Early B-cell transcription factor-2 defect as a novel cause of lipodystrophy: disruption of the adipose tissue character and integrity.

We report a novel cause of partial lipodystrophy associated with early B cell factor 2 (EBF2) nonsense variant (EBF2 8:26033143 C>A, c.493G>T, p.E165X) in a patient with an atypical form of partial lipodystrophy. The patient presented with progressive adipose tissue loss and metabolic deterioration at pre-pubertal age. In vitro and in vivo disease modeling demonstrates that the EBF2 variant impairs adipogenesis, causing excess accumulation of undifferentiated CD34+ cells, extracellular matrix proteins, and inflammatory myeloid cells in subcutaneous adipose tissues. Thus, this EBF2 p.E165X variant disrupts adipose tissue structure and function, leading to the development of partial lipodystrophy syndrome.

The Effects of Fluoxetine and Agomelatine on Neurocognitive Functions and Sleep in Patients with Major Depressive Disorder.

Background: We aimed to evaluate the effects of 6 weeks of agomelatine versus fluoxetine treatment on cognition and sleep. Methods: Agomelatine 25 mg/day and fluoxetine 20 mg/day were administered to major depressive disorder (MDD) patients. Assessments were conducted before the treatment and at the sixth week of treatment via psychometric measures and comprehensive neurocognitive assessments of various functions, including executive skills, attention, memory, verbal fluency, and speed of processing. Results: They both improved the evaluated neurocognitive test scores (P < .05), except for the scores of the Digit Span Test (P > .05), but only fluoxetine significantly improved the scores of the Controlled Oral Word Association Test (P = .018). Only in relation to the subjective sleep quality part of the Pittsburgh Sleep Quality Index (P = .035) and the Trail Making Test-B (TMT-B) (P = .046) was there an important difference between the study groups, and agomelatine showed better effects than fluoxetine in these measures. Conclusion: Both drugs improved the neurocognitive functioning in the participants. However, the better effect of agomelatine in improving the TMT-B scores suggests that it is a suitable option for MDD patients with noticeable executive disturbances.

Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy.

OBJECTIVE: Glucagon-like peptide 1 receptor agonists (GLP-1RA) are widely used for the management of diabetes mellitus (DM), but their efficacy in familial partial lipodystrophy (FPLD) is unknown. In this retrospective study, we evaluated the effect of GLP-1RA in patients with FPLD. RESEARCH DESIGN AND METHODS: We analyzed data, reported with SDs, from 14 patients with FPLD (aged 58 ± 12 years; 76.47% female) and 14 patients with type 2 DM (aged 58 ± 13 years; 71% female) before and 6 months after starting GLP-1RA. RESULTS: We observed reduction in weight (95 ± 23 to 91 ± 22 kg; P = 0.002), BMI (33 ± 6 to 31 ± 6 kg/m2; P = 0.001), HbA1c (8.2% ± 1.4% to 7.7% ± 1.4%; P = 0.02), and fasting glucose (186 ± 64 to 166 ± 53 mg/dL; P = 0.04) in patients with FPLD. The change in triglycerides after treatment was greater in the FPLD group compared with the DM group (P = 0.02). We noted acute pancreatitis in two case subjects with FPLD with longer therapy. CONCLUSIONS: Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

A Very-Low-Calorie Diet Can Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in Familial Partial Lipodystrophy.

There is no strong evidence that any specific diet is the preferred treatment for lipodystrophy syndromes. Here we remark on the benefits of a very-low-calorie diet (VLCD) in a patient with familial partial lipodystrophy type 2 (FPLD2). A 38-year-old female diagnosed with FPLD2, with a history of multiple comorbidities, underwent 16 weeks of VLCD with a short-term goal of improving her metabolic state rapidly to achieve pregnancy by in vitro fertilization (IVF). We observed a reduction of 12.3 kg in body weight and 1.4% in hemoglobin A1c. The decrease in the area under the curves of insulin (-33.2%), triglycerides (-40.7%), and free fatty acids (-34%) were very remarkable. Total body fat was reduced by 16%, and liver fat by 80%. Her egg retrieval rate and quality during IVF were far superior to past hyperstimulation. Our data encourage the use of this medical approach for other patients with similar metabolic and reproductive abnormalities due to adipose tissue insufficiency.

