Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.

Lipodystrophy syndromes are rare diseases primarily affecting the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, often leading to reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmunity in the vast majority of cases. While many subtypes are now recognized and classified, the disease remains remarkably underdiagnosed. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of European centers of excellence working in the field of lipodystrophies aiming at promoting international collaborations to increase basic scientific understanding and clinical management of these syndromes. The network has developed a European Patient Registry as a collaborative research platform for consortium members. ECLip and ECLip registry activities involve patient advocacy groups to increase public awareness and to seek advice on research activities relevant from the patients perspective. The annual ECLip congress provides updates on the research results of various network groups members.

Clinical Characteristics of Patients With Acquired Partial Lipodystrophy: A Multicenter Retrospective Study.

BACKGROUND: Barraquer-Simons syndrome (BSS) is a rare, acquired form of lipodystrophy characterized by progressive loss of upper body subcutaneous fat, which affects face, upper limbs, and trunk. The pathogenesis of the disease is not entirely known and may involve autoimmune mechanisms. AIM: This study aimed to provide a comprehensive picture of the clinical, immunological, and metabolic features of a large cohort of patients with BSS. Our primary objectives included the validation of existing diagnostic tools, the evaluation of novel diagnostic approaches, and the exploration of potential disease triggers or genetic predispositions. SUBJECTS AND METHODS: Twenty-six patients were diagnosed with BSS based on accepted criteria defined by international guidelines. Anthropometric parameters, biochemical tests, organ- and non-organ-specific autoantibodies, HLA status, and screening of the LMNB2 gene were performed. RESULTS: Patients were predominantly females (73%); fat loss occurred mostly during childhood (77%) at a median age of 8 years. Among various anthropometric measures, the ratio between the proportion of fat mass in upper limbs and lower limbs showed the best predictive value for diagnosis. A total of 11.5% of patients had diabetes, 34.6% dyslipidemia, and 26.9% hepatic steatosis. Seventy-five percent of children and 50% of adults had C3 hypocomplementemia; 76% of patients were positive for 1 or more autoantibodies. HLA-DRB1 11:03 had higher allelic frequencies compared with the general population. A single variant in the LMNB2 gene was found in 1 patient. CONCLUSION: BSS has a childhood onset and is often associated with autoimmune diseases. Skinfold thickness measurements and fat assessment by dual energy X-ray absorptiometry are useful tools to identify the disease. C3 hypocomplementemia and the presence of autoantibodies may be used as additional diagnostic supportive criteria but the prevalence of C3 hypocomplementemia may be lower than previously reported.

A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

Canagliflozin on top of dual renin-angiotensin system blockade in a woman with partial acquired lipodystrophy, type 2 diabetes and severely proteinuric chronic kidney disease: a case report.

Sodium glucose cotransporter 2 inhibitors have proven strong efficacy in reducing end-stage renal disease in patients with type 2 diabetes. We are presenting here the case of a 40-year-old woman with acquired partial lipodystrophy, type 2 diabetes and essential hypertension complicated by chronic kidney disease and proteinuria in the nephrotic range. She first came to our attention in 2012; estimated glomerular filtration rate (eGFR) was 41.5 ml/min/1.73 m2 and total proteinuria was 375 mg/24h; she was treated with dual renin angiotensin system blocking. Proteinuria significantly increased during the following years, reaching a nephrotic range (>5 g/day). A kidney biopsy revealed a tubule-interstitial involvement compatible with type 2 diabetes. Leptin replacement therapy, started in 2018, improved glycaemic control and lipid profile, also determining a reduction in insulin total daily dose. In 2019, after the publication of the CREDENCE study, canagliflozin was started on top of losartan and ramipril. After an initial, expected eGFR drop, kidney function stabilized, and albuminuria significantly reduced (from 4120 to 984 mg/24h), while serum potassium showed only minimal increase. At last follow-up (2022) total proteinuria was still reducing (510 mg/24h), while kidney function was substantially unchanged (eGFR 40 ml/min/1.73 m2). This case report suggests that, despite not recommended in international guidelines, the use of SGLT2i in combination with dual renin angiotensin system blockade should be considered in specific conditions and under close clinical monitoring.

