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.

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).

Impact of lipodystrophy on health-related quality of life: the QuaLip study.

Background: Lipodystrophy is a rare disease characterized by loss of adipose tissue. Natural history studies have demonstrated significant burden of disease; however, there is limited data on the impact of lipodystrophy on quality of life (QoL) and psychoemotional well-being. The QuaLip study is a prospective observational real-world study that aims to determine the impact of lipodystrophy on QoL and psychoemotional well-being and explore subjective burden of the disease.

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.

A new mutation in the 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 () 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.

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.

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.

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.

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.

Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

Background: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

Background: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition.

Methods: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials.

Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study.

Background: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD.

Complications of lipodystrophy syndromes.

Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems.

Metreleptin replacement treatment improves quality of life and psychological well-being in congenital generalized lipodystrophy.

The near total lack of subcutaneous fat in congenital generalized lipodystrophy (CGL) leads to the accumulation of fat in ectopic organs and severe insulin resistance, which are associated with serious metabolic abnormalities. Cosmetic aspects of the disease are likely to affect the quality of life (QoL) and physiological well-being in these individuals. Metreleptin, recombinant human leptin, replacement treatment has been shown to have benefits in treating the metabolic abnormalities of CGL.

Management of endocrine surgical disorders during COVID-19 pandemic: expert opinion for non-surgical options.

Purpose: The COVID-19 pandemic brought unprecedented conditions for overall health care systems by restricting resources for non-COVID-19 patients. As the burden of the disease escalates, routine elective surgeries are being cancelled. The aim of this paper was to provide a guideline for management of endocrine surgical disorders during a pandemic.

Effect of Leptin Therapy on Survival in Generalized and Partial Lipodystrophy: A Matched Cohort Analysis.

Context: Data quantifying the impact of metreleptin therapy on survival in non-human immunodeficiency virus (HIV)-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) are unavailable.

Objective: This study aimed to estimate the treatment effect of metreleptin on survival in patients with GL and PL.

Design/setting/patients: Demographic and clinical characteristics were used to match metreleptin-treated and metreleptin-naïve patients with GL and PL.

Association of Leptin Levels and Disease Activity in Patients with Early Rheumatoid Arthritis.

Objective: Previous studies have reported a link between metabolic parameters and disease activity in rheumatoid arthritis (RA), although the evidence is limited in early RA. We aimed to investigate the relationship between disease activity and adipocytokine levels in subjects with early RA.

Methods: Forty-seven patients with early RA (symptom duration ≤12 months) were enrolled.