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Further evidence of affected females with a heterozygous variant in FGF13 causing X-linked developmental and epileptic encephalopathy 90.
Narayanan, DL, Majethia, P, Shrikiran, A, Siddiqui, S, Dalal, A, Shukla, A
European journal of medical genetics. 2022;(1):104403
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Abstract
Developmental and epileptic encephalopathies (DEE) are a genetically heterogeneous group of disorders characterised by early onset epilepsy, epileptiform activity on electroencephalogram and associated developmental delay or neuroregression. With the advent of high throughput sequencing, novel gene-disease associations have been described for DEEs. Voltage activated sodium channels (Nav) regulate neuronal excitability. Fibroblast growth factor homologous factors (FHFs) are proteins, which bind to the C terminal cytoplasmic tails of alpha subunits of Nav channels and influence their function and surface expression. Gain of function hemizygous or heterozygous variants in FGF13 (also known as FHF2) were recently identified as the cause for X-linked developmental and epileptic encephalopathy 90 (DEE90; MIM# 301058) in seven individuals from five families, which included one female. We report an additional female, providing further evidence for a novel de novo heterozygous missense variant in FGF13, NM_004114.5: c.14T > G p.(Ile5Ser) causing X-linked DEE90. In addition, we review the genotype and phenotype of affected individuals with DEE90.
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Effects of Bariatric Surgeries on Fetuin-A, Selenoprotein P, Angiopoietin-Like Protein 6, and Fibroblast Growth Factor 21 Concentration.
Poloczek, J, Kazura, W, Kwaśnicka, E, Gumprecht, J, Jochem, J, Stygar, D
Journal of diabetes research. 2021;:5527107
Abstract
Obesity is a civilization disease representing a global health problem. Excessive body weight significantly reduces the quality of life. It is also associated with the leading causes of death, including type 2 diabetes mellitus, cardiovascular diseases, and numerous types of cancer. The mainstay of therapy is a dietary treatment. However, in morbidly obese patients, dietary treatment is often insufficient. In these patients, the most effective procedure is bariatric surgery, but it is still difficult to predict its outcome and metabolic changes. Hepatokines are proteins secreted by hepatocytes. Many of them, including fetuin-A, selenoprotein P, angiopoietin-like protein 6, and fibroblast growth factor 21, have been linked to metabolic dysfunctions. In this context, hepatokines may prove helpful. This review investigates the possible changes in hepatokine profiles after selected bariatric surgery protocols. In this regard, Roux-en-Y gastric bypass is the most studied type of surgery. The overall analysis of published research identified fetuin-A as a potential marker of metabolic alternations in patients after bariatric surgery.
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Phosphate and fibroblast growth factor 23 in diabetes.
van der Vaart, A, Yeung, SMH, van Dijk, PR, Bakker, SJL, de Borst, MH
Clinical science (London, England : 1979). 2021;(14):1669-1687
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Abstract
Diabetes is associated with a strongly elevated risk of cardiovascular disease, which is even more pronounced in patients with diabetic nephropathy. Currently available guideline-based efforts to correct traditional risk factors are only partly able to attenuate this risk, underlining the urge to identify novel treatment targets. Emerging data point towards a role for disturbances in phosphate metabolism in diabetes. In this review, we discuss the role of phosphate and the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) in diabetes. We address deregulations of phosphate metabolism in patients with diabetes, including diabetic ketoacidosis. Moreover, we discuss potential adverse consequences of these deregulations, including the role of deregulated phosphate and glucose as drivers of vascular calcification propensity. Finally, we highlight potential treatment options to correct abnormalities in phosphate and FGF23. While further studies are needed to more precisely assess their clinical impact, deregulations in phosphate and FGF23 are promising potential target in diabetes and diabetic nephropathy.
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Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences.
Panizo, S, Martínez-Arias, L, Alonso-Montes, C, Cannata, P, Martín-Carro, B, Fernández-Martín, JL, Naves-Díaz, M, Carrillo-López, N, Cannata-Andía, JB
International journal of molecular sciences. 2021;(1)
Abstract
Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.