Oxidative and DNA damage in obese patients undergoing bariatric surgery: A one-year follow-up study.

The pathogenesis of obesity and related comorbidities has long been associated with oxidative stress. The excess of adipose tissue contributes to the production of free radicals that sustain both a local and a systemic chronic inflammatory state, whereas its reduction can bring to an improvement in inflammation and oxidative stress. In our work, using the fluorescent lipid probe BODIPY® 581/591 C11 and the γH2AX foci assay, a well-known marker of DNA double strand breaks (DSB), we evaluated the extent of cell membrane oxidation and DNA damage in peripheral blood lymphocytes of normal weight (NW) controls and obese patients sampled before and after bariatric surgery. Compared to NW controls, we observed a marked increase in both the frequencies of oxidized cells or nuclei exhibiting phosphorylation of histone H2AX in preoperatory obese patients. After bariatric surgery, obese patients, resampled over one-year follow-up, improved oxidative damage and reduced the presence of DSB. In conclusion, the present study highlights the importance for obese patients undergoing bariatric surgery to also monitor these molecular markers during their postoperative follow-up.

Obesity, Hyperfiltration, and Early Kidney Damage: A New Formula for the Estimation of Creatinine Clearance.

CONTEXT: Glomerular hyperfiltration may represent a direct pathogenetic link between obesity and kidney disease. The most widely used methods to estimate creatine clearance such as Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have not been validated in subjects with obesity. OBJECTIVE: The performance of prediction formulas was compared with measured creatinine clearance (mCrCl) in subjects with obesity. METHODS: The study population included 342 patients with obesity (mean BMI 47.6 kg/m2) without primary kidney disease. A urine collection was performed over 24 hours for measurement of CrCl. RESULTS: mCrCl increased with body weight. The CG formula showed an overestimation at high CrCl, whereas an underestimation resulted from CKD-EPI and MDRD. To improve the accuracy of estimated CrCl (eCrCl), a new CG-based formula was developed:53+0.7×(140-Age)×Weight/(96xSCr)×(0.85iffemale)A cut-off point for BMI of 32 kg/m2 was identified, at which the new formula may be applied to improve eCrCl. CONCLUSION: In patients with obesity the glomerular filtration rate increases with body weight, and it is associated with the presence of albuminuria, suggesting an early kidney injury. We propose a novel formula that improves the accuracy of eCrCl to avoid missed diagnoses of hyperfiltration in patients with obesity.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had panniculitis-associated AGL. The IgG isotype was predominant, although some IgM antibodies were detected. Epitope-mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αß-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.

Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip) Cambridge, UK, 7-8 April 2022.

Lipodystrophy syndromes are rare diseases with defects in the development or maintenance of adipose tissue, frequently leading to severe metabolic complications. They may be genetic or acquired, with variable clinical forms, and are largely underdiagnosed. The European Consortium of Lipodystrophies, ECLip, is a fully functional non-profit network of European centers of excellence working in the field of lipodystrophies. It provides a favorable environment to promote large Europe-wide and international collaborations to increase the basic scientific understanding and clinical management of these diseases. It works with patient advocacy groups to increase public awareness. The network also promotes a European Patient Registry of lipodystrophies, as a collaborative research platform for consortium members. The annual congress organized gives an update of the findings of network research groups, highlighting clinical and fundamental aspects. The talks presented during the meeting in Cambridge, UK, in 2022 are summarized in these minutes.

Circulating Levels of MiRNAs From 320 Family in Subjects With Lipodystrophy: Disclosing Novel Signatures of the Disease.

