scholarly journals Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety

2020 ◽  
Vol 105 (7) ◽  
pp. 2132-2141
Author(s):  
Chandna Vasandani ◽  
Xilong Li ◽  
Hilal Sekizkardes ◽  
Beverley Adams-Huet ◽  
Rebecca J Brown ◽  
...  
Keyword(s):  
Lower Limb ◽  
False Negative ◽  
Skinfold Thickness ◽  
Diagnostic Value ◽  
Small Sample ◽  
Anthropometric Measurements ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Adult Females ◽  
Familial Partial Lipodystrophy

Abstract Context Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. Objective To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. Methods We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. Results The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. Conclusions The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.

scholarly journals SUN-LB111 Comparison of Phenotype and Metabolic Abnormalities Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Chandna Vasandani ◽  
Xilong Li ◽  
Hilal Sekizkardes ◽  
Rebecca Brown ◽  
Abhimanyu Garg
Keyword(s):  
Polycystic Ovarian Syndrome ◽  
Early Recognition ◽  
Skinfold Thickness ◽  
The United States ◽  
Metabolic Abnormalities ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Fat Loss ◽  
Familial Partial Lipodystrophy ◽  
Ovarian Syndrome

Abstract Familial partial lipodystrophy (FPLD), a rare autosomal dominant disorder, is characterized by marked loss of subcutaneous (sc) fat from the extremities, and predisposition to insulin resistance, diabetes mellitus, dyslipidemia and hepatic steatosis. FPLD2 and FPLD3 due to causal variants in LMNA and PPARG, respectively, are the two most common subtypes. Due to extremely rare prevalence of FPLD3 and limited reports in the literature, whether there are phenotypic differences between the two subtypes remain unclear. Therefore, we compared the anthropometric measurements and prevalence of metabolic abnormalities among 32 FPLD3 subjects (4 M, 28 F; mean ± SD age, 41 ± 17.2 y; body mass index (BMI), 26 ± 4.0 kg/m2) with 271 FPLD2 subjects (66 M, 205 F; age, 37.4 ± 17.0 y; BMI, 26 ± 5.0 kg/m2) from two referral centers in the United States. As compared to those with FPLD2, FPLD3 subjects had borderline higher prevalence of hypertriglyceridemia (66% vs 84%; P = 0.063), but significantly higher prevalence of diabetes (44% vs 72%; P = 0.004), past history of acute pancreatitis (13% vs 52%; P <0.001), and polycystic ovarian syndrome (26% vs 52%; P = 0.011). As compared to FPLD2, FPLD3 subjects had similar fasting triglyceride levels (median 208 vs 255 mg/dL; P=0.15), but lower high-density lipoprotein cholesterol levels (median 37.5 vs 30 mg/dL; P = 0.001), higher fasting glucose (median 95 vs 115 mg/dL; P = 0.05) and HbA1c (median 5.7 vs 7.0 %; P = 0.005) levels. Regional body fat was measured by dual energy X-ray absorptiometry in 19 FPLD3 and 105 FPLD2 subjects. In comparison to FPLD2, FPLD3 subjects had higher total fat (median 21.6% vs 26.1 %; P = 0.018); upper limb fat (median 20.3% vs 27.3%; P = 0.003) and lower limb fat (median 16.0% vs 20.8%; P = 0.007). Skinfold thickness measurements by calipers also revealed less severe fat loss from both the upper and lower extremities in FPLD3 subjects compared to FPLD2 subjects. As compared to FPLD2, FPLD3 subjects had significantly higher triceps skinfold thickness (median 5.5 mm vs 7.5 mm; P = 0.015); and thigh skinfold thickness (median 5.8 mm vs 11.3 mm; P = 0.001). There were no significant differences in the prevalence of fatty liver, plasma alanine aminotransferase and aspartate aminotransferase levels in the two subtypes. We conclude that compared to FPLD2 subjects, those with FPLD3 have milder lipodystrophy phenotype but paradoxically present with more severe metabolic complications, especially diabetes, dyslipidemia and polycystic ovarian syndrome. It is likely that this discrepancy could be due to early recognition of FPLD2 because of severe fat loss versus initial diagnosis of FPLD3 subjects due to severe metabolic complications leading to discovery of milder fat loss.

scholarly journals Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Cecchetti ◽  
M. Rosaria D’Apice ◽  
Elena Morini ◽  
Giuseppe Novelli ◽  
Carmine Pizzi ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Coiled Coil ◽  
Missense Variant ◽  
Lamin A ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Atypical Form ◽  
Amino Terminal ◽  
Familial Partial Lipodystrophy

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

scholarly journals Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

2019 ◽  
Vol 104 (12) ◽  
pp. 6025-6032 ◽  
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.

LMNA-associated partial lipodystrophy: anticipation of metabolic complications

2017 ◽  
Vol 54 (6) ◽  
pp. 413-416 ◽  
Author(s):  
Isabelle Jeru ◽  
Camille Vatier ◽  
Marie-Christine Vantyghem ◽  
Olivier Lascols ◽  
Corinne Vigouroux
Keyword(s):  
First Generation ◽  
Genetic Diagnosis ◽  
Diagnostic Procedures ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Mean Delay ◽  
Familial Partial Lipodystrophy ◽  
Similar Body ◽  
Early Occurrence

BackgroundType-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations inLMNAencoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations.MethodsThis retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5).ResultsLipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6 kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result.ConclusionsThis study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.

scholarly journals Metreleptin as A Rescue Therapy in A Patient With A Novel Mutation for Familial Partial Lipodystrophy Type 3, Originally Presenting as Type 1 Diabetes.

2021 ◽  
Author(s):  
VAIA LAMBADIARI ◽  
AIKATERINI KOUNTOURI ◽  
EIRINI MARATOU ◽  
STAVROS LIATIS ◽  
GEORGE DIMITRIADIS ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Effective Treatment ◽  
Novel Mutation ◽  
Genetic Disorder ◽  
Synthetic Analogue ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Type 3

Abstract Background: Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce. Case presentation: We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment HbA1c decreased from 10% to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl. Conclusions: This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as a difficult-to-classify and manage diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

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

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.

scholarly journals Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene

2021 ◽  
Vol 10 (6) ◽  
pp. 1259
Author(s):  
David Araújo-Vilar ◽  
Sofía Sánchez-Iglesias ◽  
Ana I. Castro ◽  
Silvia Cobelo-Gómez ◽  
Álvaro Hermida-Ameijeiras ◽  
...  
Keyword(s):  
Body Composition ◽  
Skinfold Thickness ◽  
Pathogenic Variant ◽  
The Other ◽  
Metabolic Abnormalities ◽  
Lmna Gene ◽  
Partial Lipodystrophy ◽  
Variable Expressivity ◽  
Familial Partial Lipodystrophy

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.

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