title: Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.
abstract: BACKGROUND
  Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described.
  
  
  OBJECTIVE
  The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics.
  
  
  METHODS
  Cross-sectional evaluation.
  
  
  METHODS
  Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD).
  
  
  METHODS
  Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies.
  
  
  RESULTS
  Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization.
  
  
  CONCLUSIONS
  Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.
authors.affiliation: Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Nevin
authors.identifier: http://orcid.org/0000-0003-0105-1160
authors.initials: N
authors.lastname: Ajluni
authors.affiliation: Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rasimcan
authors.initials: R
authors.lastname: Meral
authors.affiliation: Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Neidert
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Graham F
authors.initials: GF
authors.lastname: Brady
authors.affiliation: Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Buras
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: McKenna
authors.affiliation: Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: DiPaola
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.affiliation: School of Kinesiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Horowitz
authors.affiliation: Pediatric Endocrinology, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Buggs-Saxton
authors.affiliation: Departments of Pediatrics and Communicable Diseases and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amit R
authors.initials: AR
authors.lastname: Rupani
authors.affiliation: Departments of Pediatrics and Communicable Diseases and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Peedikayil E
authors.initials: PE
authors.lastname: Thomas
authors.affiliation: Departments of Pediatrics and Communicable Diseases and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Marwan K
authors.initials: MK
authors.lastname: Tayeh
authors.affiliation: Departments of Pediatrics and Communicable Diseases and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Conjeevaram
authors.affiliation: Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elif A
authors.initials: EA
authors.lastname: Oral
mesh_terms: D000293:Adolescent; D000328:Adult; D001823:Body Composition; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008060:Lipodystrophy / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D052496:Lipodystrophy, Familial Partial / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D055815:Young Adult