Natural course and comorbidities of lipodystrophy syndromes in Spain

Los síndromes lipodistróficos constituyen un grupo heterogéneo de enfermedades raras caracterizadas por la pérdida selectiva de tejido adiposo, que conlleva a un deterioro en la señalización de la insulina y otras funciones celulares, dando lugar a complicaciones metabólicas (diabetes, hipertrigliceridemia, esteatosis hepática, patología cardiovascular, etc.) que contribuyen a unas mayores tasas de mortalidad en estos pacientes. No obstante, la historia natural exacta de estos síndromes no está bien documentada, lo que lleva a grandes retrasos en el diagnóstico o incluso a diagnósticos erróneos. Así pues, la presente tesis constituye el primer estudio en vida real cuyo objetivo es el de evaluar el curso natural y las comorbilidades asociadas a lo largo de la vida de los pacientes con lipodistrofia generalizada y parcial en España (tanto adquirida como congénita) en un esfuerzo por contribuir a aumentar el conocimiento de estos síndromes infrecuentes

Focus on progressive myoclonic epilepsy in Berardinelli-Seip syndrome

This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s10072-020-04780-0S

Effect of β-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-β-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-β-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-β-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 lipodystrophyThis research was funded by the Instituto de Salud Carlos III, ISCIII and the European Regional Development Fund, ERDF (grant number PI081449), an intramural grant from the Xunta de Galicia (GPC2014/036, ED341b 2017/19, ED431B 2020/37) and a research grant from the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP). A.F.-P. receives funding from the Fundación Alfonso Martín EscuderoS

Lipodystrophy-associated progeroid syndromes

This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s42000-022-00386-7With 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.This work was supported by the Instituto de Salud Carlos III and the European Regional Development Fund (ERDF (grant number PI081449), and an intramural grant from the Xunta de Galicia (GPC2014/036, ED341b 2017/19, ED431B 2020/37). A.F.-P. is a Rio Hortega researcher (ISCIII; CM20/00155). S.S.-I. was awarded a Research Fellowship from the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

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.This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, ERDF (Grant No. PI081449), and an intramural grant from the Xunta de Galicia (GPC2014/036, ED341b 2017/19, ED431B 2020/37). A.F.-P. is a Rio Hortega researcher (ISCIII; CM20/00155). S.S.I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

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 subtypesThis study was supported by the Instituto de Salud Carlos III (grant PI22/00514), co-funded by the European Union, and an intramural grant from the Xunta de Galicia, ED431B 2020/37. A.F.-P. receives funding from the Fundación Alfonso Martín Escudero. S.S.-I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP)S

Does Seipin Play a Role in Oxidative Stress Protection and Peroxisome Biogenesis? New Insights from Human Brain Autopsies

Seipin is a widely expressed protein but with highest levels found in the brain and testes. Seipin function is not yet completely understood, therefore the aim of this study was to evaluate the expression of BSCL2 transcripts in the central nervous system (CNS) of humans and investigate the effect of their overexpression on a neuron model and their relationship with oxidative stress protection, as well as shed light on the pathogenic mechanisms of Celia’s Encephalopathy. We analyzed the expression of BSCL2 transcripts using real-time RT– PCR in samples across the brain regions of subjects who underwent necropsy and from a case with Celia’s Encephalopathy. The transcript encoding the long seipin isoform (BSCL2-203, 462 aa) is expressed primarily in the brain and its expression is inversely correlated with age in the temporal lobe, amygdala, and hypothalamus. Strong positive correlations were found between BSCL2 expression and some genes encoding protective enzymes against oxidative stress including SOD1 and SOD2, as well as peroxisome proliferator-activated receptor gamma (PPARG) in the amygdala. These results were experimentally corroborated by overexpressing BSCL2 transcripts in SH-SY5Y cells with lentiviral transduction and assessing their effects on neuron differentiated cells. Confocal microscopy studies showed that both seipin and PEX16 are closely expressed in the hypothalami of healthy human brains, and PEX16 was absent in the same region of the PELD case. We hypothesize that seipin has specific CNS functions and may play a role in peroxisome biogenesis.This work was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (grants number PI10/02873 and PI13/00314), by the Consellería de Industria, Xunta de Galicia (grants number 10PXIB208013PR and ED341b2017/19), and by Fundación Mutua Madrileña (Call 2015)S

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 fieldThis research was funded by the Instituto de Salud Carlos III (ISCIII) through the projectPI22/00514 and cofunded by the European Union, and an intramural grant from the Xunta de Galicia (grant number ED431B 2020/37). A.F.-P. is a Rio Hortega researcher (ISCIII; CM20/00155). S.S.-I. was awarded a Research Fellowship by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP)S

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.This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, ERDF (grant no. PI081449), and an intramural grant from the Xunta de Galicia, ED431B 2020/37. S.S.-I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

Modern imaging of pituitary adenomas.

Decision-making in pituitary disease is critically dependent on high quality imaging of the sella and parasellar region. Magnetic resonance imaging (MRI) is the investigation of choice and, for the majority of patients, combined T1 and T2 weighted sequences provide the information required to allow surgery, radiotherapy (RT) and/or medical therapy to be planned and long-term outcomes to be monitored. However, in some cases standard clinical MR sequences are indeterminate and additional information is needed to help inform the choice of therapy for a pituitary adenoma (PA). This article reviews current recommendations for imaging of PA, examines the potential added value that alternative MR sequences and/or CT can offer, and considers how the use of functional/molecular imaging might allow definitive treatment to be recommended for a subset of patients who would otherwise be deemed unsuitable for (further) surgery and/or RT.Cambridge NIHR Biomedical Research Centr