title: Muscle and nerve pathology in Dunnigan familial partial lipodystrophy.
abstract: OBJECTIVE
  To characterize muscle and nerve pathology in Dunnigan familial partial lipodystrophy (FPLD).
  
  
  METHODS
  We used conventional histology, immunohistochemistry, messenger RNA (mRNA) expression, gene sequencing, and clinical studies of 13 patients with neuromuscular involvement.
  
  
  RESULTS
  The clinical findings consisted of muscle hypertrophy (12/13), severe myalgias (9/13), and multiple nerve entrapment syndromes (8/13). Skeletal muscle histology demonstrated marked Type 1 and 2 muscle fiber hypertrophy and nonspecific myopathic changes, whereas numerous paranodal myelin swellings (tomacula) were found in sural nerve biopsies. We found that myostatin mRNA expression was reduced in patients with FPLD vs controls. We sequenced the myostatin gene in our subjects, but found no mutations. We then investigated whether or not SMAD, the intracellular mediator of myostatin signaling, might be impaired in patients with FPLD. We found that in FPLD muscle, a large number of SMAD molecules adhered to the nuclear membrane and were not found within the nucleus, compared with normal muscle or muscle from a patient with a non-FPLD lamin A/C disease.
  
  
  CONCLUSIONS
  The myopathy and neuropathy associated with Dunnigan familial partial lipodystrophy are distinct from other lamin A/C disorders. We hypothesize that the lipodystrophy-associated mutation interferes with SMAD signaling, linking this type of lipodystrophy to the phenotypically similar myostatin deficiency.
authors.affiliation: Muscle Research Group, Department of Neurology, Medical Faculty of the Charité, Berlin, Germany. simone.spuler@charite.de
authors.forename: S
authors.initials: S
authors.lastname: Spuler
authors.forename: T
authors.initials: T
authors.lastname: Kalbhenn
authors.forename: J
authors.initials: J
authors.lastname: Zabojszcza
authors.forename: F K H
authors.initials: FK
authors.lastname: van Landeghem
authors.forename: A
authors.initials: A
authors.lastname: Ludtke
authors.forename: K
authors.initials: K
authors.lastname: Wenzel
authors.forename: M
authors.initials: M
authors.lastname: Koehnlein
authors.forename: M
authors.initials: M
authors.lastname: Schuelke
authors.forename: L
authors.initials: L
authors.lastname: Lüdemann
authors.forename: H H
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D052496:Lipodystrophy, Familial Partial / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000473:pathology* / Q000503:physiopathology; D055435:Myostatin; D010523:Peripheral Nervous System Diseases / Q000473:pathology* / Q000503:physiopathology; D051785:Smad Proteins / Q000378:metabolism*; D013497:Sural Nerve / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C525911:MSTN protein, human; D055435:Myostatin; D051785:Smad Proteins; D016212:Transforming Growth Factor beta