Recurrent fevers, progressive lipodystrophy, and annular plaques in a child.
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ABSTRACT:
SUBMITTER: Cardis MA
PROVIDER: S-EPMC8132105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundA number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes.Case presentationWe describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient's lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy.ConclusionsMetreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.
| S-EPMC7585287 | biostudies-literature
Project description:Hereditary periodic recurrent fevers (HRF) are monogenic autoinflammatory associated to mutations of some genes, such as diseases caused by mutations of including MEFV, TNFRSF1A and MVK genes. Despite the identification of the causative genes, the intracellular implications related to each gene variant are still largely unknown. A large -scale proteomic analysis on monocytes of these patients is aimed to identify with an unbiased approach the mean proteins and molecular interaction networks involved in the pathogenesis of these conditions. Monocytes from HRF 15 patients (5 with MFV, 5 TNFRSF1A and 5with MVK gene mutation) and 15 healthy donors (HDs) were analyzed by liquid chromatography and tandem mass spectrometry before and after lipopolysaccharide (LPS) stimulation. Significant proteins were analyzed through a Cytoscape analysis using the ClueGo app to identify molecular interaction networks. Protein networks for each HRF were performed through a STRING database analysis integrated with a DISEAE database query. About 5000 proteins for each HRF were identified. LPS treatment maximizes differences between up-regulated proteins in monocytes of HRF patients and HDs, independently from the disease's activity and ongoing treatments. Proteins significantly modulated in monocytes of the different HRF allowed creating a disease-specific proteomic signatures and interactive protein network. Proteomic analysis is able to dissect the different intracellular pathways involved in the inflammatory response of circulating monocytes in HRF patients. The present data may help to identify a "monocyte proteomic signature" for each condition and unravel new possible unexplored intracellular pathways possibly involved in their pathogenesis. These data will be also useful to identify possible differences and similarities between the different HRFs and some multifactorial recurrent fevers.
| S-EPMC9260596 | biostudies-literature
Project description:Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.
| S-EPMC3500529 | biostudies-literature
Project description:Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.
| S-EPMC8124817 | biostudies-literature
Project description:Hereditary recurrent fevers (HRF) are a group of monogenic autoinflammatory diseases characterized by auto-resolving attacks of sterile inflammation caused by mutations of MEFV, TNFRSF1A and MVK genes1-3. Familial Mediterranean fever (FMF) is the prototype of a HPR and is caused by gain-of-function mutations of the MEFV gene, coding for pyrin4 5. Pyrin is part of the Pyrin-Inflammasome that controls the activation and secretion of interleukin (IL)-1β and can be activated by the cortical actin cytoskeleton remodeling induced by bacterial toxins via RhoA. Mevalonate kinase deficiency (MKD) is secondary to bi-allelic mutations of the gene coding for mevalonate kinase (MVK), an enzyme involved in the cholesterol biosynthesis. Loss-of-function MVK mutations lead to a defective sterol synthesis and to a reduced prenylation of small G proteins, such as RhoA, favoring the activation of the Pyrin-inflammasome6-8. TNF receptor-associated periodic syndrome (TRAPS) is secondary to autosomal dominant mutations of the gene coding for the type I receptor for TNF (TNFRSF1A), resulting in a heap of misfolded TNF receptor 1 in the endoplasmic reticulum, leading to oxidative stress, defective autophagy and consequent over-secretion of pro-inflammatory cytokines9 10. The clinical manifestations of HRFs are rather unspecific and consist mainly in fever, serositis, skin rash, limb and articular pain. No specific biomarkers able to distinguish one among the different HRFs have been identified, so far11. Moreover, the majority of the studies investigating the pathogenic consequences of the genes’ mutations associated with the three HRFs were focused on the few mechanisms classically associated to the pro-inflammatory activation of cells of the innate immunity (NF-kB and MAPK activation, IL-1b activation and secretion). Conversely, an unbiased analysis of possible additional intracellular pathways involved in the different conditions has not been exploited. Recently, large-scale proteomics based on high-resolution mass spectrometry (MS) has offered a systems-wide hypothesis-free method to analyze intracellular pathways in order to identify new disease biomarkers12-14. Here, we analyzed the proteomic signature of unstimulated and stimulated monocytes of patients with FMF, TRAPS and MKD, describing the dysregulated intracellular pathways associated with each condition for the identification of possible biomarkers and possible novel therapeutic targets.
