Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0235394 (wasting)
8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are a number of hypophosphatemic disorders due to renal phosphate wasting that cannot be explained by elevated levels of parathyroid hormone. The circulating factors responsible for the phosphaturia have been designated as phosphatonins. Studies of patients with tumor-induced osteomalacia and other genetic diseases of phosphate metabolism have resulted in the identification of a number of hormones that regulate phosphate homeostasis, including matrix extracellular phosphoglycoprotein (MEPE), secreted frizzled-related protein 4 (sFRP-4), dentin matrix protein 1 (DMP1), fibroblast growth factor 7 (FGF7), fibroblast growth factor 23 (FGF23), and Klotho. Our understanding of the actions of these hypophosphatemic peptides has been enhanced by studies in mice either overexpressing or not expressing these hormones. This review focuses on FGF23 since its regulation is disordered in diseases that affect children, such as X-linked hypophosphatemia, autosomal dominant and recessive hypophosphatemic rickets as well as chronic kidney disease. Recent studies have shown that FGF23 is unique among the FGFs in its requirement for Klotho for receptor activation. Here, we also discuss new potentially clinically important data pointing to the receptor(s) that mediate the binding and action of FGF23 and Klotho.
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PMID:Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. 1966 98

Hereditary forms of renal phosphate wasting have been studied thoroughly in the past years. X-linked Hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR) are known genetic disorders in which a disturbance of phosphatonins is a causative factor in the pathogenesis. We describe a comparable but yet undescribed disorder in a family in which a 53 year old man presented with a spontaneous fracture after suffering for years with severe fatigue and musculoskeletal pains. A low serum phosphate was discovered. The two subsequent generations of this family developed the same symptoms but at an earlier age. Almost all family members have been investigated and the majority appears to have low bone density and/or renal phosphate wasting and/or low serum phosphate. Remarkably no rickets was found. No elevation of FGF23 or mutations in the gene encoding FGF23 were found. We believe this is a new familial disorder of bone metabolism and phosphate homeostasis in which a disturbance of bone modulators may play a central role.
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PMID:A familial disorder with low bone density and renal phosphate wasting. 1971 54

Cell-based therapy is a possible avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. We have demonstrated that cultured myogenic progenitors derived from the adult skeletal muscle side population can engraft into dystrophic fibers of non-irradiated, non-chemically injured mouse models of DMD (mdx(5cv)) after intravenous and intraarterial transplantation, with engraftment rates approaching 10%. In an effort to elucidate the cell-surface markers that promote progenitor cell extravasation and engraftment after systemic transplantation, we found that expression of the chemokine receptor CXCR4, whose ligand SDF-1 is overexpressed in dystrophic muscle, enhances the extravasation of these cultured progenitor cells into skeletal muscle after intraarterial transplantation. At 1 day post-transplantation, mice that received CXCR4-positive enhanced green fluorescent protein (eGFP)-positive cultured cells derived from the skeletal muscle side population displayed significantly higher amounts of eGFP-positive mononuclear cells in quadriceps and tibialis anterior than mice that received CXCR4-negative eGFP-positive cells derived from the same cultured population. At 30 days posttransplantation, significantly higher engraftment rates of donor cells were observed in mice that received CXCR4-positive cells compared with mice transplanted with CXCR4-negative fractions. Our data suggest that CXCR4 expression by muscle progenitor cells increases their extravasation into skeletal muscle shortly after transplantation. Furthermore, this enhanced extravasation likely promotes higher donor cell engraftment rates over time.
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PMID:CXCR4 enhances engraftment of muscle progenitor cells. 1976 Jul 89

Tumor-induced osteomalacia (TIO) is an acquired disorder of isolated renal phosphate wasting associated with tumors, typically of mesenchymal origin. Patients with TIO share similar biochemical and skeletal phenotypes with patients who have autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia. The study of TIO introduced the idea of the existence of circulating factors, referred to as 'phosphatonins', produced by the tumor, which act upon the kidney to reduce phosphate reabsorption. Although several factors have been identified, the phosphatonin FGF-23, also identified as the causative factor in ADHR, is currently the best characterized of these factors relative to phosphate handling. This review describes the importance of TIO in understanding phosphate homeostasis in the context of new endocrine interactions between the skeleton and the kidney.
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PMID:Tumor-induced osteomalacia. 2022 70

