Asymmetric muscle weakness due to ACTA1 mosaic mutations

Neurology. 2020 Dec 15;95(24):e3406-e3411. doi: 10.1212/WNL.0000000000010947. Epub 2020 Sep 28.

Abstract

Objective: To characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.

Methods: The patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy.

Results: Both patients presented with early-onset hypotonia, delayed motor milestones, scoliosis, and reduced pulmonary function. Patient P1 manifested unilateral muscle weakness exclusively affecting the left side of the body; the asymmetry was less pronounced in patient P2. Muscle biopsies from both patients showed nemaline rods as the main histopathologic hallmark, and MRI revealed major fatty infiltrations in selective head, proximal, and distal muscles, correlating with the degree of muscle weakness asymmetry. Exome sequencing on blood DNA from both patients identified de novo ACTA1 missense mutations in a small number of reads, suggesting mutation mosaicism. Subsequent Sanger sequencing confirmed the presence of the mutations on muscle DNA, while they were barely detectable on blood DNA.

Conclusions: De novo mutations can occur anytime during embryonic development and may result in a mosaic pattern of affected cells and tissues and lead to the development of an asymmetric clinical picture. The present study points out that mosaic mutations might not be easily detectable on leukocyte DNA and thereby escape routine genetic analysis, and possibly account for a significant number of molecularly undiagnosed patients.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics*
  • Biopsy
  • Child
  • Electromyography
  • Humans
  • Magnetic Resonance Imaging
  • Mosaicism*
  • Muscle Weakness / diagnosis*
  • Muscle Weakness / genetics*
  • Muscle Weakness / physiopathology*
  • Mutation, Missense
  • Pedigree
  • Whole Exome Sequencing

Substances

  • ACTA1 protein, human
  • Actins