Lipodystrophy (LD) indicates a group of rare disorders, with generalized or partial loss of white adipose tissue (WAT) often associated with metabolic derangements. Heterogeneity/wide spectrum of the disease and lack of biomarkers make diagnosis often difficult. MicroRNAs are important to maintain a correct WAT function and WAT is a source of circulating miRNAs (cmiRs). miRNAs from 320 family were previously detected in the WAT and variably associated to the metabolic syndrome. Our aim was then to investigate if LD can result in altered abundance of cmiRs-320. We collected samples from a cohort of LD subjects of various subtypes and from age matched controls. Use of quantitative PCR determined that cmiRs- 320a-3p, 320b, 320c, 320e are upregulated, while 320d is downregulated in LD. CmiRs-320 power as classifiers was more powerful in the most extreme and defined forms of LD, including the generalized and the Dunnigan subtypes. cmiR-320a-3p showed significant inverse relationships with plasma leptin (P < 0.0001), typically low in LD. The hepatic enzymes gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the marker of inflammation C-reactive protein (CRP) were inversely related to cmiR 320d (P < 0.05, for CRP and GGT; P < 0.01, for AST and ALT). Gene ontology analysis revealed cell-cell adhesion as a process regulated by 320 miRNAs targets, thus disclosing a novel route to investigate origin of WAT loss/dysfunction. In conclusion, cmiRs-320 constitute novel biomarkers of LD, abundance of miR320a-3p is inversely associated to indicators related to WAT function, while downregulation of cmiR-320d predicts an altered hepatic profile and higher inflammation.

Brain effect of bariatric surgery in people with obesity.

BACKGROUND/OBJECTIVES: The link between obesity and brain function is a fascinating but still an enigmatic topic. We evaluated the effect of Roux-en-Y gastric bypass (RYGB) on peripheral glucose metabolism, insulin sensitivity, brain glucose utilization and cognitive abilities in people with obesity. SUBJECTS/METHODS: Thirteen subjects with obesity (F/M 11/2; age 44.4 ± 9.8 years; BMI 46.1 ± 4.9 kg/m2) underwent 75-g OGTT during a [18F]FDG dynamic brain PET/CT study at baseline and 6 months after RYGB. At the same timepoints, cognitive performance was tested with Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Trail making test (TMT) and Token test (TT). Glucose, insulin, C-peptide, GLP-1, GIP, and VIP levels were measured during OGTT. Leptin and BDNF levels were measured before glucose ingestion. RESULTS: RYGB resulted in significant weight loss (from 46.1 ± 4.9 to 35.3 ± 5.0 kg/m2; p < 0.01 vs baseline). Insulin sensitivity improved (disposition index: from 1.1 ± 0.2 to 2.9 ± 1.1; p = 0.02) and cerebral glucose metabolic rate (CMRg) declined in various brain areas (all p ≤ 0.01). MMSE and MoCA score significantly improved (p = 0.001 and p = 0.002, respectively). TMT and TT scores showed a slight improvement. A positive correlation was found between CMRg change and HOMA-IR change in the caudate nucleus (ρ = 0.65, p = 0.01). Fasting leptin decreased (from 80.4 ± 13.0 to 16.1 ± 2.4 ng/dl; p = 0.001) and correlated with CMRg change in the hippocampus (ρ = 0.50; p = 0.008). CMRg change was correlated with cognitive scores changes on the TMT and TT (all p = 0.04 or less). CONCLUSIONS: Bariatric surgery improves CMRg directly related to a better cognitive testing result. This study highlights the potential pleiotropic effects of bariatric surgery. TRIAL REGISTRY NUMBER: NCT03414333.

Ketogenic Diet and Weight Loss: Is There an Effect on Energy Expenditure?

A dysregulation between energy intake (EI) and energy expenditure (EE), the two components of the energy balance equation, is one of the mechanisms responsible for the development of obesity. Conservation of energy equilibrium is deemed a dynamic process and alterations of one component (energy intake or energy expenditure) lead to biological and/or behavioral compensatory changes in the counterpart. The interplay between energy demand and caloric intake appears designed to guarantee an adequate fuel supply in variable life contexts. In the past decades, researchers focused their attention on finding efficient strategies to fight the obesity pandemic. The ketogenic or "keto" diet (KD) gained substantial consideration as a potential weight-loss strategy, whereby the concentration of blood ketones (acetoacetate, 3-ß-hydroxybutyrate, and acetone) increases as a result of increased fatty acid breakdown and the activity of ketogenic enzymes. It has been hypothesized that during the first phase of KDs when glucose utilization is still prevalent, an increase in EE may occur, due to increased hepatic oxygen consumption for gluconeogenesis and for triglyceride-fatty acid recycling. Later, a decrease in 24-h EE may ensue due to the slowing of gluconeogenesis and increase in fatty acid oxidation, with a reduction of the respiratory quotient and possibly the direct action of additional hormonal signals.

