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.

Effect of ß-Estradiol on Adipogenesis in a 3T3-L1 Cell Model of Prelamin A Accumulation.

The accumulation of farnesylated prelamin A has been suggested as one of the mechanisms responsible for the loss of fat in type 2 familial partial lipodystrophy due to variants in the LMNA gene. In this rare disease, fat loss appears in women after puberty, affecting sex-hormone-dependent anatomical areas. This study investigated the impact of 17-ß-estradiol on adipogenesis in murine preadipocytes subjected to a pharmacologically induced accumulation of farnesylated and non-farnesylated prelamin A. To induce the accumulation of non-farnesylated or farnesylated prelamin A, 3T3-L1 cells were treated with the farnesyltransferase inhibitor 277 or the methyltransferase inhibitor N-acetyl-S-farnesyl-l-cysteine methylester. Subsequently, the cells were induced to undergo adipocyte differentiation in the presence or absence of 17-ß-estradiol. Prelamin A accumulation was assessed through immunofluorescence, while real-time PCR and Western blot techniques were used to quantify several adipogenic genes and evaluate protein levels, respectively. The results showed that 17-ß-estradiol increased adipogenesis, although the combination of this hormone plus farnesylated prelamin A led to a reduction in the number of mature adipocytes and the expression of the different genes involved in adipogenesis. In conclusion, the influence of farnesylated prelamin A accumulation on adipogenesis manifested only in the presence of estradiol. These in vitro findings suggest a potential mechanism that could explain the characteristic phenotype in women suffering type 2 familial partial lipodystrophy.

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.

Clinical Characterisation and Comorbidities of Acquired Generalised Lipodystrophy: A 14-Year Follow-Up Study.

Acquired generalised lipodystrophy (AGL) is a rare disorder characterised by the gradual loss of fat that tends to generalise over time, the origin of which is still not fully clarified. The aim of this study was to offer a detailed description of seven patients with AGL (five women, 33.8 ± 18.6 years of age), evaluated over the last 14 years, in order to augment the knowledge of this disorder. The onset of the phenotype occurred during childhood and adolescence in five cases, and in adulthood in two cases. Three patients reported infections or vaccine administration prior to the development of lipodystrophy, and two subjects reported nodular swelling. The most frequent physical features were phlebomegaly, umbilical protrusion/hernia, and acanthosis nigricans. Skinfolds and body composition analysis showed the generalised absence of fat, with the exception of one patient in whom fat loss was spared in the trunk. The loss of fat in the palms/soles was observed in five subjects. Regarding metabolic comorbidities, throughout follow-up, two patients developed type 1 diabetes and one type 2 diabetes; three also presented hypertriglyceridaemia, one of whom developed acute pancreatitis, and no macrovascular complications were observed. Only one patient showed decreased complement C4. Autoimmunity was present in all cases, and six patients manifested Hashimoto's thyroiditis, type 1 diabetes, autoimmune hepatitis, and/or celiac disease. Thus, there are certain clinical characteristics of AGL that may be considered important diagnostic criteria to differentiate this disorder from other lipodystrophy subtypes.

The value of waist circumference as a preditor of cardiovascular risk in adult patients with classic phenylketonuria / Valor del perímetro cintura en la predicción del riesgo cardiovascular en pacientes adultos con fenilcetonuria clásica

Background and aims We aimed to evaluate the differences in some cardiovascular risk (CVR) factors between adult patients without and with phenylketonuria (PKU) and to explore the correlation between waist circumference (WC) and body mass index (BMI) with the previous variables. Methods This was an observational case–control study that included patients older than 18 years with a diagnosis of classic PKU. The controls were age- and sex-matched individuals. We collected demographic, epidemiological, clinical, and laboratory variables, including WC, BMI, and lipid profile parameters. Results A total of 72 patients (25 controls and 47 cases) were included with a mean age of 36 years, of which 45 (62%) were women. Adult PKU patients showed lower high-density lipoprotein cholesterol (HDL-c) and higher triglyceride (TG) levels than the control group. We found an association between WC and uric acid (B=0.024, P=0.013, 95%CI: 0.005–0.043), TG (B=0.768, P=0.024, 95%CI: 0.107–1.428), and HDL-c (B=−0.254, P=0.026, 95%CI: −0.477 to (−0.032)) levels in PKU patients. However, we did not find any trend between WC and uric acid, TG and HDL-c levels that reached statistical significance (P<0.05) in patients without PKU. Conclusions Waist circumference rather than BMI may better represent the CVR in patients with PKU (AU)

