2026-06-08 | Polypharmacy's paradox: accelerated decline in a rare case of Lafora body disease.
Lafora body disease (LBD) is a rare autosomal recessive progressive myoclonic epilepsy characterized by neurodegene-ration due to an intracellular accumulation of poorly branched polyglucosan inclusions. Effective pharmacological management remains challenging due to the risk of drug-induced exacerbation of symptoms and adverse interactions. We present the case of an 18-year-old male with intractable seizures, myoclonus, and cognitive regression. Electroencephalogram showed frequent generalized polyspike discharges, and histopathology confirmed Lafora bodies. The patient was initially prescribed a broad polypharmacy regimen including sodium valproate, carbamazepine, phenytoin, and phenobarbitone - leading to detrimental pharmacokinetic and pharmacodynamic interactions, worsening his neurological status. A stepwise revision with withdrawal of contraindicated agents and rational introduction of levetiracetam, clobazam, and perampanel improved seizure control and alertness. This case highlights the hazards of unstructured polypharmacy in LBD and stresses the need for individualized pharmacotherapy. Novel disease-modifying options like metformin, targeting glycogen metabolism, offer future therapeutic potential in altering disease trajectory.
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2026-03-28 | SINEUP-Mediated Overexpression of Endogenous α-Amylase as a Therapeutic Approach in Lafora Disease.
Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. This study aimed to evaluate the feasibility of promoting Lafora body degradation by increasing the protein levels of human pancreatic amylase, a glycogen-degrading enzyme, through the SINEUP approach. Methods: Two SINEUP constructs specifically targeting human pancreatic amylase were designed and tested in continuous tumor-derived cell lines of central nervous system origin, as well as in primary fibroblasts obtained from a patient with Lafora disease. Human pancreatic amylase protein and mRNA levels were assessed to determine the specificity of SINEUP-mediated regulation. Enzymatic activity assays were performed to evaluate functional protein upregulation, and intracellular glycogen content was measured in patient-derived fibroblasts. Results: Both SINEUP constructs significantly increased human pancreatic amylase protein expression without affecting mRNA levels, confirming a post-transcriptional mechanism of action. The elevated protein levels were associated with a significant increase in enzymatic activity. In primary fibroblasts derived from a Lafora disease patient, enhanced amylase expression correlated with a marked reduction in intracellular glycogen content. Conclusions: These findings provide proof of concept that SINEUP-mediated upregulation of glycogen-degrading enzymes may represent a viable therapeutic strategy to counteract Lafora body accumulation. Further studies are warranted to assess the efficacy, safety, and translational potential of this approach, particularly in relevant animal models of Lafora disease.
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2025-12-25 | The biochemical dynamics of the glycogen phosphatase laforin directly impact brain metabolism.
Laforin is the only known glycogen phosphatase. Mutations in the laforin gene lead to the fatal childhood dementia and progressive myoclonic epilepsy known as Lafora disease (LD). A hallmark of LD is aberrant, cytoplasmic, glycogen-like aggregates known as Lafora bodies. Surprisingly, recent reports indicate that overexpression of a phosphatase-deficient laforin mutant, with the catalytic cysteine mutated to serine (LCS), prevented the formation of Lafora bodies in a laforin KO mouse model. This finding led to questions regarding the biological relevance of laforin phosphatase activity and its role in LD etiology. In this study, we defined the in vitro and in vivo effects of the LCS mutation. LCS protein lacks catalytic activity but exhibits significantly higher binding to phosphate and long glucan chains compared with WT laforin. In addition, LCS exhibits altered dynamics via hydrogen-deuterium exchange mass spectrometry and interacts more robustly with its binding partners malin and protein targeting to glycogen. We demonstrate that these altered dynamics result in aberrant retention of the LCS protein in the brain of the LCS knock-in mouse model, compared with laforin levels in WT mice. To examine the metabolic consequences of these biophysical changes, we compared the brain metabolomic phenotypes of LCS mice to WT and laforin KO mice. Furthermore, LCS mice display a distinct and significant global perturbation in metabolism. These results indicate a key signaling role for glycogen phosphorylation in glycogen metabolism, revealing an important biological role for laforin catalytic phosphatase activity.
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