Deciphering the Clinical Presentations in LMNA-related Lipodystrophy: Report of 115 Cases and a Systematic Review.

CONTEXT: Lipodystrophy syndromes are a heterogeneous group of rare genetic or acquired disorders characterized by generalized or partial loss of adipose tissue. LMNA-related lipodystrophy syndromes are classified based on the severity and distribution of adipose tissue loss. OBJECTIVE: We aimed to annotate all clinical and metabolic features of patients with lipodystrophy syndromes carrying pathogenic LMNA variants and assess potential genotype-phenotype relationships. METHODS: We retrospectively reviewed and analyzed all our cases (n = 115) and all published cases (n = 379) curated from 94 studies in the literature. RESULTS: The study included 494 patients. The most common variants in our study, R482Q and R482W, were associated with similar metabolic characteristics and complications though those with the R482W variant were younger (aged 33 [24] years vs 44 [25] years; P < .001), had an earlier diabetes diagnosis (aged 27 [18] vs 40 [17] years; P < .001) and had lower body mass index levels (24 [5] vs 25 [4]; P = .037). Dyslipidemia was the earliest biochemical evidence described in 83% of all patients at a median age of 26 (10) years, while diabetes was reported in 61% of cases. Among 39 patients with an episode of acute pancreatitis, the median age at acute pancreatitis diagnosis was 20 (17) years. Patients who were reported to have diabetes had 3.2 times, while those with hypertriglyceridemia had 12.0 times, the odds of having pancreatitis compared to those who did not. CONCLUSION: This study reports the largest number of patients with LMNA-related lipodystrophy syndromes to date. Our report helps to quantify the prevalence of the known and rare complications associated with different phenotypes and serves as a comprehensive catalog of all known cases.

Impact of Nonalcoholic Fatty Liver Disease (NAFLD) on Weight Loss After Bariatric Surgery.

OBJECTIVE: Obesity and associated comorbidities, such as NAFLD, impose a major healthcare burden worldwide. Bariatric surgery remains the most successful approach for sustained weight loss and the resolution of obesity-related complications. However, the impact of preexisting NAFLD on weight loss after bariatric surgery has not been previously studied. The goal of this study is to assess the impact of preexisting NAFLD on weight loss outcomes up to 5 years after weight loss surgery. RESEARCH DESIGN AND METHODS: Data from the Michigan Bariatric Surgery Cohort (MI-BASiC) was extracted to examine the effect of baseline NAFLD on weight loss outcomes. The cohort included a total of 714 patients older than 18 years of age undergoing gastric bypass (GB; 380 patients) or sleeve gastrectomy (SG; 334 patients) at the University of Michigan between January 2008 and November 2013. Repeated measure analysis was used to determine if preexisting NAFLD was a predictor of weight loss outcomes up to 5 years post-surgery. RESULTS: We identified 221 patients with an established clinical diagnosis of NAFLD at baseline. Multivariable repeated measure analysis with adjustment for covariates shows that patients with preexisting NAFLD had a significantly lower percentage of total and excess weight loss compared to patients without preexisting NAFLD. Furthermore, our data show that baseline dyslipidemia is an indicator of the persistence of NAFLD after bariatric surgery. CONCLUSIONS: Our data show that patients' body weight loss in response to bariatric surgery is impacted by factors such as preexisting NAFLD. Additionally, we show that NAFLD may persist or recur in a subset of patients after surgery, and thus careful continued follow-up is recommended.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

Neural correlates of mental state decoding and mental state reasoning in schizophrenia.

