Abstract
Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Highlights
Pompe disease (OMIM 232300) is an autosomal recessive disease caused by a defect in the lysosomal alpha glucosidase due to bi-allelic pathogenic mutations in the alpha 1,4-glucosidase gene (GAA)
Infants with infantile onset Pompe disease (IOPD) are associated with pathogenic variants, e.g. c.525delT, c.2481+102_2646+13del, that affect both alleles severely, resulting in near absence of GAA enzyme activity (
Disturbed autophagy contributes to the muscle pathology and autophagic vacuoles (AV) are frequently present in muscle biopsies from patients with Pompe disease [21,24–29]
Summary
Pompe disease (OMIM 232300) is an autosomal recessive disease caused by a defect in the lysosomal alpha glucosidase due to bi-allelic pathogenic mutations in the alpha 1,4-glucosidase gene (GAA). Infants with infantile onset Pompe disease (IOPD) are associated with pathogenic variants, e.g. c.525delT, c.2481+102_2646+13del, that affect both alleles severely, resulting in near absence of GAA enzyme activity (G is the most common and is associated with a milder phenotype [9,11,12,15]. Histopathological changes were correlated with individual genotypes in 37 patients To our knowledge, this is the largest cohort of detailed muscle biopsy analysis in LOPD, and individual correlation of detailed muscle morphology with the GAA genotype has not been described before
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