Familial Partial Lipodystrophy Type Research Articles

Circulating exosomal circRNA-miRNA-mRNA network in a familial partial lipodystrophy type 3 family with a novel PPARG frameshift mutation c.418dup.

Familial partial lipodystrophy 3 (FPLD3) is a rare genetic disorder caused by loss-of-function mutations in the PPARG gene, characterized by a selective absence of subcutaneous fat and associated metabolic complications. However, the molecular mechanisms of FPLD3 remain unclear. In this study, we recruited a 17-yr-old Chinese female with FPLD3 and her family, identifying a novel PPARG frameshift mutation (exon 4: c.418dup: p.R140Kfs*7) that truncates the PPARγ protein at the seventh amino acid, significantly expanding the genetic landscape of FPLD3. By performing next-generation sequencing of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in plasma exosomes, we discovered 59 circRNAs, 57 miRNAs, and 299 mRNAs were significantly altered in the mutation carriers compared with the healthy controls. Integration analysis highlighted that the circ_0001597-miR-671-5p pair and 18 mRNAs might be incorporated into the metabolic regulatory networks of the FPLD3 induced by the novel PPARG mutation. Functional annotation suggested that these genes were significantly enriched in glucose- and lipid metabolism-related pathways. Among the circRNA-miRNA-mRNA network, we identified two critical regulators, early growth response-1 (EGR1), a key transcription factor known for its role in insulin signaling pathways and lipid metabolism, and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which gets involved in the biosynthesis of triglycerides and lipolysis. Circ_0001597 regulates the expression of these genes through miR-671-5p, potentially contributing to the pathophysiology of FPLD3. Overall, this study clarified a circulating exosomal circRNA-miRNA-mRNA network in a FPLD3 family with a novel PPARG mutation, providing evidence for exploring promising biomarkers and developing novel therapeutic strategies for this rare genetic disorder.NEW & NOTEWORTHY Through the establishment of a ceRNA regulatory networks in a novel PPARG frameshift mutation c.418dup-induced FPLD3 pedigree, this study reveals that circ_0001597 may contribute to the pathophysiology of FPLD3 by sequestering miR-671-5p to regulate the expression of EGR1 and AGPAT3, pivotal genes situated in the triglyceride (TG) synthesis and lipolysis pathways. Current findings expand our molecular understanding of adipose tissue dysfunction, providing potential blood biomarkers and therapeutic avenues for lipodystrophy and associated metabolic complications.

Bilateral developmental cataracts in a child with familial lipodystrophy

Bilateral developmental cataracts are usually caused due to hereditary metabolic disorder or intrauterine infections. Familial lipodystrophy type 7 has variable phenotypes with early-onset cataracts and lower limb spasticity, with most reports showing the onset of cataracts in the second decade of life. We report a rare case of bilateral congenital cataract in a child aged 3 years and 9 months with genetically proven familial partial lipodystrophy type 7. Bilateral developmental cataracts need complete physical examination and genetic analysis to detect unusual and rare causes like familial partial lipodystrophy.

Serum levels of adiponectin differentiate generalized lipodystrophies from anorexia nervosa.

The differential diagnosis of lipodystrophy involves other disorders characterized by severe fat loss and may be sometimes challenging. Owing to the rarity of lipodystrophy, it is relevant to search for tools and assays that differentiate it from other diseases that may mimic it. We conducted a study on leptin and high molecular weight (HMW) adiponectin serum concentrations in a series of patients diagnosed with lipodystrophy and compared them with those found in anorexia nervosa, one of the illnesses that may be cause of a missed diagnosis of lipodystrophy. Leptin and HMW adiponectin serum concentrations were measured in six patients diagnosed with generalized lipodystrophy (GL), six with progeroid syndromes (PS), 13 with familial partial lipodystrophy type 1 (FPLD1, Kobberling syndrome), 10 with familial partial lipodystrophy type 2 (FPLD2, Dunnigan syndrome), 18 with acquired partial lipodystrophy (APL) and 12 affected by anorexia nervosa (AN). Measurements were compared to those obtained in 12 normal weight healthy subjects. Serum leptin concentrations were reduced to a similar degree in GL, PS and AN, proportionally to the extent of fat loss. Serum concentrations of HMW adiponectin were found extremely low in patients with GL and PS, while comparable to normal weight subjects in patients with AN. Serum HMW adiponectin can be regarded as a useful tool to discriminate between generalized lipodystrophy syndromes (including PS) and AN.

