ABSTRACT
BACKGROUND: The Triggering Receptor Expressed on Myeloid Cells 2 protein (TREM2) plays a crucial role in various biological processes, including osteoclast differentiation, and disease-associated microglia (DAM) activation to regulate neuroinflammation, and phagocytosis in the brain. Genetic variations in TREM2 are implicated in neurodegenerative disorders, such as Nasu-hakola disease (NHD), characterized by bone lesions, neuropsychiatric disorders, and early-onset dementia. METHODS: We studied 3 siblings with suspected NHD. Whole-exome sequencing was conducted on the proband to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants in the two other affected siblings, a healthy sister, and the parents. RESULTS: We identified a novel homozygous deletion (c.549del; p.(Leu184Serfs*5)) in TREM2. Our literature review reveals 16 TREM2 mutations causing early-onset dementia and bone lesions. CONCLUSION: These findings, alongside previous research, elucidate the clinical spectrum of TREM2-related diseases, aiding accurate diagnosis and patient care. This knowledge is vital for understanding TREM2-dependent DAM and its involvement in the pathogenesis of neurodevelopmental disorders which can help to develop targeted therapies and improve outcomes for TREM2-affected individuals.
Subject(s)
Homozygote , Lipodystrophy , Membrane Glycoproteins , Osteochondrodysplasias , Receptors, Immunologic , Siblings , Subacute Sclerosing Panencephalitis , Female , Humans , Consanguinity , Lipodystrophy/genetics , Lipodystrophy/pathology , Membrane Glycoproteins/genetics , Osteochondrodysplasias/genetics , Osteochondrodysplasias/pathology , Pedigree , Receptors, Immunologic/genetics , Subacute Sclerosing Panencephalitis/genetics , Subacute Sclerosing Panencephalitis/pathologyABSTRACT
Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.
Subject(s)
Lipoma , Lipomatosis , Humans , Lipomatosis/pathology , Lipoma/pathology , Lipoma/genetics , Lipomatosis, Multiple Symmetrical/pathology , Lipomatosis, Multiple Symmetrical/diagnosis , Lipodystrophy/pathology , Lipodystrophy/genetics , Adipose Tissue/pathology , Adiposis Dolorosa/pathology , Adiposis Dolorosa/diagnosisABSTRACT
Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.
Subject(s)
Adaptor Proteins, Signal Transducing , Adipocytes , Diet, High-Fat , Mice, Knockout , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Tumor Microenvironment , YAP-Signaling Proteins , Animals , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adipocytes/metabolism , Adipocytes/pathology , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Diet, High-Fat/adverse effects , Disease Progression , Lipodystrophy/metabolism , Lipodystrophy/pathology , Lipodystrophy/genetics , Mice, Inbred C57BL , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/genetics , Obesity/metabolism , Obesity/pathology , Signal Transduction , Trans-Activators/metabolism , Trans-Activators/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Verteporfin/pharmacology , YAP-Signaling Proteins/metabolismABSTRACT
Adipose dysfunction in lipodystrophic SEIPIN deficiency is associated with multiple metabolic disorders and increased risks of developing cardiovascular diseases, such as atherosclerosis, cardiac hypertrophy, and heart failure. Recently, adipose transplantation has been found to correct adipose dysfunction and metabolic disorders in lipodystrophic Seipin knockout mice; however, whether adipose transplantation could improve lipodystrophy-associated cardiovascular consequences is still unclear. Here, we aimed to explore the effects of adipose transplantation on lipodystrophy-associated metabolic cardiovascular diseases in Seipin knockout mice crossed into atherosclerosis-prone apolipoprotein E (Apoe) knockout background. At 2 months of age, lipodystrophic Seipin/Apoe double knockout mice and nonlipodystrophic Apoe knockout controls were subjected to adipose transplantation or