Nevin Ajluni1, Rasimcan Meral1, Adam H Neidert1, Graham F Brady2, Eric Buras1, Barbara McKenna3, Frank DiPaola4, Thomas L Chenevert5, Jeffrey F Horowitz6, Colleen Buggs-Saxton7, Amit R Rupani8, Peedikayil E Thomas8, Marwan K Tayeh8, Jeffrey W Innis8, M Bishr Omary2,9, Hari Conjeevaram2, Elif A Oral1. 1. Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA. 2. Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 4. Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Radiology, University of Michigan, Ann Arbor, MI, USA. 6. School of Kinesiology, University of Michigan, Ann Arbor, MI, USA. 7. Pediatric Endocrinology, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA. 8. Departments of Pediatrics and Communicable Diseases and Human Genetics, University of Michigan, Ann Arbor, MI, USA. 9. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Abstract
CONTEXT: 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. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: 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.
CONTEXT: 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. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: 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.
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