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series.

Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.

THU241 Novel PPARG Pathogenic Gene Variant In Newly Diagnosed Familial Partial Lipodystrophy With Childhood Onset

Abstract Disclosure: E.K. Chang: None. K. Greve: None. L. Escobar: None. Background: Familial partial lipodystrophy (FPL) is characterized by progressive, selective body fat loss and is often associated with various metabolic complications including insulin resistance. In particular, FPL Type 3 due to PPARG (peroxisome proliferator-activated receptor gamma) mutations is a very rare subtype with a prevalence of less than 1 per 1,000,000 people overall. This case report describes a clinical case of a child presenting with genetic testing revealing a novel PPARG pathogenic gene variant. Clinical Case: A 9 year old female with history of adoption and unknown family history presented with severe abdominal pain and intractable emesis in the setting of COVID19 infection. Her hospital CT scan of the abdomen was remarkable for pancreatitis and hepatosplenomegaly. Glucose was elevated at 356 mg/dL with normal liver function tests. HgA1c was 11%. Triglycerides were above 4425 mg/dL. Her overall clinical picture was consistent with new onset diabetes mellitus and acute pancreatitis. Physical exam was notable for xanthomatosis and acanthosis nigricans. She was later noted to have partial subcutaneous fat loss of the upper and lower extremities, with preserved fat in the face, neck, and truncal region. She was initiated on insulin therapy and discharged to home once symptomatically improved from her pancreatitis with downtrending triglycerides to less than 450 mg/dL. Her diabetes autoantibodies (Glutamic acid decarboxylase, Islet Antigen-2, Zinc transporter 8 antibodies) resulted as normal, and she was able to discontinue insulin with HgA1c trending down to 4.8% within 4 months of hospital discharge. She underwent whole exome sequencing per recommendation of her lipid specialist and geneticist, which identified a likely pathogenic, previously undescribed variant of PPARG: c.1050_1054dup, p.(Glu352Alafs*12) and a variant of uncertain significance for MC4R: c.409A&amp;gt;G, p.(Ile137Val). This particular variant of PPARG represents a frameshift mutation, resulting in a premature stop codon, likely leading to a loss of normal PPARG function. PPARG mutations are specific to FPL Type 3, which is reportedly associated with atypical fat distribution, diabetes mellitus, hypertriglyceridemia, hypertension, and pancreatitis, consistent with many features of this case. Conclusion: This is the first case to describe the unique PPARG variant c.1050_1054dup, p.(Glu352Alafs*12) which is associated with FPL Type 3. This child's clinical course and evaluation can help with identifying affected individuals of this very rare type of FPL. Presentation: Thursday, June 15, 2023

FRI458 Rare Pathogenic Missense Variants in LMNA Identified in Women with Polycystic Ovary Syndrome (PCOS)

