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Novel autophagic vacuolar myopathies: Phenotype and genotype features

Filomena Napolitano1,2, Chiara Terracciano1,3, Giorgia Bruno1

  • 1Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter University Center for Research in Neurosciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Neuropathology and Applied Neurobiology
|January 4, 2021
PubMed
Abstract

Insights

Autophagic vacuolar myopathies (AVMs) are a group of muscle disorders. Whole exome sequencing revealed novel gene mutations in patients with AVMs, suggesting impaired autophagy can reduce GAA activity.

Area of Science:

  • Neurology
  • Genetics
  • Cell Biology

Background:

  • Autophagic vacuolar myopathies (AVMs) are a heterogeneous group of muscle disorders characterized by autophagic vacuoles.
  • Glycogen storage disease type II (GSDII), caused by lysosomal acid α-glucosidase (GAA) deficiency, is a well-characterized AVM.

Purpose of the Study:

  • To investigate the mutational profile of seven neuromuscular patients with clinical, myopathological, and biochemical similarities to AVMs.
  • To explore the genetic underpinnings of AVMs beyond known GAA mutations.

Main Methods:

  • A diagnostic protocol for late-onset GSDII (LO-GSDII) was applied, including PAS-positive lymphocyte counts, DBS-GAA assays, muscle biopsy analysis, and GAA sequencing.
  • Whole exome sequencing (WES) was employed to identify genetic variations in patients negative for pathogenic GAA mutations.

Main Results:

  • Patients presented with limb girdle-like muscle weakness, hyperCKaemia, vacuolated PAS-positive lymphocytes, glycogen accumulation, and impaired autophagy.
  • While GAA sequencing revealed no mutations, WES identified novel mutations in genes involved in the lysosomal-autophagic pathway.
  • Decreased GAA activity was observed, correlating with impaired autophagy.

Conclusions:

  • Reduced GAA activity can occur in conditions of impaired autophagy, highlighting a broader connection than previously understood.
  • WES is recommended for genetically undefined AVM cases to uncover novel genetic causes.
  • PAS-positive lymphocytes and decreased GAA activity are potential biomarkers for AVMs, alongside autophagic vacuoles.
Keywords:
AVM conditionGAA activityautophagic myopathiescomplex genetic profilinggenetic heterogeneitymuscle biopsyvacuolated PAS-positive lymphocyteswhole exome sequencing

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