Spectrum of Disease Associated with Partial Lipodystrophy (PL): Lessons from a Trial Cohort

Abstract

Context

Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described.

Objective

Define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics.

Design

Cross-sectional evaluation.

Participants

23 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 MRI, histopathological and immunofluorescence examinations of liver biopsies.

Results

7 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 %fat trunk to %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 hemoglobin 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) score 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

PL 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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