sham operation. Seven months later, mice were euthanized. Our data showed that although adipose transplantation had no significant impact on endogenous adipose atrophy or gene expression, it remarkably increased plasma leptin but not adiponectin concentration in Seipin/Apoe double knockout mice. This led to significantly reduced hyperlipidemia, hepatic steatosis, and insulin resistance in Seipin/Apoe double knockout mice. Consequently, atherosclerosis burden, intraplaque macrophage infiltration, and aortic inflammatory gene expression were all attenuated in Seipin/Apoe double knockout mice with adipose transplantation. However, adipocyte morphology, macrophage infiltration, or fibrosis of the perivascular adipose tissue was not altered in Seipin/Apoe double knockout mice with adipose transplantation, followed by no significant improvement of vasoconstriction or relaxation. In conclusion, we demonstrate that adipose transplantation could alleviate lipodystrophy-associated metabolic disorders and atherosclerosis but has an almost null impact on perivascular adipose abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe double knockout mice.NEW & NOTEWORTHY Adipose transplantation (AT) reverses multiply metabolic derangements in lipodystrophy, but whether it could improve lipodystrophy-related cardiovascular consequences is unknown. Here, using Seipin/Apoe double knockout mice as a lipodystrophy disease model, we showed that AT partially restored adipose functionality, which translated into significantly reduced atherosclerosis. However, AT was incapable of reversing perivascular adipose abnormality or vascular dysfunction. The current study provides preliminary experimental evidence on the therapeutic potential of AT on lipodystrophy-related metabolic cardiovascular diseases.
Subject(s)
Adipose Tissue , Atherosclerosis , GTP-Binding Protein gamma Subunits , Lipodystrophy , Mice, Knockout , Animals , Mice , Adipose Tissue/metabolism , Adipose Tissue/transplantation , Apolipoproteins E/genetics , Apolipoproteins E/deficiency , Apolipoproteins E/metabolism , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , GTP-Binding Protein gamma Subunits/deficiency , GTP-Binding Protein gamma Subunits/genetics , GTP-Binding Protein gamma Subunits/metabolism , Heterotrimeric GTP-Binding Proteins/genetics , Heterotrimeric GTP-Binding Proteins/metabolism , Insulin Resistance , Leptin/blood , Leptin/metabolism , Lipodystrophy/metabolism , Lipodystrophy/genetics , Lipodystrophy/pathology , Mice, Inbred C57BLABSTRACT
Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.
Subject(s)
Lipodystrophy , Skin , Humans , Fibrosis , Skin/pathology , Lung/pathology , Extracellular Matrix/pathology , Fibroblasts/pathology , Lipodystrophy/pathology , LipidsSubject(s)
Lipodystrophy , Humans , Follow-Up Studies , Retrospective Studies , Lipodystrophy/pathology , Skin/pathology , ChinaABSTRACT
BACKGROUND AND AIMS: Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non-syndromic, obesity-associated non-alcoholic fatty liver disease (NS-NAFLD). METHODS: In a cross-sectional comparison of people with NS-NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan® controlled attenuation parameter (CAP) and insulin resistance by HOMA-IR, Adipo-IR, and NMR-based LP-IR. RESULTS: Insulin resistance was greater in PL versus NS-NAFLD by HOMA-IR (p = 0.005), Adipo-IR (p = 0.01) and LP-IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA-IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS-NAFLD for any given HOMA-IR. In contrast, Adipo-IR and LP-IR correlated with CAP only in the NS-NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of ß-hydroxybutyrate, a marker of ß-oxidation, and large triglyceride-rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both). CONCLUSION: Liver fat content was comparable in subjects with PL-associated NAFLD and NS-NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS-NAFLD.
