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Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Late onset Pompe disease (LOPD) is a slowly progressive metabolic myopathy with variable clinical severity. The advent of enzyme replacement therapy (ERT) has modified the natural course of the disease, though the treatment effect on adult patients is modest compared to infants with the classic form. This study aims to describe the long-term clinical outcome of the Greek LOPD cohort, as assessed by 6 min walk test, muscle strength using MRC grading scale and spirometry. ERT efficacy was estimated using statistical methodology that is novel in the context of Pompe disease, which at the same time is well-suited to longitudinal studies with small samples and missing data (local non-linear regression analysis). Improvement over baseline was significant at 1 year for motor performance and muscle strength (p < 0.05), and at 2 years for FVC-U and FVC-S (p < 0.05). A subgroup analysis showed that the onset of the disease before adulthood (18 years), a male gender, and a latency of more than 2 years between the onset of symptoms and ERT administration are unfavorable prognostic factors. Conclusively, this study presents longitudinal data from the Greek LOPD cohort supporting previous observations, that therapeutic delay is related to worse prognosis and treatment effects may decline after several years of ERT., Competing Interests: Declaration of Competing Interest GPK and CP have received honoraria for lectures or educational seminars from Sanofi Genzyme. There are no other competing financial, professional, or personal interests that might have influenced the work described in this manuscript, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pompe disease is a rare autosomal recessive disorder characterized by the deficiency of acid α-glycosidase resulting in lysosomal accumulation of glycogen. The late-onset disease form is characterized by progressive skeletal and respiratory muscle dysfunction. In addition to the recently introduced enzyme replacement therapy (ERT), treatments such as protein-enriched diet and exercise training have been proposed, although little is known about their effectiveness on the physical condition of such patients. Aim of the present study was to investigate the effect of exercise training on muscular strength and body composition in five patients with late-onset Pompe disease receiving ERT. All subjects followed a 20 week lasting program of supervised aerobic and progressive resistance exercise training. Before and after the training period, body composition was determined with dual X-ray absorptiometry and isometric muscular strength was measured with a specialized load transducer. Functional capacity was assessed using the 6-min shuttle walk test. A significant increase in muscular strength (15-50% at various body parts, p<0.05) and 6-minute walking distance (203.8 ± 177 m before vs. 248.2 ± 184 m after, p<0.01) was observed after training, whereas total and lower extremities lean body mass did not change significantly. These results suggest that exercise training has a positive effect on muscular strength and functional capacity in patients on ERT with late-onset Pompe disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]