2026-06-12 | TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.

Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking. We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme. Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme. These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.

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2026-05-15 | Combined omalizumab and desensitization to control IgE-mediated hypersensitivity in enzyme replacement therapy for late-onset Pompe disease.

Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50% of the target dose and escalating stepwise to the full therapeutic dose, resulting in uninterrupted treatment. Follow-up showed stable neuromuscular and respiratory function, progressive decline in BAT reactivity, and improved quality of life. This case highlights the critical role of BAT in diagnosing and monitoring IgE-mediated HSRs, the efficacy of individualized desensitization protocols, and the utility of omalizumab as an adjunctive therapy in refractory cases. In rare diseases like Pompe, documenting such integrated allergological strategies provides practical guidance for maintaining access to life-prolonging therapy and offers a reproducible framework for managing complex allergic complications.

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2026-05-14 | Clinical, pathological and genetic features as well as follow-up of 68 patients with late-onset Pompe disease: a single-center retrospective study.

Pompe disease is a muscular lysosomal storage disorder characterized by autosomal recessive inheritance and caused by deficiency of the acid alpha-glucosidase (GAA) enzyme. Late-onset Pompe disease (LOPD) exhibits heterogeneous clinical presentations, which are influenced by the type of GAA mutation and residual enzyme activity. In this study, we conducted a retrospective analysis of 68 Chinese LOPD patients over a 17-year period at a single center to delineate the real-world disease status and survival outcomes. Among the 47 patients who received enzyme replacement therapy (ERT), the mortality rate was 6.4%, compared to 57.1% in the 21 patients who did not receive ERT. Muscle pathology analysis revealed that glycogenin accumulation appears earlier than autophagy marker, but this finding is exploratory and requires validation in larger studies. The severity of muscle pathology correlated with lower body mass index (BMI), shorter 6-min walk test (6MWT) and spinal curvature abnormalities. The most frequent GAA gene mutation identified was c.2238G > C (p.W746C), present in 43.3% of patients. In an exploratory subgroup analysis (n = 10), patients who initiated ERT shortly after diagnosis exhibited greater improvements in muscle strength and 6MWT results compared to those who started treatment later; however, the small sample size precludes definitive conclusions. In summary, our exploratory findings hypothesize that glycogenin may be an early pathological marker, but this requires prospective validation. ERT was associated with higher survival probability in this cohort, although survival bias limits causal inference. Earlier ERT initiation showed an association with better functional outcomes in a small subgroup. Lower BMI, shorter 6MWT, and spinal curvature abnormalities correlated with more severe muscle pathology in univariate analyses. All findings should be interpreted as hypothesis-generating due to study limitations.

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