Subject(s)
Insulin Resistance , Lipodystrophy , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/pathology , Cross-Sectional Studies , Liver/pathology , Obesity/complications , Obesity/metabolism , Adipose Tissue/metabolism , Adipose Tissue/pathology , Triglycerides , Lipodystrophy/metabolism , Lipodystrophy/pathologyABSTRACT
BACKGROUND: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome is a rare, hereditary, autoinflammatory disease. However, there are few cases reported in the literature. Therefore, we conduct this systematic review to summarize current evidence. METHODS: We conducted a systematic search in July 2021 using 11 different electronic databases. The included articles were screened according to our inclusion and exclusion criteria and assessed using an appropriate quality assessment tool. Then, the relevant data were extracted and summarized in tables accordingly. Each step of the previous one was done by 3 independent reviewers, and the conflicts were resolved by discussion and sometimes by counseling a senior member. RESULTS: The final included studies were 18 articles with 34 cases (mean age = 8 years, male/female = 19/15). The most reported symptoms and signs were fever 97.1%, erythematous plaques 76.5%, arthralgia 67.6%, hepatomegaly 61.8%, violaceous hue 61.8%, lipodystrophy in extremities 53.1% in addition to low weight and height. Rare features were reported too. The laboratories were not specific, which may be explained by a systemic inflammatory response. Vasculitis was the dominant feature in the skin biopsy, whereas the calcification in the basal ganglia was a prominent sign in many cases. CONCLUSIONS: Fever, skin lesions, and systemic inflammatory response were the prominent features of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. The clinical picture is the main guide in addition to the pathological findings. Mutation detection is the confirmatory test. Prednisolone is the most effective reported treatment for acute presentations in the literature.
Subject(s)
Dermatitis , Lipodystrophy , Skin Diseases , Sweet Syndrome , Humans , Male , Female , Child , Sweet Syndrome/diagnosis , Sweet Syndrome/drug therapy , Sweet Syndrome/pathology , Skin Diseases/diagnosis , Skin Diseases/drug therapy , Skin Diseases/pathology , Lipodystrophy/diagnosis , Lipodystrophy/genetics , Lipodystrophy/pathology , Fever/diagnosis , Chronic Disease , Systemic Inflammatory Response SyndromeABSTRACT
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.
Subject(s)
Lipodystrophy, Familial Partial , Lipodystrophy , Male , Humans , Female , Lipodystrophy, Familial Partial/diagnostic imaging , Lipodystrophy, Familial Partial/pathology , Lipodystrophy/pathology , Magnetic Resonance Imaging , Pubic Bone , ROC Curve , Pelvis/diagnostic imaging , Pelvis/pathologyABSTRACT
BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; OMIM# 615381) is a rare autosomal dominant disorder, with only a few reported cases worldwide. Herein, we describe the clinical features and underlying molecular etiology of MDPL syndrome in an 8-year-old Chinese patient. METHODS: We performed otological, endocrine, ultrasound, and radiological examinations, as well as genetic testing. Additionally, the literature concerning MDPL was reviewed to do a retrospective analysis of the pathogenesis, genotype-phenotype correlation, and clinical management. RESULTS: The proband was diagnosed with MDPL, presenting with mandibular hypoplasia, a characteristic facial appearance, lipodystrophy, and sensorineural hearing loss (SNHL). Whole-exome sequencing and bioinformatics analysis revealed a de novo missense variant in the POLD1 gene, NM_002691.4:c.3185A>G (NP_002682.2:p.(Gln1062Arg)). The retrospective analysis showed wide variation in the MDPL phenotype, but the most frequent features included mandibular hypoplasia, characteristic facial appearance, lipodystrophy, and SNHL. CONCLUSIONS: This study supplements the mutational spectrum of POLD1. The genetic analysis contributes to the diagnosis of syndromic deafness, and it has a vital role in clinical management and future genetic consultation.