Introducción y objetivos Nuestro objetivo fue evaluar las diferencias en algunos factores de riesgo cardiovascular entre pacientes adultos sin y con fenilcetonuria (FCU) y explorar la correlación del perímetro cintura (PC) e índice de masa corporal (IMC) con las variables previas. Métodos Fue un estudio de casos y controles que incluyó pacientes mayores de 18 años con diagnóstico de FCU clásica. Los controles fueron individuos emparejados por edad y sexo. Se recogieron variables demográficas, epidemiológicas, clínicas y de laboratorio, destacando PC, IMC y parámetros del perfil lipídico. Resultados Se reclutaron 72 pacientes (25 controles y 47 casos) con una edad media de 36 años (62% mujeres). Respecto al grupo control, los pacientes adultos con FCU mostraron niveles más bajos de colesterol de lipoproteínas de alta densidad (HDL-c) y más altos de triglicéridos. En los pacientes con FCU, PC se asoció con los niveles de ácido úrico (B=0,024, P=0,013, 95% CI: 0,005-0,043), triglicéridos (B=0,768, P=0,024, 95% CI: 0,107-1.428) y HDL-c (B=−0,254, P=0,026, 95% CI: −0,477–[−0,032]). Sin embargo, no encontramos ninguna tendencia entre WC y dichas variables que alcanzara significación estadística en los pacientes sin FCU. Aunque observamos una buena correlación entre el IMC y PC en pacientes sin y con FCU, el aumento de PC por unidad de aumento de IMC podría ser mayor en estos últimos. Conclusiones Perímetro de cintura podría representar mejor que IMC el riesgo cardiovascular en pacientes con FCU (AU)

Natural history and comorbidities of generalised and partial lipodystrophy syndromes in Spain.

The rarity of lipodystrophies implies that they are not well-known, leading to delays in diagnosis/misdiagnosis. The aim of this study was to assess the natural course and comorbidities of generalised and partial lipodystrophy in Spain to contribute to their understanding. Thus, a total of 140 patients were evaluated (77.1% with partial lipodystrophy and 22.9% with generalised lipodystrophy). Clinical data were collected in a longitudinal setting with a median follow-up of 4.7 (0.5-17.6) years. Anthropometry and body composition studies were carried out and analytical parameters were also recorded. The estimated prevalence of all lipodystrophies in Spain, excluding Köbberling syndrome, was 2.78 cases/million. The onset of phenotype occurred during childhood in generalised lipodystrophy and during adolescence-adulthood in partial lipodystrophy, with the delay in diagnosis being considerable for both cohorts. There are specific clinical findings that should be highlighted as useful features to take into account when making the differential diagnosis of these disorders. Patients with generalised lipodystrophy were found to develop their first metabolic abnormalities sooner and a different lipid profile has also been observed. Mean time to death was 83.8 ± 2.5 years, being shorter among patients with generalised lipodystrophy. These results provide an initial point of comparison for ongoing prospective studies such as the ECLip Registry study.

A murine model of BSCL2-associated Celia's encephalopathy.

Celia's encephalopathy or progressive encephalopathy with/without lipodystrophy is a neurodegenerative disease with a fatal prognosis in childhood. It is generally caused by the c.985C > T variant in the BSCL2 gene, leading to the skipping of exon 7 and resulting in an aberrant seipin protein (Celia-seipin). To precisely define the temporal evolution and the mechanisms involved in neurodegeneration, lipodystrophy and fatty liver in Celia's encephalopathy, our group has generated the first global knock-in murine model for the aberrant human transcript of BSCL2 (Bscl2Celia/Celia) using a strategy based on the Cre/loxP recombination system. In order to carry out a characterization at the neurological, adipose tissue and hepatic level, behavioral studies, brain PET, metabolic, histological and molecular studies were performed. Around 12% of homozygous and 5.4% of heterozygous knock-in mice showed severe neurological symptoms early in life, and their life expectancy was dramatically reduced. Severe generalized lipodystrophy and mild hepatic steatosis were present in these affected animals, while serum triglycerides and glucose metabolism were normal, with no insulin resistance. Furthermore, the study revealed a reduction in brain glucose uptake, along with patchy loss of Purkinje cells and the presence of intranuclear inclusions in cerebellar cortex cells. Homozygous, non-severely-affected knock-in mice showed a decrease in locomotor activity and greater anxiety compared with their wild type littermates. Bscl2Celia/Celia is the first murine model of Celia's encephalopathy which partially recapitulates the phenotype and severe neurodegenerative picture suffered by these patients. This model will provide a helpful tool to investigate both the progressive encephalopathy with/without lipodystrophy and congenital generalized lipodystrophy.

The value of waist circumference as a preditor of cardiovascular risk in adult patients with classic phenylketonuria.

