Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Neurology. 2011 Nov 29;77(22):1951-9. doi: 10.1212/WNL.0b013e31823a0ebe. Epub 2011 Nov 16.


Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM.

Methods: Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy.

Results: We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles.

Conclusions: FHL1 dystrophies can be associated with MFM pathology. Mutations in the LIM2 domain are associated with reducing bodies composed of distinct tubulofilaments. A mutation extraneous to LIM domains resulted in a mild late-onset phenotype with MFM pathology but no reducing bodies.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Cohort Studies
  • Female
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics*
  • LIM Domain Proteins / chemistry
  • LIM Domain Proteins / deficiency
  • LIM Domain Proteins / genetics*
  • Male
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology*
  • Muscle Proteins / chemistry
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Dystrophies / diagnosis
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / pathology*
  • Mutation / genetics
  • Myofibrils / genetics
  • Myofibrils / pathology*
  • Young Adult


  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins