title: Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy.
abstract: 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.
authors.affiliation: Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA. selcen.duygu@mayo.edu
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.forename: Mark B
authors.initials: MB
authors.lastname: Bromberg
authors.forename: Steven S
authors.initials: SS
authors.lastname: Chin
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D060588:LIM Domain Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D009124:Muscle Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009210:Myofibrils / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins
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