Subject(s)
Deafness , Lipodystrophy , Humans , China , Deafness/genetics , DNA Polymerase III/genetics , Facies , Lipodystrophy/genetics , Lipodystrophy/complications , Lipodystrophy/pathology , Mutation , Pedigree , Phenotype , Retrospective Studies , Syndrome , ChildABSTRACT
Lipodystrophy (LD) is an acquired or congenital rare condition consisting of hyperlipidaemia, glucose intolerance/ insulin resistance, and almost complete absence and storage of adipose tissue. Colon perforations can be observed in type 4 congenital LD. Here, we aimed to present a case of sigmoid colon perforation which developed in a young woman with the diagnosis of LD. Extensive purulent peritonitis, significant wall thickening, and oedema in the sigmoid colon were detected during surgical exploration. Anterior resection with end colostomy procedure was then performed. Although bowel perforation has been theoretically reported to occur in LD, the presented case is the first adult patient in the literature. These individuals tend to develop colon perforation as a result of histological changes in their gastrointestinal tract. This situation should always be taken into consideration in order to avoid delay in diagnosis, especially in patients who present with abdominal pain and have a history of LD. Key Words: Intestinal perforation, Congenital lipodystrophy, Peritonitis, Sigmoid colon.
Subject(s)
Colonic Diseases , Intestinal Perforation , Lipodystrophy, Congenital Generalized , Lipodystrophy , Peritonitis , Adult , Colon, Sigmoid/surgery , Colonic Diseases/surgery , Female , Humans , Intestinal Perforation/complications , Intestinal Perforation/diagnosis , Intestinal Perforation/surgery , Lipodystrophy/complications , Lipodystrophy/pathology , Lipodystrophy, Congenital Generalized/pathology , Peritonitis/complications , Peritonitis/diagnosis , Peritonitis/surgeryABSTRACT
POLD1 (DNA polymerase delta 1, catalytic subunit) is a protein-coding gene that encodes the large catalytic subunit (POLD1/p125) of the DNA polymerase delta (Polδ) complex. The consequence of missense or nonsynonymous SNPs (nsSNPs), which occur in the coding region of a specific gene, is the replacement of single amino acid. It may also change the structure, stability, and/or functions of the protein. Mutation in the POLD1 gene is associated with autosomal dominant predisposition to colonic adenomatous polyps, colon cancer, endometrial cancer (EDMC), breast cancer, and brain tumors. These de novo mutations in the POLD1 gene also result in autosomal dominant MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy). In this study, genetic variations of POLD1 which may affect the structure and/or function were analyzed using different types of bioinformatics tools. A total of 17038 nsSNPs for POLD1 were collected from the NCBI database, among which 1317 were missense variants. Out of all missense nsSNPs, 28 were found to be deleterious functionally and structurally. Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.
Subject(s)
DNA Polymerase III , Lipodystrophy , DNA Polymerase III/chemistry , DNA Polymerase III/genetics , DNA Polymerase III/metabolism , Humans , Lipodystrophy/complications , Lipodystrophy/genetics , Lipodystrophy/pathology , Mutation , Polymorphism, Single Nucleotide/genetics , SyndromeABSTRACT
Cellulite is a morphological alteration of the tegument tissue, directly interfering in self-esteem with etiology and pathophysiology far from being a consensus. Although the visual diagnosis of cellulitis is well known, it does not represent the real pathological condition of the subcutaneous tissue. The aim of the study was to investigate the hypothesis that the more heterogeneous tissue pattern analyzed by infrared thermography, the more severe is the cellulite grade. Forty female participants were selected and 60 thighs were analyzed by clinical anamnesis and infrared thermography. Classical visual analysis was correlated to the tissue heterogeneity measured by thermography. R Spearman's correlation between visual evaluation and thermography was 0.92. Phototype presented a negative significant correlation of 0.67 with classical visual analysis. In the present study, we presented a simple method based on infrared thermography that can be adopted in any esthetics office with a correlation of 0.92 with the visual classic evaluation, but, besides, may be very helpful to the clinician to decide which treatment will be adopted, i.e., an aggressive and inflammatory approach such as the radiofrequency of shockwave therapy or an anti-inflammatory approach such as photobiomodulation, depending on the inflammatory status of cellulite.