BACKGROUND AND AIMS: We aimed to evaluate the differences in some cardiovascular risk (CVR) factors between adult patients without and with phenylketonuria (PKU) and to explore the correlation between waist circumference (WC) and body mass index (BMI) with the previous variables. METHODS: This was an observational case-control study that included patients older than 18 years with a diagnosis of classic PKU. The controls were age- and sex-matched individuals. We collected demographic, epidemiological, clinical, and laboratory variables, including WC, BMI, and lipid profile parameters. RESULTS: A total of 72 patients (25 controls and 47 cases) were included with a mean age of 36 years, of which 45 (62%) were women. Adult PKU patients showed lower high-density lipoprotein cholesterol (HDL-c) and higher triglyceride (TG) levels than the control group. We found an association between WC and uric acid (B=0.024, P=0.013, 95%CI: 0.005-0.043), TG (B=0.768, P=0.024, 95%CI: 0.107-1.428), and HDL-c (B=-0.254, P=0.026, 95%CI: -0.477 to (-0.032)) levels in PKU patients. However, we did not find any trend between WC and uric acid, TG and HDL-c levels that reached statistical significance (P<0.05) in patients without PKU. CONCLUSIONS: Waist circumference rather than BMI may better represent the CVR in patients with PKU.

The Metreleptin Effectiveness and Safety Registry (MEASuRE): concept, design and challenges.

BACKGROUND: Metreleptin, a recombinant analog of human leptin, is an approved therapy, adjunct to diet, to treat the metabolic complications of leptin deficiency in patients with lipodystrophy - a group of rare diseases characterized by a paucity of adipose tissue. MEASuRE (Metreleptin Effectiveness And Safety Registry) is a post-authorization, voluntary registry that gathers long-term safety and effectiveness data on metreleptin. Here, we present the aims and evolution of MEASuRE. METHODS: MEASuRE was established to collect data from patients receiving commercially supplied metreleptin in the United States (US) and European Union (EU). MEASuRE aims to determine the incidence and severity of safety events and describe the clinical characteristics and therapeutic outcomes in the metreleptin-treated population. A key feature of MEASuRE is that it accumulates data from different sources to meet post-authorization objectives. US data are received directly from treating physicians via a contract research organization-mediated electronic data capture system. In the EU, data are received via the European Registry of Lipodystrophies managed by the European Consortium of Lipodystrophies (ECLip), a platform established by researchers and physicians to advance the knowledge of lipodystrophy. MEASuRE complies with applicable regulatory requirements governing privacy, and the storage, management, and access of data. RESULTS: Leveraging processes, infrastructure, and data from the ECLip registry presented several challenges that were addressed during MEASuRE's development, including the expansion of the ECLip registry to accommodate MEASuRE-specific data elements, extensive data matching processes to ensure data consistency regardless of source, and rigorous data validation following the amalgamation of global data. Through the support of ECLip, MEASuRE is now a fully operational registry with the capacity for gathering and integrating standardized US- and EU-derived data. As of 31st October 2022, 15 US and four EU sites have participated in the MEASuRE, enrolling 85 patients globally. CONCLUSIONS: Our experiences show that a post-authorization product registry can be successfully integrated into an existing patient registry. We propose that, through collaboration with existing registries and use of their established resources, patient enrolment timelines and data collection for new registries can be expedited. The learnings presented here may be applicable to other registries with similar objectives. TRIAL REGISTRATION: NCT02325674; Registered 25 December 2014 - Retrospectively registered'. https://clinicaltrials.gov/ct2/show/NCT02325674 .

Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review.

Type 2 familial partial lipodystrophy (FPLD2) is a laminopathic lipodystrophy due to pathogenic variants in the LMNA gene. Its rarity implies that it is not well-known. The aim of this review was to explore the published data regarding the clinical characterisation of this syndrome in order to better describe FPLD2. For this purpose, a systematic review through a search on PubMed until December 2022 was conducted and the references of the retrieved articles were also screened. A total of 113 articles were included. FPLD2 is characterised by the loss of fat starting around puberty in women, affecting limbs and trunk, and its accumulation in the face, neck and abdominal viscera. This adipose tissue dysfunction conditions the development of metabolic complications associated with insulin resistance, such as diabetes, dyslipidaemia, fatty liver disease, cardiovascular disease, and reproductive disorders. However, a great degree of phenotypical variability has been described. Therapeutic approaches are directed towards the associated comorbidities, and recent treatment modalities have been explored. A comprehensive comparison between FPLD2 and other FPLD subtypes can also be found in the present review. This review aimed to contribute towards augmenting knowledge of the natural history of FPLD2 by bringing together the main clinical research in this field.

The role of phenylalanine levels in the neuropsychological and neuroanatomical status of adult patients with phenylketonuria: The impact of fluctuations.

