Spectrum of disease associated with partial lipodystrophy: 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.

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…The male-to-female ratio is 7:15. Among them, 15 patients had p.Ser605del, including our case; three patients had p.Arg507Cys [11][12][13][14][15][16] and only one had the novel mutation p.Ile1070Ans [16], and two related female patients had the recently identified mutation, p.Glu1067Lys [17]. Thus, the mutation detected in our patient, p.Ser605del, might constitute a hotspot for MDPL syndrome (Table 2, Fig.…”

“…2C). The deletion was reported as a pathogenic variant in patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL syndrome) [11][12][13][14][15][16][17]. In addition, no pathogenic mutations were also found in other lipodystrophy-related genes, including FBN1, LIPE, NK, PIK3R1, PSMB8, RTRF, and BANF1, as well as in the Werner helicase gene (WRN) by either Sanger sequencing or WES [21].…”

“…Thus, according to both the unique phenotypic mani- festations and the WES analysis, the patient was diagnosed as having MDPL syndrome; MIM #615381 in the Online Mendelian Inheritance in Man database [11][12][13][14][15][16][17].…”

“…To date, 21 patients with POLD1-related MDPL syndrome [11][12][13][14][15][16][17]26] have been reported in English publications, most frequently from European countries ( Table 2). The male-to-female ratio is 7:15.…”

“…Notably, a new causal factor of progressive lipodystrophy associated with MDPL syndrome has been identified [11][12][13][14][15][16][17]. Mutations in the polymerase delta 1 (POLD1) gene have been detected in several patients with MDPL, suggesting that MDPL is the result of POLD1 gene mutation.…”