Lipodystrophy lmna

OBJECTIVE: To assess the effects of pharmacologic and/or surgical interventions in monogenic insulin resistance (IR), stratified by genetic aetiology. DESIGN: Systematic review. DATA SOURCES: PubMed, MEDLINE and Embase, from 1 January 1987 to 23 June 2021. REVIEW METHODS: Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual subject data were extracted and duplicate data removed...

Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases...

INTRODUCTION: The transition to metabolically unhealthy obesity (MUO) is driven by the limited expandability of adipose tissue (AT). Familial Partial Lipodystrophy type 2 (FPLD2) is an alternative model for AT dysfunction that is suitable for comparison with obesity. While MUO is associated with low-grade systemic inflammation, studies of inflammation in FPLD2 have yielded inconsistent results. Consequently, comparison of inflammation markers between FPLD2 and obesity is of great interest to better understand the pathophysiological defects of FPLD2...

Type 2 familial partial lipodystrophy (FPLD2) is a laminopathic lipodystrophy due to pathogenic variants in the LMNA gene. Its rarity implies that it is not well-known. The aim of this review was to explore the published data regarding the clinical characterisation of this syndrome in order to better describe FPLD2. For this purpose, a systematic review through a search on PubMed until December 2022 was conducted and the references of the retrieved articles were also screened. A total of 113 articles were included...

The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype...

The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells)...

AIM: Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant. METHODS: A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled...

Context: Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. Objective: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. Methods: A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases...

Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the LMNA (MIM 150330) gene. APS has heterogeneous clinical manifestations, and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy...

Lipodystrophy syndrome caused by LMNA gene mutation is a group of autosomal dominant monogenic diseases, characterized by selective fat loss and metabolic abnormalities with insulin resistance. In this review, we summarize the clinical manifestations caused by multiple pathogenic LMNA mutations reported so far, including metabolic complications, cardiovascular abnormalities, gonadal axis disorders, myopathy, and renal abnormalities. Meanwhile, we also clarify the possible pathogenic mechanism, diagnosis, and treatment, in order to improve the understanding of the disease and to provide a reference for basic research and clinical diagnosis and treatment of this disease...

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the LMNA gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. Progerin is permanently farnesylated, carboxymethylated, and strongly anchored to the nuclear envelope. This leads to abnormalities, such as altered nuclear shape, mitochondrial dysfunction, and inflammation. HGPS patients display symptoms of physiological aging, including atherosclerosis, alopecia, lipodystrophy, and arthritis...

LMNA mutation is associated with type-2 familial partial lipodystrophy ( FPLD2 ). The disease causes a disorder characterized by anomalous accumulation of body fat in humans. The dysfunction at the molecular level is triggered by a lamin A/C mutation, impairing the cell metabolism. In human fibroblasts and preadipocytes, a trend for ATP production, mainly supported by mitochondrial oxidative metabolism, is detected. Moreover, primary cell lines with FPLD2 mutation decrease the mitochondrial ATP production if compared with the control , even if no differences are observed in the oxygen consumption rate of bioenergetic parameters (i...

CONTEXT: Familial partial lipodystrophy type 2 (FPLD2) results from autosomal dominant mutations in the LMNA gene, causing lack of subcutaneous fat deposition and excess ectopic fat accumulation, leading to metabolic complications and reduced life expectancy. The rarity of the condition means that the natural history of FPLD2 throughout childhood is not well understood. We report outcomes in a cohort of 12 (5M) children with a genetic diagnosis of FPLD2, under the care of the UK National Severe Insulin Resistance Service (NSIRS) which offers multidisciplinary input including dietetic, in addition to screening for comorbidities...

OBJECTIVES: Familial partial lipodystrophy type 2 is the most well-known subtype of lipodystrophy. We describe for the first time the phenotype of a case with lipodystrophy, who carried heterozygous mutation c.G1394A (p.G465D) in the LMNA gene. CASE PRESENTATION: A 17-year-old girl was diagnosed with FPLD2 due to severe loss of subcutaneous fat in the extremities, buttocks and metabolic complications. However, there was no accumulation of fat over her face and neck, which is remarkably different from the FPLD2 clinical phenotypes...

Lamin proteins which constitute the nuclear lamina in almost all higher eukaryotes, are mainly of two types A & B encoded by LMNA and LMNB1/B2 genes respectively. While lamin A remains the principal product of LMNA gene, variants like lamin C, C2 and A∆10 are also formed as alternate splice products. Role of lamin A in aging has been highlighted in recent times due to its association with progeroid or premature aging syndromes which is classified as a type of laminopathy. Progeria caused by accelerated accumulation of lamin A Δ50 or progerin occurs due to a mutation in this LMNA gene leading to defects in post translational modification of lamin A...

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by the selective loss of adipose tissue. Its estimated prevalence is as low as 1 in 1 million. The deficiency of metabolically active adipose tissue is closely linked with a wide range of metabolic complications, such as insulin resistance, lipoatrophic diabetes, dyslipidemia with severe hypertriglyceridemia, hypertension or hepatic steatosis. Moreover, female patients often develop hyperandrogenism, hirsutism, polycystic ovaries and infertility...

BACKGROUND: Pathogenic variants in the lamin A/C gene (LMNA) can lead to a wide range of phenotypes from dilated and arrhythmogenic cardiomyopathies and conduction abnormalities to partial lipodystrophies. This case highlights a coincidental pathogenic LMNA variant identified in a patient with sudden cardiac arrest (SCA). We demonstrate the need for careful interpretation of pathogenic variants identified in cardiomyopathy genes by highlighting a case in which a coincidental pathogenic LMNA variant was found in a patient with premature ventricular complex (PVC)-induced ventricular fibrillation (VF)...

Leptin replacement therapy (LRT) has drastically improved the prognosis of patients with lipodystrophy, but pro-inflammatory properties of leptin could become evident in the long term. Here, we report a 30-year-old Japanese woman with generalized lipodystrophy-associated progeroid syndrome due to a heterozygous LMNA variant (c.29C > T; p.T10I), who was diagnosed with severe aortic stenosis (AS) after more than a decade of LRT, which required transcatheter aortic valve implantation. Given her marked hypoadiponectinemia and the LMNA variant, our patient might have been susceptible to progeria-associated disorders, including aortic stenosis, which could have been exaggerated by the prolonged 'imbalanced adipokines' caused by LRT between pro-inflammatory leptin and anti-inflammatory adiponectin...

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French)...

PURPOSE: SARS-CoV-2 infection may cause varying degrees of cardiac injury and the presence of underlying cardiovascular morbidities contributes to the frequency and severity of occurrence of this complication. Lipodystrophy syndromes are frequently characterized by severe metabolic derangements that represent relevant cardiovascular risk factors. Besides causing lipodystrophy, mutations in the lamin A/C (LMNA) gene can lead to a wide spectrum of tissue-specific disorders including cardiac involvement...