Theory of mind skills are disrupted in schizophrenia. However, various theory of mind tasks measure different neurocognitive domains. This multimodal neuroimaging study aimed to investigate the neuroanatomical correlates of mental state decoding and reasoning components of theory of mind in schizophrenia and healthy controls (HCs) using T1-weighted and diffusion-weighted (DTI) magnetic resonance imaging (MRI). Sixty-two patients with schizophrenia and 34 HCs were included. The Reading the Mind in the Eyes (RMET) and Hinting tests were used to evaluate mental state decoding and reasoning, respectively. Correlations between social cognition and cortical parameters (thickness, volume, surface area), or DTI scalars (fractional anisotropy, axial diffusivity, radial diffusivity) were cluster-based corrected for multiple comparisons. In schizophrenia, RMET scores showed positive correlations in 3 clusters, including left insula thickness, right superior-temporal thickness, left superior-temporal-sulcus volume, and DTI analysis revealed that fractional anisotropy showed positive correlations in 3 clusters, including right inferior-fronto-occipital fasciculus, left forceps-major, left inferior-fronto-occipital fasciculus. In schizophrenia, Hinting test scores showed positive correlations in 3 clusters in T1-weighted MRI, including left superior-temporal-sulcus volume, left superior-temporal-sulcus surface area, left pars-orbitalis volume. In conclusion, this study provided evidence for the involvement of particular cortical regions and white matter tracts in mental state decoding and reasoning.

Impact of diabetes on weight loss outcomes after bariatric surgery: Experience from 5-year follow-up of Michigan Bariatric Surgery Cohort.

OBJECTIVE: For patients with obesity and diabetes, bariatric surgery can lead to the remission of both diseases. However, the possible impact of diabetes on the magnitude of weight loss outcomes after bariatric surgery has not been precisely quantified. RESEARCH DESIGN AND METHODS: Data from Michigan Bariatric Surgery Cohort (MI-BASiC) was extracted to examine the effect of baseline diabetes on weight loss outcomes. Consecutive patients older than 18 years of age undergoing gastric bypass (GB) or sleeve gastrectomy (SG) for obesity at University of Michigan between January 2008 and November 2013 were included. Repeated measures analysis was used to determine if diabetes was a predictor of weight loss outcomes over 5 years postsurgery. RESULTS: Out of the 714 included patients, 380 patients underwent GB [mean BMI 47.3 ± 0.4 kg/m2 , diabetes 149 (39.2%)] and 334 SG [mean BMI 49.9 ± 0.5 kg/m2 , diabetes 108 (32.3%)]. Multivariable repeated measures analysis showed, after adjusting for covariates, that individuals with diabetes had a significantly lower percentage of total (p = .0023) and excess weight loss (p = .0212) compared to individuals without diabetes. CONCLUSIONS: Our data demonstrate that patients with diabetes undergoing bariatric surgery would experience less weight loss than patients without diabetes.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Abnormal Structural Network Communication Reflects Cognitive Deficits in Schizophrenia.

Schizophrenia has long been thought to be a disconnection syndrome and several previous studies have reported widespread abnormalities in white matter tracts in individuals with schizophrenia. Furthermore, reductions in structural connectivity may also impair communication between anatomically unconnected pairs of brain regions, potentially impacting global signal traffic in the brain. Therefore, we used different communication models to examine direct and indirect structural connections (polysynaptic) communication in large-scale brain networks in schizophrenia. Diffusion-weighted magnetic resonance imaging scans were acquired from 62 patients diagnosed with schizophrenia and 35 controls. In this study, we used five network communication models including, shortest paths, navigation, diffusion, search information and communicability to examine polysynaptic communication in large-scale brain networks in schizophrenia. We showed less efficient communication between spatially widespread brain regions particulary encompassing cortico-subcortical basal ganglia network in schizophrenia group relative to controls. Then, we also examined whether reduced communication efficiency was related to clinical symptoms in schizophrenia group. Among different measures of communication efficiency, only navigation efficiency was associated with global cognitive impairment across multiple cognitive domains including verbal learning, processing speed, executive functions and working memory, in individuals with schizophrenia. We did not find any association between communication efficiency measures and positive or negative symptoms within the schizophrenia group. Our findings are important for improving our mechanistic understanding of neurobiological process underlying cognitive symptoms in schizophrenia.

A National Multicenter Study of Leptin and Leptin Receptor Deficiency and Systematic Review.