Abstract Disclosure: R. Bauer: None. L. Gorsic: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility among reproductive age women. In addition to experiencing reproductive symptoms, women with PCOS are at elevated risk of developing obesity, insulin resistance (IR), and type 2 diabetes. Familial partial lipodystrophy type 2 (FPLD2) is a disorder of lipid storage and insulin resistance caused by dominant missense alleles in the gene encoding the intermediate filaments lamin A/C (LMNA). Women with this Mendelian disorder of IR also experience symptoms of PCOS such as amenorrhea and hyperandrogenism. We, therefore, hypothesize that genetic variation in LMNA also contributes to PCOS, which is a common form of IR. In other words, we hypothesize that PCOS falls into the phenotypic spectrum of disorders caused by variation in LMNA.Objective: We aim to identify and evaluate variation in LMNA that underlies PCOS pathogenesis. Methods: To test our hypothesis, we sequenced the LMNA gene in 602 women with PCOS and 125 reproductively healthy women. We comprehensively screened LMNA for genetic variation that is likely to alter the lamin A/C proteins, including missense, nonsense, splicing or frameshift variants. We identified 7 missense variants in 8 cases and no variants in reproductively healthy controls (χ2= 3.1, p=0.081, OR &amp;gt; 1.78, with study controls; χ2= 46.8, p&amp;lt;1x10-8, OR= 8.5 with gnomAD non-Finnish European cohort population controls). To determine which of these variants are pathogenic, we systematically evaluated them according to criteria outlined by the American College of Medical Genetics (ACMG). These guidelines evaluate pathogenicity of variants through multiple lines of evidence, including population data, computational predictions, and functional studies. Results: We identified 5 pathogenic variants in LMNA and 2 that are likely pathogenic. When assessed individually, 6 of the 7 variants are significantly enriched in our cohort when compared to gnomAD non-Finnish European population controls (OR &amp;gt; 5.0). All of the LMNA variants are likely damaging as predicted by 3 computational methods: CADD score ≥ 15, FATHMM prediction of “Damaging”, and MutationTaster classification as “disease causing.” Additionally, many of the variants have previously been identified in individuals with lipodystrophy. Conclusion: Together with previous identification of LMNA variants in women with PCOS by our lab (Urbanek et al. 2009 JCEM) and others (Crespo et al. 2022 JES), this work further establishes LMNA variation as a pathogenic mechanism for PCOS. Presentation Date: Friday, June 16, 2023

Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson-Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called "progerin". Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone.

Kobberling disease: Familial Partial Lipodystrophy type 1 associated with thyroid cancer

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Familial partial lipodystrophy type 2 and obesity, two adipose tissue pathologies with different inflammatory profiles

IntroductionThe 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.ObjectiveTo compare the levels of inflammatory biomarkers between a population of patients with FPLD2 due to the same ‘Reunionese’ LMNA variant and a population of patients with obesity (OB group).MethodsAdiponectin, leptin, IL-6, TNF-α and MCP-1 plasma levels were measured by enzyme-linked immuno assays for 60 subjects with FPLD2 and for 60 subjects with obesity. The populations were closely matched for age, sex, and diabetic status.ResultsMetabolic outcomes were similar between the two populations. Adiponectinemia and leptinemia were lower in the FPLD2 group than in the OB group (p < 0.01 for both), while MCP-1 levels were higher in the FPLD2 than in the OB group (p < 0.01). Levels of other inflammatory markers were not significantly different.ConclusionsInsulin-resistant patients with FPLD2 and obesity share common complications related to AT dysfunction. Inflammatory biomarker analyses demonstrated that MCP-1 levels and adiponectin levels differ between patients with FPLD2 and patients with obesity. These two AT pathologies thus appear to have different inflammatory profiles.

Inguinal Fat Compensates Whole Body Metabolic Functionality in Partially Lipodystrophic Mice with Reduced PPARγ Expression.

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of PpargC/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of PpargC/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in PpargC/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in PpargC/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of PpargC/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes

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. 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. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed. In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers. OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.

RF24 | PSUN126 A Very-Low Calorie Diet Can Reduce Insulin Resistance and Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in a Patient With Familial Partial Lipodystrophy Type 2