Hypophosphatemic rickets (HR) is a group of rare disorders caused by excessive renal phosphate wasting. The purpose of this cross-sectional study of 38 HR patients was to characterize the phenotype of adult HR patients. Moreover, skeletal and endodontic severity scores were defined to assess possible gender differences in disease severity in patients with genetically verified X-linked HR. Compared to normal reference data, i.e., z = 0, HR patients had significantly lower final height, with a mean difference in z-score of -1.9 (95% CI -2.4 to -1.4, P < 0.001). Compared to paired z-scores of final height, z-scores of leg length were significantly lower and those of sitting height were significantly higher (P < 0.001), resulting in disproportion as indicated by the significantly elevated sitting height ratio, mean difference in z-score of 2.6 (95% CI 2.1-3.1, P < 0.001). Z-scores of head circumference (median 1.4, range -0.4 to 5.5, P < 0.001) and z-scores of bone mineral density (BMD) of the lumbar spine (median 1.9, range -1.5 to 8.6, P < 0.001) were significantly elevated compared to normal reference data. The relative risk (RR) of fracture was reduced (RR = 0.34, 95% CI 0.20-0.57, P < 0.001). The skeletal severity score tended to be higher in males compared to females (P = 0.07), and no gender difference in endodontic severity was found. In conclusion, adult HR patients were characterized by short stature and were disproportioned. They had elevated BMD of the lumbar spine and a reduced risk of fractures. We found a tendency for males to be more severely affected than females.
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PMID:Phenotype presentation of hypophosphatemic rickets in adults. 2052 10

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.
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PMID:The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. 2085 67

Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle-wasting disease caused by mutations in the DMD gene. Since the disease was described by physicians in the 19th century, information about the subject has been accumulated. One author (Sugita) was one of the coworkers who first reported that the serum creatine kinase (CK) level is elevated in progressive muscular dystrophy patients. Even 50 years after that first report, an elevated serum CK level is still the most useful marker in the diagnosis of DMD, a sensitive index of the state of skeletal muscle, and useful to evaluate therapeutic effects. In the latter half of this article, we describe recent progress in the therapy of DMD, with an emphasis on gene therapies, particularly exon skipping.
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PMID:Progress in muscular dystrophy research with special emphasis on gene therapy. 2068 32

We herein report the joint occurrence of an autistic disorder (AD) and X-linked hypophosphatemia. X-linked hypophosphatemia (XLH), an X-linked dominant disorder, is the most common of the inherited renal phosphate wasting disorders. Autism is a pervasive developmental disorder that occurs mainly due to genetic causes. In approximately 6-15% of cases, the autistic phenotype is a part of a broader genetic condition called syndromic autism.Therefore, reports of cases with the joint occurrence of a known genetic syndrome and a diagnosis of ASD by a child psychiatrist are relevant. A joint occurrence does not, however, mean that there is always a causal link between the genetic syndrome and the autistic behavioural phenotype. In this case, there are a number of arguments countering a causal link.
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PMID:Autism and X-linked hypophosphatemia: A possible association? 2083 91

Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare, adult-onset, X-linked, recessive trinucleotide, polyglutamine (poly-G) disorder, caused by expansion of an unstable CAG-tandem-repeat in exon 1 of the androgen-receptor (AR) gene on chromosome Xq11-12. Poly-Q-expanded AR accumulates in nuclei, undergoes fragmentation and initiates degeneration and loss of motor neurons and dorsal root ganglia. Phenotypically, patients present with weakness and wasting of the facial, bulbar and extremity muscles, sensory disturbances, and endocrinological disturbances, such as gynecomastia and reduced fertility. In the limb muscles weakness and wasting may be symmetric or asymmetric, proximal or distal, or may predominate at the lower or upper limb muscles. There may be mild to severe hyper-CK-emia, elevated testosterone or other sexual hormones, abnormal motor and sensory nerve conduction studies, and neuropathic or rarely myopathic alterations on muscle biopsy. BSMA is diagnosed if the number of CAG-repeats exceeds 40. No causal therapy is available but symptomatic therapy may be beneficial for weakness, tremor, endocrinological abnormalities, muscle cramps, respiratory failure, or dysphagia. The course is slowly progressive and the ability to walk lost only late in life. Only few patients require ventilatory support and life expectancy is only slightly compromised.
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PMID:Perspectives of Kennedy's disease. 2084 73

Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets.
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PMID:Hereditary disorders of renal phosphate wasting. 2092


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