Subject(s)
Cellulite , Lipodystrophy , Cellulite/drug therapy , Cellulite/therapy , Female , Humans , Lipodystrophy/diagnosis , Lipodystrophy/pathology , Subcutaneous Fat , Thermography , ThighABSTRACT
BACKGROUND: Gynoid lipodystrophy is one of the most common cosmetical problems in women. AIMS: The study aims to examine the pathomorphology and histology of subcutaneous tissue in women with gynoid lipodystrophy exposed to local compression/vibration therapy using a non-invasive Beautylizer Therapy Cosmospheres V medical device. METHODS: The study enrolled 25 virtually healthy women aged 25-45 years with gynoid lipodystrophy grades I and II. The women included in the study completed a 10-session month-long therapeutic course with a non-invasive Beautylizer Therapy Cosmospheres V medical device. Bioptic punch-size samples were taken from the gluteal region prior to and following the 10-session therapy course with the device. RESULTS: After completing a 10-session treatment course, a decrease in the mean adipocyte area from 123.08 ± 13.60 µm to 67.14 ± 4.20 µm was observed in punch bioptic samples of subcutaneous fat tissues of women with gynoid lipodystrophy as compared with the pre-treatment indices. CONCLUSION: Thus, local application of 10-session therapy with a non-invasive Beautylizer Therapy Cosmospheres V medical device in women with gynoid lipodystrophy demonstrated a positive effect on the histological structure of the hypodermis.
Subject(s)
Lipodystrophy , Subcutaneous Tissue , Humans , Female , Pilot Projects , Vibration , Lipodystrophy/therapy , Lipodystrophy/pathology , Subcutaneous FatABSTRACT
Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with "mandibuloacral dysplasia type A" (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype-phenotype correlations.
Subject(s)
Acro-Osteolysis/genetics , Lamin Type A/genetics , Lipodystrophy/genetics , Mandible/abnormalities , Phenotype , Acro-Osteolysis/pathology , Adult , Child , Child, Preschool , Female , Humans , Lipodystrophy/pathology , Male , Mandible/pathology , Mutation, MissenseABSTRACT
Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.
Subject(s)
Lipodystrophy/metabolism , Lipodystrophy/pathology , Lymphocytes/metabolism , Lymphocytes/pathology , Osteochondrodysplasias/metabolism , Osteochondrodysplasias/pathology , Proteomics , Subacute Sclerosing Panencephalitis/metabolism , Subacute Sclerosing Panencephalitis/pathology , Cluster Analysis , Discriminant Analysis , Humans , Membrane Glycoproteins/metabolism , Protein Interaction Maps , Receptors, Immunologic/metabolism , Systems BiologyABSTRACT
CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (Nâ =â 27), and 3 to 5 years (Nâ =â 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, Pâ <â .0001), A1c (9.5â ±â 3.0, 6.5â ±â 1.6, 6.5â ±â 1.9%, Pâ <â .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], Pâ <â .001). Only HOMA-IR improved in PLD (Pâ <â .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8â ±â 1.7, 9.1â ±â 1.3, 8.3â ±â 1.7 mm, Pâ <â .01), and LV mass (140.7â ±â 45.9, 128.7â ±â 37.9, 110.9â ±â 29.1 g, Pâ <â .01), and increased septal e' velocity (8.6â ±â 1.7, 10.0â ±â 2.1, 10.7â ±â 2.4 cm/s, Pâ <â .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.
Subject(s)
Cardiomegaly/prevention & control , Hypertrophy, Left Ventricular/prevention & control , Leptin/analogs & derivatives , Lipodystrophy/complications , Lipodystrophy/drug therapy , Adolescent , Adult , Blood Pressure , Cardiomegaly/etiology , Echocardiography , Female , Glycated Hemoglobin/analysis , Humans , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Insulin Resistance , Leptin/therapeutic use , Lipodystrophy/pathology , Lipodystrophy, Congenital Generalized/complications , Lipodystrophy, Congenital Generalized/diet therapy , Male , Middle Aged , National Institutes of Health (U.S.) , Prospective Studies , Triglycerides/blood , United States , Ventricular Septum/pathology , Ventricular Septum/physiopathology , Young AdultABSTRACT
Diabetes mellitus is a significant worldwide health concern and cutaneous manifestations are common. This review describes characteristic skin findings of diabetes, general skin findings related to diabetes, and findings related to diabetes treatment with a focus on clinical presentation, diagnosis, pathophysiology, epidemiology, and treatment. As the prevalence of diabetes continues to rise, cutaneous manifestations of diabetes mellitus likely will be encountered more frequently by physicians in all disciplines including dermatologists and primary care physicians. Accordingly, knowledge regarding the prevention, diagnosis, and management of cutaneous manifestations is an important aspect in the care of patients with diabetes.