Abstract Background Lipodystrophy syndromes are associated with inadequate adipocyte capacity that results in an earlier threshold for ectopic deposition and metabolic dysfunction. We have previously reported that patients with familial partial lipodystrophy (FPLD) present with metabolic severity equivalent to what is observed at 8-12 BMI points higher in a population with common obesity. Currently, there is no strong evidence that any specific diet is the preferred treatment, but bariatric surgery has been reported to improve metabolic outcomes in a few patients. Here, we report the effect of an aggressive calorie-restricted diet in a patient with FPLD who showed remarkable benefit after 16 weeks of the intervention. Clinical Case This is a 38-year-old female diagnosed with FPLD type 2, with LMNA p. R482Q mutation who had a history of recurrent pancreatitis, NAFLD, impaired ovulation, and diabetes mellitus. She had a short-term goal of improving her metabolic state rapidly to achieve pregnancy by IVF. Upon presentation, body weight was 81.6kg, BMI 23.2kg/m2, HbA1c 7.7% and triglycerides 215mg/dL. She was started on very-low calorie diet (VLCD) (800 kcal/day) employing a formula total liquid diet meal replacement: 160 kcal per shake (18g total carbohydrates, 15g net carbohydrates, 3.5g fat, and 16g protein) with the goal to reduce body weight by 15% as has been described for patients in the University of Michigan Weight Management Program. After 1 week on diet, she discontinued glucose and lipid lowering therapies. After 12-weeks of VLCD followed by 4 weeks of transition to low-calorie diet (incorporating 3 meal replacements, one meal, and ad libitum non-starchy vegetables), we observed 12.3kg of body weight and a 1.4% decrease in HbA1c. Insulin resistance was reduced by 66.7 and 61.5% (HOMA-IR and ADIPO-IR, respectively). Fasting insulinemia was reduced by 64.2%. We also performed an OGTT with 75g of glucose for 180 min and observed a decrease in the area under the curve of insulin (-33.2%), triglycerides (-40.7%), and free fatty acids (-34%). DEXA scan showed a reduction in total body fat of 16%. Liver fat via the chemical shift MRI method was reduced from 10±2% to 2±1%. She did not experience any adverse events during the intervention. More importantly, her egg retrieval rate and egg quality during IVF were far superior to past attempts. Conclusion This case illustrates the strong effect and safety of a VLCD intervention in a patient with lipodystrophy. We observed rapid reduction in body weight, and in insulin resistance leading to the remission of diabetes mellitus, hypertriglyceridemia and fatty liver disease. Moreover, there was improved response to ovulation induction. Our data encourage the use of this medical approach for other patients with similar metabolic and reproductive abnormalities due to adipose tissue distribution abnormalities. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants.

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. To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. 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. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia. Compared with subjects with FPLD2, subjects with FPLD3 had significantly increased prevalence of hypertriglyceridemia (66% vs 84%) and diabetes (44% vs 72%); and had higher median fasting serum triglycerides (208 vs 255 mg/dL), and mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% vs 27%) and lower limb fat (16% vs 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs 11.3 mm), calf (4 vs 6 mm), triceps (5.5 vs 7.5 mm), and biceps (4.3 vs 6.8 mm). Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.

Describing the natural history of clinical, biochemical and radiological outcomes of children with familial partial lipodystrophy type 2 (FPLD2) from the United Kingdom: A retrospective case series.

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. To describe the natural history of clinical, biochemicaland radiological outcomes of children with FPLD2. A retrospective case note review of children with a genetic diagnosis of FPLD2 who had been seen in the paediatric NSIRS was performed. Twelve (5M)individuals diagnosed with FPLD2 via genetic testing before age 18 and who attended the NSIRS clinic were included. Relationships between metabolic variables (HbA1c, triglycerides, fasting insulin, fasting glucose and alanine transaminase[ALT]) across time, from first visit to most recent, were explored using a multivariate model, adjusted for age and gender. The age of development of comorbidities was recorded. Three patients (all female) developed diabetes between 12 and 19 years and were treated with Metformin. Onefemale has hypertrophic cardiomyopathy and four(1M)patients developed mild hepatic steatosis at a median [range]age of 14(12-15)years. Three (1M)patients reported mental health problems related to lipodystrophy. There was no relationship between biochemical results and age. Patients with diabetes had higher concentrations of ALT than patients who did not have diabetes, adjusted for age, gender and body mass indexstandard deviation scores. Despite dietetic input, some patients, more commonly females, developed comorbidities after the age of 10. The absence of relationships between biochemical results and age likely reflects a small cohort size. We propose that, whileclinical review and dietetic support are beneficial for children with FPLD2, formal screening for comorbidities before age 10 may not be of benefit. Clinical input from an multidisciplinary team including dietician, psychologistand clinician should be offered after diagnosis.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins)

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). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

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

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. 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. 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 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 four cases. 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.

Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2.

