and may underlie the generation of polyglucosans in Lafora disease. The increased glutamate + glutamine and reduced GABA indicate altered neurotransmission and energy metabolism, which may contribute to the disease’s intractable epilepsy. These results suggest a possible basis of polyglucosan formation and potential contributions to the epilepsy of Lafora disease. If confirmed in larger human and animal model studies, measurements of the dysregulated metabolites by magnetic resonance spectroscopy could be developed into non-invasive biomarkers for clinical trials.