Novel autophagic vacuolar myopathies: Phenotype and genotype features

Neuropathol Appl Neurobiol. 2021 Aug;47(5):664-678. doi: 10.1111/nan.12690. Epub 2021 Feb 1.

Abstract

Background: Autophagic vacuolar myopathies (AVMs) are an emerging group of heterogeneous myopathies sharing histopathological features on muscle pathology, in which autophagic vacuoles are the pathognomonic morphologic hallmarks. Glycogen storage disease type II (GSDII) caused by lysosomal acid α-glucosidase (GAA) deficiency is the best-characterised AVM.

Aims: This study aimed to investigate the mutational profiling of seven neuromuscular outpatients sharing clinical, myopathological and biochemical findings with AVMs.

Methods: We applied a diagnostic protocol, recently published by our research group for suspected late-onset GSDII (LO-GSDII), including counting PAS-positive lymphocytes on blood smears, dried blood spot (DBS)-GAA, muscle biopsy histological and immunofluorescence studies, GAA activity assay and expression studies on muscle homogenate, GAA sequencing, GAA multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES).

Results: The patients had a limb girdle-like muscular pattern with persistent hyperCKaemia; vacuolated PAS-positive lymphocytes, glycogen accumulation and impaired autophagy at muscle biopsy. Decreased GAA activity was also measured. While GAA sequencing identified no pathogenic mutations, WES approach allowed us to identify for each patient an unexpected mutational pattern in genes cooperating in lysosomal-autophagic machinery, some of which have never been linked to human diseases.

Conclusions: Our data suggest that reduced GAA activity may occur in any condition of impaired autophagy and that WES approach is advisable in all genetically undefined cases of autophagic myopathy. Therefore, deficiency of GAA activity and PAS-positive lymphocytes should be considered as AVM markers together with LC3/p62-positive autophagic vacuoles.

Keywords: AVM condition; GAA activity; autophagic myopathies; complex genetic profiling; genetic heterogeneity; muscle biopsy; vacuolated PAS-positive lymphocytes; whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Autophagy / physiology
  • Exome Sequencing / methods
  • Genotype*
  • Glycogen Storage Disease Type II / genetics
  • Glycogen Storage Disease Type II / pathology
  • Humans
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / pathology*
  • Lysosomes / metabolism
  • Muscular Diseases / genetics
  • Muscular Diseases / pathology*
  • Mutation / genetics
  • Phenotype*
  • alpha-Glucosidases / genetics
  • alpha-Glucosidases / metabolism

Substances

  • alpha-Glucosidases

Supplementary concepts

  • Vacuolar myopathy