2022-08-12 | PXD024068 | Pride
Project description:ObjectiveNormal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function.MethodsAdipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth factors and nutrients. Thus, mTORC1 is poised to be a critical intracellular regulator of adipocyte metabolism. Here, we investigate the role of mTORC1 in mature adipocytes by generating and characterizing mice in which the Adiponectin-Cre driver is used to delete floxed alleles of Raptor, which encodes an essential regulatory subunit of mTORC1.ResultsRaptor (Adipoq-cre) mice have normal white adipose tissue (WAT) mass for the first few weeks of life, but soon thereafter develop lipodystrophy associated with hepatomegaly, hepatic steatosis, and insulin intolerance. Raptor (Adipoq-cre) mice are also resistant to becoming obese when consuming a high fat diet (HFD). Resistance to obesity does not appear to be due to increased energy expenditure, but rather from failed adipose tissue expansion resulting in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption. Deleting Raptor in WAT also decreases C/EBP? expression and the expression of its downstream target adiponectin, providing one possible mechanism of mTORC1 function in WAT.ConclusionsmTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy.
| S-EPMC4877665 | biostudies-literature
Project description:Rapidly progressive Alzheimer's disease (rpAD) is a particularly aggressive form of Alzheimer's disease, with a median survival time of 7-10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer's disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer's disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n = 22 for each patient group) and protein expression differences were quantified. On average, 913 ± 30 (mean ± SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p = 0.0017) and significantly lower levels of astrocytic proteins (p = 1.08 × 10-6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provide new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer's disease.
| S-EPMC5503748 | biostudies-literature
Project description:BACKGROUND:Tetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine homeostasis, and catecholamine and serotonin biosynthesis. GTP-Cyclohydrolase I deficiency (OMIM 600225) is an extremely rare variant of inborn error of BH4 synthesis which exists in recessive and dominant forms. The recessive form presents with complex neurological and autonomic dysfunction whilst the dominant form presents as Dopa-responsive dystonia. CASE PRESENTATION:We describe a South Asian child who initially presented with neurological dysfunction and recurrent vomiting and later developed recurrent hyperthermia for several months. The child did not have screening for hyperphenylalaninemia at birth and was found to have marked hyperphenylalaninemia after clinical presentation at 5?months. Further evaluation revealed BH4 deficiency. GTP-Cyclohydrolase I deficiency (GTPCH) was identified based on normal dihydro pteridine reductase activity and markedly reduced neopterin in dried blood spot test. After institution of treatment and control of high phenylalanine levels, clinical deterioration decelerated yet with noticeable residual neurological dysfunction. CONCLUSION:To authors' knowledge, this is first report of GTPCH deficiency in a South Asian child. The case highlights practical issues regarding diagnosis of GTPCH deficiency, especially in countries without broader universal newborn screening programs for early detection of inherited metabolic disorders. Testing for GTPCH deficiency should be considered for patients with unexplained neurological and autonomic symptoms following initial metabolic screen.
| S-EPMC6570886 | biostudies-literature
Project description:Mutations in the PTRF gene, coding for cavin-1, cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. In CGL4, symptoms are variable comprising, in addition to myopathy, smooth and skeletal muscle hypertrophy, cardiac arrhythmias, and skeletal abnormalities. Secondary features are atlantoaxial instability, acanthosis nigricans, hepatomegaly, umbilical prominence and metabolic abnormalities related to insulin resistance, such as diabetes mellitus, hyperlipidemia and hepatic steatosis.We describe a 3 year-old child of Moroccan origin with mild muscle phenotype, mainly characterized by mounding, muscle pain, hyperCKemia and mild caveolin 3 reduction on muscle biopsy. No CAV3 gene mutation was detected; instead we found a novel mutation, a homozygous single base pair deletion, in the PTRF gene. Only after detection of this mutation a mild generalized loss of subcutaneous fat, at first underestimated, was noticed and the diagnosis of lipodystrophy inferred.The PTRF gene should be investigated in patients with hyperCKemia, mild myopathy associated with spontaneous or percussion-induced muscle contractions like rippling or mounding, and no CAV3 mutation. The analysis should be performed even if cardiac or metabolic alterations are absent, particularly in young patients in whom lipodystrophy may be difficult to ascertain.
| S-EPMC3846852 | biostudies-other
Project description:Background:Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods:We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results:Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions:Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
| S-EPMC6283411 | biostudies-literature