Familial Partial Lipodystrophy Due to a Mutation in Pparg Resulting in Severe Hypertriglyceridemia, Hepatosteatosis and Insulin Resistance

The metabolic syndrome (MetS) is a common phenotype that is clinically defined by threshold values applied to measures of central obesity, dysglycemia, dyslipidemia, and/or elevated blood pressure, which must be present concurrently in any one of a variety of combinations. Insulin resistance, although not a defining component of the MetS, is nonetheless considered to be a core feature. MetS is important because it is rapidly growing in prevalence and is strongly related to the development of cardiovascular disease. To define etiology, pathogenesis and expression of MetS, we have studied patients, specifically Canadian families and communities. One example is familial partial lipodystrophy (FPLD), a rare monogenic form of insulin resistance caused by mutations in either LMNA, encoding nuclear lamin A/C (subtype FPLD2), or in PPARG, encoding peroxisomal proliferator-activated receptor-γ (subtype FPLD3). Because it evolves slowly and recapitulates key clinical and biochemical attributes, FPLD seems to be a useful monogenic model of MetS. A second example is the disparate MetS prevalence between two Canadian aboriginal groups that is mirrored by disparate prevalence of diabetes and cardiovascular disease. Careful phenotypic evaluation of such special cases of human MetS by using a wide range of diagnostic methods, an approach called “phenomics,” may help uncover early presymptomatic disease biomarkers, which in turn might reveal new pathways and targets for interventions for MetS, diabetes, and atherosclerosis.

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Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.100 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A50-A51

Author(s):

Maria Cristina Foss de Freitas ◽

Baris Akinci ◽

Adam Neidert ◽

Rita Hench ◽

Elif A Oral

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Body Fat ◽

Fat Mass ◽

Subcutaneous Fat ◽

Hormonal Changes ◽

Loss Of Function ◽

Partial Lipodystrophy ◽

Number Of Patients ◽

Familial Partial Lipodystrophy

Abstract Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

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Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800008 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1252-1256 ◽

Cited By ~ 14

Author(s):

Patricia B. Mory ◽

Felipe Crispim ◽

Teresa Kasamatsu ◽

Monica A. L. Gabbay ◽

Sergio A. Dib ◽

...

Keyword(s):

Insulin Resistance ◽

De Novo ◽

Subcutaneous Fat ◽

Lmna Gene ◽

Metabolic Complications ◽

Partial Lipodystrophy ◽

Severe Insulin Resistance ◽

Severe Hypertriglyceridemia ◽

Exon 1 ◽

Total Body

Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confirmed by DEXA (total body fat 8.6%). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identified a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.T10I mutation in LMNA gene.

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ApoC-III Levels Correlate with Insulin Resistance and HbA1c in Familial Partial Lipodystrophy—Observations from the Broaden Study

Diabetes ◽

10.2337/db18-623-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 623-P

Author(s):

RASIMCAN MERAL ◽

ANDRES DIGENIO ◽

ADAM H. NEIDERT ◽

JOSEPH TAMI ◽

ELIF A. ORAL ◽

...

Keyword(s):

Insulin Resistance ◽

Partial Lipodystrophy ◽

Familial Partial Lipodystrophy

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Familial Partial Lipodystrophy: A Monogenic Form of the Insulin Resistance Syndrome

Molecular Genetics and Metabolism ◽

10.1006/mgme.2000.3092 ◽

2000 ◽

Vol 71 (4) ◽

pp. 539-544 ◽

Cited By ~ 39

Author(s):

Robert A. Hegele

Keyword(s):

Insulin Resistance ◽

Insulin Resistance Syndrome ◽

Partial Lipodystrophy ◽

Monogenic Form ◽

Familial Partial Lipodystrophy

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Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00849 ◽

2019 ◽

Vol 104 (12) ◽

pp. 6025-6032 ◽

Cited By ~ 6

Author(s):

Isabelle Jéru ◽

Marie-Christine Vantyghem ◽

Elise Bismuth ◽

Pascale Cervera ◽

Sara Barraud ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary ◽

Liver Steatosis ◽

Subcutaneous Fat ◽

Diagnostic Challenge ◽

Metabolic Complications ◽

Partial Lipodystrophy ◽

Patients With Diabetes ◽

Familial Partial Lipodystrophy ◽

Center For Rare Diseases

Abstract Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

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Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.5.7500 ◽

2001 ◽

Vol 86 (5) ◽

pp. 2289-2295 ◽

Cited By ~ 19

Author(s):

Hartmut H.-J. Schmidt ◽

Janine Genschel ◽

Peter Baier ◽

Martina Schmidt ◽

Johann Ockenga ◽

...

