Hepatic steatosis in Dunnigan-type familial partial lipodystrophy.
ABSTRACT Characterization of familial clusters of subjects with metabolic derangements predisposing to hepatic steatosis and nonalcoholic steatohepatitis could facilitate genomic studies to identify risk factors for their development. Dunnigan-type familial partial lipodystrophy (FPLD) is an autosomal dominantly inherited disorder caused by mutations in the LMNA gene. Affected subjects have loss of subcutaneous fat from the extremities and symptoms similar to those characterizing the metabolic syndrome, including insulin resistance and dyslipidemia. The goal of this study was to determine the prevalence of steatosis in subjects with FPLD.
We examined 18 subjects from six families with FPLD for mutations in LMNA and analyzed plasma lipid and serum glucose concentrations. Liver ultrasound and serum aminotransferase activities were used as indicators of steatosis or steatohepatitis. In two subjects, histological examination of hepatic tissue was performed.
All subjects had FPLD-causing mutations in LMNA. Plasma lipids were measured in 17 subjects, 16 of whom had hyperlipidemia and 14 presented with either documented insulin resistance or diabetes mellitus. Hepatic steatosis was present in 15 subjects who had ultrasound examinations and 9 of these had elevated serum aminotransferase activities. Liver biopsy confirmed steatosis in 2 subjects.
Hepatic steatosis is part of the clinical phenotype of FPLD. This familial disorder may provide a human metabolic model system to facilitate genomic and environmental studies to determine risk factors for hepatic steatosis and nonalcoholic steatohepatitis.
SourceAvailable from: Callinice D Capo-Chichi[Show abstract] [Hide abstract]
ABSTRACT: The lamins are nuclear envelope proteins and main constituent of nuclear lamina surrounding the internal membrane of nuclear envelope. The lamina is the scaffold for nuclear envelope architecture and a framework composed of intermediate filament proteins such as type A and B lamins. Type A lamins (lamin A/C) are encoded by LMNA gene and are at the center of several biological functions essential for cells. Several studies have shown that mutations in LMNA gene are responsible for laminophathies associated with abnormalities in skeletal muscle, in heart, in adipose tissue, bone tissue and neuronal tissue. Lamin A and lamin C are synthesized from the differential splicing of the same messenger RNA but they have different type of maturations. The mutations in LMNA gene affect more often the maturation of lamin A and most of the physiological pathologies are linked to the absence of functional lamin A. Lamin A is a biomarker of differentiated cells and its synthesis is stimulated by vitamin A in embryonic stem cells. The suppressions of lamin A in vivo by endogen épigénétique modifications or in vitro by the interference RNA (iRNA) techniques or enzymatic degradations, reveal the central role of lamin A in the regulation of genes involved in cell division, DNA replication, DNA repair, gene transcription, chromatin organization, cell metabolism, sensitivity to insulin, cell motility, cell signaling, and cell immunity. Epithelial cell that had lost the capacity to express functional lamin A are frequently transformed in cancerous cells while adipose cells that had lost functional lamin A also lack the capacity to metabolize lipids and become resistant to insulin. In this review we emphasize the molecular mechanism involved in cancer genesis, in insulin-resistance and diabetes when the expression of lamin A is altered or lost as well as methods to restore lamins A/C expression.
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ABSTRACT: This report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. Mutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. The patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. Very rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described.Diabetes & Metabolism 01/2014; 40(3). DOI:10.1016/j.diabet.2013.12.008 · 2.85 Impact Factor
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ABSTRACT: Familial partial lipodystrophy, Dunnigan variety, is a recognised autosomal dominant disorder which is caused by heterozygous missense mutations in the lamin A/C gene. Dunnigan lipodystrophy is characterised by a variable loss of fat from the extremities and trunk, as well as an excess of subcutaneous fat in the chin and supraclavicular area. The associated metabolic abnormalities include: insulin resistance, diabetes, dyslipidaemia and low leptin levels. The authors studied the case of a 24-year-old caucasian pregnant woman, with a past medical history of acute pancreatitis, combined dyslipidaemia and diabetes mellitus. At 7 weeks of pregnancy she was referred to the outpatient endocrinology and obstetrics clinic for diabetes care. A physical examination revealed that she presented a loss of fat from the extremities and trunk and also had an excess of subcutaneous fat in the chin. Triglyceride levels were persistently high, and glycaemic control was only achieved through the administration of high doses of insulin (1.8 U/Kg/day). Dunnigan lipodystrophy was suspected and thus a genetic study was requested, which revealed the presence of c.1444C > T (p.Arg482Trp) heterozygote mutation in the lamin A/C gene. This case is used to illustrate the importance of being able to recognise the clinical signs of this rare lipodystrophic syndrome, which may cause potentially severe consequences, and also the difficulties in treating it during pregnancy.BMC Research Notes 04/2015; 8(1):140. DOI:10.1186/s13104-015-1065-4