Subject(s)
Diabetes Complications/pathology , Diabetes Mellitus/epidemiology , Skin Diseases/diagnosis , Skin Diseases/prevention & control , Skin Diseases/physiopathology , Acanthosis Nigricans/etiology , Acanthosis Nigricans/pathology , Acanthosis Nigricans/therapy , Dermatologists/statistics & numerical data , Diabetic Foot/etiology , Diabetic Foot/pathology , Diabetic Foot/therapy , Global Health/statistics & numerical data , Humans , Knowledge , Lipodystrophy/etiology , Lipodystrophy/pathology , Lipodystrophy/therapy , Middle Aged , Necrobiosis Lipoidica/etiology , Necrobiosis Lipoidica/pathology , Necrobiosis Lipoidica/therapy , Physicians, Primary Care/statistics & numerical data , Prevalence , Scleredema Adultorum/etiology , Scleredema Adultorum/pathology , Scleredema Adultorum/therapy , Skin Diseases/epidemiologyABSTRACT
AIM: Our previous results showed that Colgalt1 knock-out resulted in fetal death on day E11.5, and collagen secretion was retarded. This study aimed to elucidate the role of Collagen ß(1-O) galactosyltransferase 2 (Colgalt2) in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). METHODS: Colgalt2-/- mice were fed a high-fat diet (HFD) or methionine-and choline-deficient diet (MCD). Nanopore long-read RNA-Seq analysis of liver tissues was used to profile genomic variation. In vitro, hepatocyte steatosis and differentiation of primary pre-adipocytes were induced. RESULTS: Colgalt2-/- mice exhibited lipodystrophy, increased body weight, and hepatic lipid accumulation at 6â¯weeks of age. Colgalt2 deficiency aggravated hepatic steatosis in mice fed an HFD or a standard laboratory chow diet. Colgalt2 deficiency promotes steatohepatitis in MCD-fed mice. In HFD mice, Colgalt2 deficiency caused lipodystrophy and decreased plasma HMW, total adiponectin, and leptin levels. Colgalt2 deficiency also reduced circulating HMW/Total adiponectin in mice fed a HFD diet without differences of adiponectin mRNA and protein level in WT and Colgalt2-/- mice. The nanopore long-read RNA-Seq analysis results revealed transcriptional changes in the adiponectin receptor downstream signaling pathway and lipogenic genes, including the AMPK signaling pathway, adipocytokine signaling pathway, and lipid metabolism (Cidea, Cidec, CD36, and PPARγ). Colgalt2 deficiency did not promote lipid accumulation in OA-induced HepG2 cells or primary hepatocytes. However, Colgalt2 deficiency inhibited adipogenesis and reduced PPARγ, adipogenesis-related transcription factors, and expression during adipocyte differentiation. CONCLUSIONS: In mice, Colgalt2 deficiency contributes to lipodystrophy and promotes NAFLD related to HMW adiponectin. These results suggest that Colgalt2 could be a novel and promising therapeutic strategy for the treatment of NAFLD.
Subject(s)
Adiponectin/metabolism , Galactosyltransferases/genetics , Lipodystrophy/genetics , Non-alcoholic Fatty Liver Disease/genetics , Adipose Tissue, White/metabolism , Animals , Disease Models, Animal , Disease Progression , Galactosyltransferases/physiology , Lipid Metabolism/genetics , Lipodystrophy/metabolism , Lipodystrophy/pathology , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathologyABSTRACT
Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.