Keyword(s):

Lmna Gene ◽

Genetic Trait ◽

Lipoprotein Subfractions ◽

Partial Lipodystrophy ◽

Severe Hypertriglyceridemia ◽

Eruptive Xanthomas ◽

Familial Partial Lipodystrophy ◽

Tunnel Syndrome ◽

Apolipoprotein E Genotype

Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg482Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.

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A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies

Acta Endocrinologica ◽

10.1530/eje-21-0282 ◽

2021 ◽

Author(s):

Guillaume Treiber ◽

Ania Flaus – Furmaniuk ◽

Alice Guilleux ◽

Samir Medjane ◽

Oriane Bonfanti ◽

...

Keyword(s):

Insulin Resistance ◽

Resistance Index ◽

Biological Data ◽

Metabolic Complications ◽

Alcoholic Fatty Liver ◽

Partial Lipodystrophy ◽

Conduction Disturbances ◽

Cardiac Phenotype ◽

Familial Partial Lipodystrophy ◽

Cardiac Manifestations

Aims: LMNA-linked Familial Partial Lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. Methods: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n=65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. Results: Two-thirds of patients with FPLD2 (n=51) and one-third of controls (n=6) displayed lipodystrophy and/or lean or android morphotype (p=0.02). Although age and body mass index (BMI) were not statistically different between the two groups, the insulin resistance index (median HOMA-IR 3.7 vs 1.5, p=0.001), and the prevalence of diabetes, dyslipidaemia and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all p≤0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (p=0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides p≤0.03), and tended to develop diabetes more frequently, and earlier (p=0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in 4 cases. Conclusions: The level of expression of the LMNA ‘Reunionese’ variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

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Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin

Acta Endocrinologica ◽

10.1530/eje-08-0272 ◽

2008 ◽

Vol 159 (3) ◽

pp. 347-353 ◽

Cited By ~ 30

Author(s):

A Gambineri ◽

R K Semple ◽

G Forlani ◽

S Genghini ◽

I Grassi ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Lamin A ◽

Ovary Syndrome ◽

Partial Lipodystrophy ◽

Severe Insulin Resistance ◽

Insulin Resistant ◽

Fat Deposits ◽

Familial Partial Lipodystrophy

ContextDespite the very high prevalence of the polycystic ovary syndrome (PCOS), the underlying pathogenetic mechanism has remained obscure.ObjectiveTo determine the cause of two sisters' PCOS associated with severe insulin resistance.DesignClinical case report.MethodsTwo sisters who presented with hyperandrogenism and menstrual disorders in the context of PCOS, and were subsequently found to be severely insulin resistant. Physical examination revealed muscular hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, in spite of excess fat deposits in the face, neck and dorsocervical region. Known genes involved in familial partial lipodystrophy were screened. At the same time, metformin (1700 mg/day) was commenced. After 2–3 years of uninterrupted therapy, lack of clinical improvement led to the introduction of pioglitazone (30 mg/day).ResultsBoth sisters were found to be heterozygous for the R482Q mutation in the lamin A/C gene (LMNA) gene, establishing the definitive diagnosis as Dunnigan-type familial partial lipodystrophy complicated by severe insulin resistance and secondary PCOS. Treatment with pioglitazone resulted in progressive amelioration of insulin resistance, hyperinsulinaemia and hyperandrogenaemia. Menses also improved, with restoration of a eumenorrhoeic pattern, and the framework of ultrasound PCO was in complete remission.ConclusionsAssessment of insulin sensitivity and adipose tissue topography should be a key part of the initial evaluation of patients with PCOS. Identifying such forms of PCOS with monogenic insulin resistance as the primary pathogenic abnormality may have practical implications for therapy, since they respond to thiazolidinediones, but not to metformin.

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