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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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Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23.
Ito, N, Fukumoto, S
Calcified tissue international. 2021;(1):104-115
Abstract
Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.
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The Effect of a Life-Style Intervention Program of Diet and Exercise on Irisin and FGF-21 Concentrations in Children and Adolescents with Overweight and Obesity.
Karampatsou, SI, Genitsaridi, SM, Michos, A, Kourkouni, E, Kourlaba, G, Kassari, P, Manios, Y, Charmandari, E
Nutrients. 2021;(4)
Abstract
Overweight and obesity in childhood and adolescence represent major public health problems of our century, and account for increased morbidity and mortality in adult life. Irisin and Fibroblast Growth Factor 21 (FGF-21) have been proposed as prognostic and/or diagnostic biomarkers in subjects with obesity and metabolic syndrome, because they increase earlier than other traditional biomarkers. We determined the concentrations of Irisin and FGF-21 in children and adolescents with overweight and obesity before and after one year of a life-style intervention program of diet and physical exercise and explored the impact of body mass index (BMI) reduction on the concentrations of Irisin, FGF-21 and other cardiometabolic risk factors. Three hundred and ten (n = 310) children and adolescents (mean age ± SD: 10.5 ± 2.9 years) were studied prospectively. Following one year of the life-style intervention program, there was a significant decrease in BMI (p = 0.001), waist-to-hip ratio (p = 0.024), waist-to-height ratio (p = 0.024), and Irisin concentrations (p = 0.001), and an improvement in cardiometabolic risk factors. There was no alteration in FGF-21 concentrations. These findings indicate that Irisin concentrations decreased significantly as a result of BMI reduction in children and adolescents with overweight and obesity. Further studies are required to investigate the potential role of Irisin as a biomarker for monitoring the response to lifestyle interventions and for predicting the development of cardiometabolic risk factors.
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Acute effects of dietary phosphorus intake on markers of mineral metabolism in hemodialysis patients: post hoc analysis of a randomized crossover trial.
Tsai, WC, Wu, HY, Chiu, YL, Yang, JY, Pai, MF, Wu, YR, Lin, WY, Hung, KY, Chien, KL, Hsu, SP, et al
Renal failure. 2021;(1):141-148
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Abstract
BACKGROUND Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations. METHODS This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models. RESULTS Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2-0.4, p < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, -0.11 to -0.01, p = .01), an increase in iPTH of 5.4% (95% CI, 1.4-9.3, p = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0-8.0, p = .001). Dietary phosphorus intake was not related to cFGF23. CONCLUSIONS Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.
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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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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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Increased serum levels of fibroblast growth factor 23 after an ultradistance run.
Kerschan-Schindl, K, Skenderi, K, Wahl-Figlash, K, Gelles, K, Föger-Samwald, U, Thalmann, M, Tsironi, M, Szekeres, T, Pietschmann, P
Journal of science and medicine in sport. 2021;(3):297-300
Abstract
OBJECTIVES Healthy bones need to be loaded on a regular basis. However, overstrenuous exercise causes uncoupling of bone metabolism. Thus, it is important to be aware of exercise-induced alterations in bone metabolism. The aim of this observational study was to determine whether participation in an ultradistance run has an impact on the phosphaturic hormone fibroblast growth factor 23 (FGF23), which is produced by osteocytes and suppresses osteoblast differentiation as well as matix mineralization. DESIGN Observational study. METHODS Nine participants of the Spartathlon (246km) had venous blood samples taken before and within 15min after finishing the race as well as during recovery. Serum levels of FGF23, phosphate, and blood urea nitrogen were determined. RESULTS FGF23 increased 6.5-fold from pre-race to post-race (2.2pmol/L [IQR: 0.4; 3.2pmol/L] to 14.4pmol/L [IQR: 4.7; 20.0pmol/L]; p=0.001). Thereafter, serum levels of FGF23 fell to 1.4pmol/L [IQR: 0.5; 1.7pmol/L] (p<0.0001). The differences in FGF23 levels between pre-race and recovery (3 days after the start) did not achieve statistical significance (p=0.614). Serum levels of phosphate and blood urea nitrogen also did not change significantly. CONCLUSIONS Since FGF23 plays a central role in mineral homeostasis, the transient overexpression of FGF23 may be an important contributor to the short-term uncoupling of bone metabolism induced by overstrenuous exercise.
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Resistance training attenuates circulating FGF-21 and myostatin and improves insulin resistance in elderly men with and without type 2 diabetes mellitus: A randomised controlled clinical trial.
Shabkhiz, F, Khalafi, M, Rosenkranz, S, Karimi, P, Moghadami, K
European journal of sport science. 2021;(4):636-645
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Abstract
Fibroblast growth factor 21 (FGF-21) and myostatin have been proposed to be potential therapeutic target for insulin resistance in age-related metabolic disorders including type 2 diabetes (T2D). Moreover, despite the potential metabolic effect of resistance training on insulin resistance, aging, and T2D; the effect of this type of exercise training on FGF-21 and myostatin in elderly men with and without T2D are unknown. Forty-four elderly men were assigned to either the RT training (RT; without T2D: 12, with TD2 = 10) or the control group (C; without T2D: 12, with TD2 = 10). The RT group performed 12-wk resistance training intervention, 3 days/wk, 10 repetitions with 70% 1RM. At the baseline, the elderly men with T2D had a higher FGF-21 (p = 0.002) and myostatin (p = 0.02) concentrations and lower muscle strength (p = 0.01) than the elderly men without T2D. RT resulted in significant decrease in FGF-21 and myostatin concentration and increase in muscle strength in both elderly men with and without T2D (P = 0.001, for all) as well as decrease in HOMA-IR in only elderly men without T2D (P = 0.001). There was no significant difference in the RT-induced FGF-21 reduction between elderly men with and without T2D (p = 0.77, p = 0.28, respectively), but, RT caused a larger reduction in circulating myostatin in elderly men without T2D than with T2D (P = 0.007). Taken together, our results demonstrated that 12 weeks of RT induced an overall significant reduction of FGF-21 and myostatin in elderly men with and without T2D; with higher reduction of myostatin in elderly men without T2D.
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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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New Therapies for Hypophosphatemia-Related to FGF23 Excess.
Athonvarangkul, D, Insogna, KL
Calcified tissue international. 2021;(1):143-157
Abstract
FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.