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (LmnaADKO). Although LmnaADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. LmnaADKO mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas LmnaADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. LmnaADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

Body Composition And Bone Mineral Differences According to Lamin A (LMNA) Genotype in Familial Partial Lipodystrophy Type 2

Phenotypic heterogeneity is well known in Familial Partial Lipodystrophy Type 2 (FPLD2), a rare form of adipose tissue disorder caused by pathogenic mutations in LMNA gene. Animal studies from our group have identified an association between adipose tissue loss and an increase in bone mineral density (BMD) in a mouse model with adipose tissue specific knockout of LMNA gene. Aiming to translate this observation to patients with FPLD2, we analyzed body composition data obtained by dual X-ray absorptiometry from 61 patients diagnosed with FPLD2 and 61 individuals with no diagnosis of FPLD (nFPLD) matched for sex, age and body mass index. As expected, we observed lower total fat mass in FPLD2 patients compared to nFPLD (15.8±9.3 kg vs. 28.5±12.4 kg, p=0.001), as well as lower fat mass in regions of arms, legs and trunk. Interestingly, patients with FPLD2 showed lower bone mineral density (BMD) compared to nFPLD 1.0±0.2 g/cm3 vs 1.2±0.1 g/cm3, p=0.01) and lower t-score (0.2±1.8 vs.1.5±1.2). We then aimed to determine if the patients with FPLD2 displayed differences with respect to genotype. For these analyses, the FPLD2 group was divided according to the pathogenic variant; 42 with mutations on the hot spot codon of the LMNA gene (R482: 50.2 ± 164.8 years, 76% women) and 19 with non-hot spot codon mutations (nR482: 44.8 ± 12.8 years, 78% women). Patients in the R482 group were older when they were first diagnosed with lipodystrophy (39.6 ± 18.6 years vs. 36.5 ± 12.3 years, p=0.05). Also, nR482 group presented with more progeroid characteristics. Patients in n-R482 group also had lower weight compared to R482 and nFPLD groups (64.4±14.4 vs. 73.3±18.5 and 77.6±16.6 kg, p=0.01), as well as lower total fat mass (15.3±5.1 vs. 15.8±9.3 and 25.7±11.4 kg, p=0.01) and fat mass ratio (5.8±1.9 vs. 5.9±3.1 and 9.0±4.1, p= 0.01). Control group bone mass was significantly higher in arms, legs and trunk compared to the R482 and nR482 groups. Moreover, the R482 group had lower bone mass in the legs compared to nR482 (690.5±227.2 vs.703.5±95.3 g, p=0.01), while showing higher trunk bone mass (676.4±266.7 vs. 674.1±79.3, p=0.04), in addition to greater fat mass in the legs (3.3±1.6 vs. 2.6±0.7 kg, p=0.05) and trunk areas (10.3±6.1 vs. 10.0±4.2 kg, p=0.03). There were no differences in total bone mass, BMD, and t-scores, according to genotype. Our data showed more fat preservation in LMNA R482 than nR482, presumably leading to a later lipodystrophy diagnosis. Furthermore, bone mass in different regions may be affected by LMNA genotype; however, more studies are needed to define the bone phenotype and fracture risk in FPLD2 population fully.

Targeted Therapeutic Approach in Patients With Familial Partial Lipodystrophy Type 3