CONTEXT: Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity. OBJECTIVE: To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships. METHODS: Our cohort included 18 patients (LEP = 11, LEPR = 7), 8 of whom had been previously reported. A systematic literature review was conducted in July 2022. Forty-two of 47 studies on LEP/LEPR were selected. RESULTS: Of 10 new cases, 2 novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40 + 5G > C). Eleven patients with LEP deficiency received metreleptin, 4 of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age [3 (9) vs 7 (13) years, P = .02] and had a higher median body mass index (BMI) SD score [3.1 (2) vs 2.8 (1) kg/m2, P = 0.02], which was more closely associated with frameshift variants (P = .02). Patients with LEP deficiency were more likely to have hyperinsulinemia (P = .02). CONCLUSION: Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefitted from long-term metreleptin, with 1 losing efficacy due to neutralizing antibodies.

Pelvis Magnetic Resonance Imaging to Diagnose Familial Partial Lipodystrophy.

CONTEXT: The diagnosis of familial partial lipodystrophy (FPLD) is currently made based on clinical judgment. OBJECTIVE: There is a need for objective diagnostic tools that can diagnose FPLD accurately. METHODS: We have developed a new method that uses measurements from pelvic magnetic resonance imaging (MRI) at the pubis level. We evaluated measurements from a lipodystrophy cohort (n = 59; median age [25th-75th percentiles]: 32 [24-44]; 48 females and 11 males) and age- and sex-matched controls (n = 29). Another dataset included MRIs from 289 consecutive patients. RESULTS: Receiver operating characteristic curve analysis revealed a potential cut-point of ≤13 mm gluteal fat thickness for the diagnosis of FPLD. A combination of gluteal fat thickness ≤13 mm and pubic/gluteal fat ratio ≥2.5 (based on a receiver operating characteristic curve) provided 96.67% (95% CI, 82.78-99.92) sensitivity and 91.38% (95% CI, 81.02-97.14) specificity in the overall cohort and 100.00% (95% CI, 87.23-100.00) sensitivity and 90.00% (95% CI, 76.34-97.21) specificity in females for the diagnosis of FPLD. When this approach was tested in a larger dataset of random patients, FPLD was differentiated from subjects without lipodystrophy with 96.67% (95% CI, 82.78-99.92) sensitivity and 100.00% (95% CI, 98.73-100.00) specificity. When only women were analyzed, the sensitivity and the specificity was 100.00% (95% CI, 87.23-100.00 and 97.95-100.00, respectively). The performance of gluteal fat thickness and pubic/gluteal fat thickness ratio was comparable to readouts performed by radiologists with expertise in lipodystrophy. CONCLUSION: The combined use of gluteal fat thickness and pubic/gluteal fat ratio from pelvic MRI is a promising method to diagnose FPLD that can reliably identify FPLD in women. Our findings need to be tested in larger populations and prospectively.

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.

Negative symptoms are associated with modularity and thalamic connectivity in schizophrenia.

Negative symptoms, including avolition, anhedonia, asociality, blunted affect and alogia are associated with poor long-term outcome and functioning. However, treatment options for negative symptoms are limited and neurobiological mechanisms underlying negative symptoms in schizophrenia are still poorly understood. Diffusion-weighted magnetic resonance imaging scans were acquired from 64 patients diagnosed with schizophrenia and 35 controls. Global and regional network properties and rich club organization were investigated using graph analytical methods. We found that the schizophrenia group had higher modularity, clustering coefficient and characteristic path length, and lower rich connections compared to controls, suggesting highly connected nodes within modules but less integrated with nodes in other modules in schizophrenia. We also found a lower nodal degree in the left thalamus and left putamen in schizophrenia relative to the control group. Importantly, higher modularity was associated with greater negative symptoms but not with cognitive deficits in patients diagnosed with schizophrenia suggesting an alteration in modularity might be specific to overall negative symptoms. The nodal degree of the left thalamus was associated with both negative and cognitive symptoms. Our findings are important for improving our understanding of abnormal white-matter network topology underlying negative symptoms in schizophrenia.