Autoimmunity in lipodystrophy syndromes.

Lipodystrophy syndromes are rare, heterogeneous disorders characterized by the complete or partial deficiency of adipose tissue and are classified according to the extent of fat loss in generalized or partial subtypes, or based on the pathogenic mechanisms in genetic or acquired. While in most cases of congenital forms of lipodystrophy a genetic alteration can be identified, the pathogenic mechanisms responsible for the acquired diseases are not fully clarified. Based on the evidence of a positive association between most acquired lipodystrophies and autoimmune disorders including immune mediated alterations in the adipose tissue of patients affected by acquired lipodystrophy, a reaction against white adipose tissue antigens is postulated. Recent acquisitions have shed new light on the possible pathogenic mechanisms and identified novel forms of acquired lipodystrophy which are possibly immune-mediated. The aim of this review is to give an update on acquired lipodystrophies describing pathogenic mechanisms involved and the relationships between acquired lipodystrophies and other autoimmune disorders. Larger studies based on international disease registries are needed to collect accurate information on the prevalence, risk factors, genetic predisposition, natural history, disease markers and treatment efficacy of these ultrarare disorders.

Complement Factor D (adipsin) Levels Are Elevated in Acquired Partial Lipodystrophy (Barraquer-Simons syndrome).

Complement overactivation has been reported in most patients with Barraquer-Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts (p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS (r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient's adipose tissue, we observed decreased CFD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment.

Bariatric surgery restores visual cortical plasticity in nondiabetic subjects with obesity.

BACKGROUND/OBJECTIVES: Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, leptin, and brain-derived neurotrophic factor (BDNF). SUBJECTS/METHODS: NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m2) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects. RESULTS: A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = -0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUCactive GLP-1 and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = -0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP. CONCLUSIONS: Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels.

Partial Lipodystrophy and LMNA p.R545H Variant.

Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

Lipodystrophy as a Late Effect after Stem Cell Transplantation.

Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying mechanisms of the disease. The findings suggest that HSCT-associated lipodystrophies may be seen as a novel form of acquired lipodystrophy.

Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation.

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene (LMNA) mutation c.1045 C > T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.

Plasma N-acetylaspartate: Development and validation of a quantitative assay based on HPLC-MS-MS and sample derivatization.

N-acetylaspartate is a human endogenous compound synthesized by neurons, which is involved in neuronal metabolism. It is used as a marker in brain magnetic resonance spectroscopy to investigate several neurological and metabolic disorders, that can be related to a variation of its concentration with respect to reference values. N-acetylaspartate is present also in biological fluids, such as plasma, urine, and cerebrospinal fluid, where it can be quantified. Here we describe the development and validation, in compliance with the EMA guidelines, of a novel assay method for the quantification of N-acetylaspartate in plasma based on tandem mass spectrometry coupled to liquid chromatography. Its peculiarity lies in the fact that sample preparation includes an esterification step, which significantly improves the chromatographic performances and, consequently, also the method sensitivity, reproducibility and accuracy. Instrumental LLOQ is 0.06 ng/mL, i.e. at least 300 times lower than the medium N-acetylaspartate concentration in samples, accuracy is in the range 98-103%, while precision lies between 1 and 3%. The method robustness was tested in about 1000 injections of plasma samples, 96 of which were used also to assess the reference ranges in control subjects (16.46-63.40 ng/mL). Controls were then compared to plasma samples from type 2 diabetic patients. Contrary to brain magnetic resonance spectroscopy, which demonstrated a decrease in the N-acetylaspartate levels in right frontal and parieto-temporal region of type 2 diabetic patients, plasma analysis showed no statistical difference with respect to controls. However, the method here described can be profitably used in studies concerning different disorders with CNS involvement, as confirmed by reports available in the literature.

Correction to: Immunological features of patients affected by Barraquer-Simons syndrome.

Following the publication of the original article [1], the authors have requested to amend the Abstract and Discussion section as follows.

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease.

Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase ß (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144*) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.