Introduction: Familial partial lipodystrophy (FPLD) syndromes are genetic disorders characterized by selective lipoatrophy affecting the upper and lower extremities leading to severe insulin resistance and metabolic complications. We describe a patient diagnosed with a pathogenic variant in the peroxisome proliferator-activated receptor γ (PPARγ) gene that causes FPLD type 3 (FPLD3) subsequently treated with pioglitazone with excellent response. Clinical Case: A 52-year-old Hispanic woman with type 2 diabetes mellitus and hypertension presented with epigastric pain and vomiting. Workup revealed elevated lipase to 1889 U/L and triglycerides to 4117 mg/dL, consistent with hypertriglyceridemia-induced pancreatitis. CT abdomen showed acute pancreatitis with hepatic steatosis. Family history was significant for hypertension, diabetes, and hyperlipidemia in her father, mother, and five siblings. Examination revealed facial and truncal obesity, lipoatrophy of her limbs and buttocks, acanthosis nigricans, and hepatomegaly. The patient was treated with an insulin drip with decline in triglyceride levels (450 mg/dL) and discharged on atorvastatin, fenofibrate, metformin, and pioglitazone. Laboratory evaluation revealed an HbA1c of 9%, normal thyroid and liver function tests, and a serum leptin of 1.2 ng/ ml (N females: 4.7–23.7 ng/ml). Lipoprotein electrophoresis showed type 4 lipoproteinemia. A liver fibroscan showed hepatic steatosis with portal fibrosis. Genetic testing was notable for an autosomal dominant pathogenic heterozygous loss-of-function mutation in the ligand binding domain AF-2 region of PPARγ (c.452 A>G) confirming FPLD3. Pioglitazone was increased to 30mg/day with improvement in HbA1c to 8.3% and dyslipidemia at three-month follow up. Conclusion: FPLD3 is caused by loss-of-function mutations in PPARγ, a transcription factor involved in adipogenesis1. FPLD is estimated to affect 1 per 1 million, with FPLD3 reported in approximately 30 individuals worldwide per National Organization for Rare Disorders. Treatment is currently directed at reducing insulin resistance, dyslipidemia, and their sequelae of pancreatitis and cardiovascular disease. Thiazolidinediones (TZDs), PPARγ agonists targeting insulin sensitivity and adipocyte differentiation, have been used in FPLD with variable results. Different mutations in the ligand-binding domains of PPARγ may affect the binding capacity to synthetic agonists, affecting clinical response. Use of TZDs in individuals with PPARγ mutations (R308P, A261E) have been shown to improve hyperglycemia and dyslipidemia2. Our patient was treated with pioglitazone with excellent response to therapy in three months. TZDs may offer a targeted approach to treat FPLD3 based on PPARγ ligand-dependent responsiveness.

The Long-Term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy

Abstract Metreleptin is an approved treatment for patients with generalized lipodystrophy but still under investigation for patients with partial forms of the disease in the US. This open-label single-arm study in partial lipodystrophy (PL) allowed continued treatment of patients who volunteered and completed treatment under our previous 1-year protocol and who derived significant clinical benefit. The primary outcome was percent change in fasting triglyceride levels and the secondary outcome was percent change in hemoglobin A1c levels (time frame: 5 years on metreleptin or last observation carried forward in both instances). The hypothesis was that these metabolic parameters would stay stable over the observation period. The study enrolled 11 participants (11 females; 3 ≤ 18 years; 8 between 18–65 years). Four patients had familial partial lipodystrophy type 2 (FPLD2) caused by LMNA pathogenic variants (R482Q in two subjects, R482W in one subject, and R349W in one subject), two patients had POLD1 associated PL (E1067K), four patients had FPLD1, and one patient had atypical PL. Variants of uncertain significance (VUS) in genes of interest were detected in two patients with FPLD1 and one patient with atypical PL. Four subjects completed 48 months (actual 60 months on metreleptin). Data from 3 subjects were excluded from final data analyses due to early loss to follow-up (n = 1), serious adverse event withdrawal (n = 1; development of persistent neutralizing antibody shortly after 18 months of drug exposure), and death (n = 1). The remaining 4 subjects withdrew from the study either through their own volition or due to the investigator decision (last observation carried forward in these 4 subjects). As expected, the median percent change from baseline triglyceride and hemoglobin A1c levels were not significant (55.76 percent (range: -66.79 to 203.80; p &amp;gt; 0.05), and 2.55 percent (range: -27.52 to 25.00; p &amp;gt; 0.05), respectively). Serious adverse events were reported in 8 of 11 patients and additional adverse events were observed in all patients. Apart from neutralizing antibody development in one subject causing substantial metabolic derangement, adverse events were considered not to be directly related to the study drug. Death was caused by a sudden cardiac event related to the specific molecular etiology (LMNA R349W) in one case. This interventional study provided valuable information on the efficacy and safety of long-term metreleptin in PL. Although nonsignificant fluctuations were observed in triglycerides, hemoglobin A1c levels were generally stable over time and the initial improvement seen in the first year were sustained. Adverse events were common but more likely due to the complex nature of the underlying disease. Although rare, neutralizing antibodies can develop in patients with PL treated with metreleptin.