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Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.
Courbon, G, Martinez-Calle, M, David, V
Current opinion in nephrology and hypertension. 2020;(4):359-366
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Abstract
PURPOSE OF REVIEW Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD. RECENT FINDINGS New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival. SUMMARY New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.
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Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease.
Babitt, JL, Sitara, D
Current opinion in nephrology and hypertension. 2019;(4):304-310
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Abstract
PURPOSE OF REVIEW Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors. RECENT FINDINGS It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities. SUMMARY Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.
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FGF23 and Phosphate-Cardiovascular Toxins in CKD.
Vogt, I, Haffner, D, Leifheit-Nestler, M
Toxins. 2019;(11)
Abstract
Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients.
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[Novel hormones related to the calcium and phosphate homeostasis in kidney disease].
Mace, ML, Ølgaard, K, Lewin, E
Ugeskrift for laeger. 2018;(21)
Abstract
Calcium and phosphate levels are regulated by a complex interplay between parathyroid hormone (PTH), calcitriol, fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho. Kidney failure causes severe disturbances in the mineral and bone homeostasis resulting in phosphate retention, hypocalcaemia and high plasma levels of FGF23 and PTH, and the patients develop fragile bones and vascular calcifications. Today's treatments aim to lower the levels of phosphate and PTH. Future studies need to clarify, if lowering the FGF23 level or supplementation with αKlotho will improve survival for patients with chronic kidney disease.
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Non-renal-Related Mechanisms of FGF23 Pathophysiology.
Hanudel, MR, Laster, M, Salusky, IB
Current osteoporosis reports. 2018;(6):724-729
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Abstract
PURPOSE OF REVIEW We will review non-renal-related mechanisms of fibroblast growth factor 23 (FGF23) pathophysiology. RECENT FINDINGS FGF23 production and metabolism may be affected by many bone, mineral, and kidney factors. However, it has recently been demonstrated that other factors, such as iron status, erythropoietin, and inflammation, also affect FGF23 production and metabolism. As these non-mineral factors are especially relevant in the setting of chronic kidney disease (CKD), they may represent emerging determinants of CKD-associated elevated FGF23 levels. Moreover, FGF23 itself may promote anemia and inflammation, thus contributing to the multifactorial etiologies of these CKD-associated comorbidities. CKD-relevant, non-mineral-related, bidirectional relationships exist between FGF23 and anemia, and between FGF23 and inflammation. Iron deficiency, anemia, and inflammation affect FGF23 production and metabolism, and FGF23 itself may contribute to anemia and inflammation, highlighting complex interactions that may affect aspects of CKD pathogenesis and treatment.
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Biology of Fibroblast Growth Factor 23: From Physiology to Pathology.
Courbebaisse, M, Lanske, B
Cold Spring Harbor perspectives in medicine. 2018;(5)
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Abstract
Fibroblast growth factor (FGF)23 is a phosphaturic hormone produced by osteocytes and osteoblasts that binds to FGF receptors in the presence of the transmembrane protein αKlotho. FGF23 mainly targets the renal proximal tubule to inhibit calcitriol production and the expression of the sodium/phosphate cotransporters NaPi2a and NaPi2c, thus inhibiting renal phosphate reabsorption. FGF23 also acts on the parathyroid glands to inhibit parathyroid hormone synthesis and secretion. FGF23 regulation involves many systemic and local factors, among them calcitriol, phosphate, and parathyroid hormone. Increased FGF23 is primarily observed in rare acquired or genetic disorders, but chronic kidney disease is associated with a reactional increase in FGF23 to combat hyperphosphatemia. However, high FGF23 levels induce left ventricular hypertrophy (LVH) and are associated with an increased risk of mortality. In this review, we describe FGF23 physiology and the pathological consequences of high or low FGF23 levels.