We aimed to evaluate the role of plasma phenylalanine (Phe) levels and its fluctuations in some neurocognitive domains and brain magnetic resonance imaging (MRI) findings in adult patients with phenylketonuria (PKU). It was an observational study that included patients older than 18 years with early-treated classical PKU. Plasma Phe levels were measured every other month throughout 2 years and predictor variables were the mean, maximum (max), minimum (min), range (min-max), and plasma Phe levels at the time of cognitive testing. Patients were evaluated for executive function, processing speed, visual attention, and fluid cognitive abilities using the Trail Making Test (TMT) and for the presence of brain MRI abnormalities. In all, 22 patients with a mean age of 34 years were included, of which 18 (81%) were women. Patients with higher range and maximum Phe levels had a poorer time-based performance on TMT form A and form B. Patients with brain MRI abnormalities had higher range, maximum, and mean Phe levels. Range of Phe levels showed a good performance for MRI abnormalities (area under the curve (AUC): 0.881, standard error (SE): 0.095, 95% CI: 0.695-0.999, p = 0.044) and for the poorest time-based performances on TMT form A (AUC: 0.822, SE: 0.092, 95% CI: 0.641-0.999, p = 0.024) and B (AUC: 0.816, SE: 0.094, 95% CI: 0.632-0.999, p = 0.021). Greater Phe variability may have a negative impact on some neurocognitive domains and could be related to the severity of brain structural damage in adult patients with PKU.

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.

Lipodystrophy-associated progeroid syndromes.

With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally recovered. As a consequence, an ectopic deposition of lipids frequently occurs, which usually leads to insulin resistance, atherogenic dyslipidemia, and hepatic steatosis. These disorders include certain accelerated aging syndromes or progeroid syndromes. Even though each of them has unique clinical features, most show common clinical characteristics that affect growth, skin and appendages, adipose tissue, muscle, and bone and, in some of them, life expectancy is reduced. Although the molecular bases of these Mendelian disorders are very diverse and not well known, genomic instability is frequent as a consequence of impairment of nuclear organization, chromatin structure, and DNA repair, as well as epigenetic dysregulation and mitochondrial dysfunction. In this review, the main clinical features of the lipodystrophy-associated progeroid syndromes will be described along with their causes and pathogenic mechanisms, and an attempt will be made to identify which of López-Otín's hallmarks of aging are present.

Familial partial lipodystrophy syndromes.

Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.

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.

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

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

Celia's Encephalopathy (BSCL2-Gene-Related): Current Understanding.

Seipin, encoded by the BSCL2 gene, is a protein that in humans is expressed mainly in the central nervous system. Uniquely, certain variants in BSCL2 can cause both generalized congenital lipodystrophy type 2, upper and/or lower motor neuron diseases, or progressive encephalopathy, with a poor prognosis during childhood. The latter, Celia's encephalopathy, which may or may not be associated with generalized lipodystrophy, is caused by the c.985C >T variant. This cytosine to thymine transition creates a cryptic splicing zone that leads to intronization of exon 7, resulting in an aberrant form of seipin, Celia seipin. It has been proposed that the accumulation of this protein, both in the endoplasmic reticulum and in the nucleus of neurons, might be the pathogenetic mechanism of this neurodegenerative condition. In recent years, other variants in BSCL2 associated with generalized lipodystrophy and progressive epileptic encephalopathy have been reported. Interestingly, most of these variants could also lead to the loss of exon 7. In this review, we analyzed the molecular bases of Celia's encephalopathy and its pathogenic mechanisms, the clinical features of the different variants, and a therapeutic approach in order to slow down the progression of this fatal neurological disorder.

Variable Expressivity and Allelic Heterogeneity in Type 2 Familial Partial Lipodystrophy: The p.(Thr528Met) LMNA Variant.

Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the LMNA gene. In this study, five FPLD2-diagnosed patients carrying the c.1583C>T, p.(Thr528Met) variant in exon 9 of the LMNA gene and with obvious clinical heterogeneity were evaluated. Specific polymorphisms in LMNA and in PPARG were also detected. Exhaustive clinical course, physical examination, biochemical features and family history were recorded, along with the assessment of anthropometric features and body composition by dual-energy X-ray absorptiometry. Preadipocytes obtained from a T528M patient were treated with the classic adipose differentiation medium with pioglitazone. Various adipogenes were evaluated by real-time PCR, and immunofluorescence was used to study intracellular localization of emerin, lamin A and its precursors. As demonstrated with Oil red O staining, the preadipocytes of the T528M patient failed to differentiate, the expression of various adipogenic genes was reduced in the lipodystrophic patient and immunofluorescence studies showed an accumulation of farnesylated prelamin A in T528M cells. We conclude that the T528M variant in LMNA could lead to FPLD2, as the adipogenic machinery is compromised.