Impact of X-Linked Hypophosphatemia on Muscle Symptoms

Abstract

X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.

Keywords: FGF23; X-linked hypophosphatemia; muscle weakness; skeletal muscle; skeletal muscle dysfunction.

Figure 1

Regulation of phosphate by FGF23. FGF23 decreases the reabsorption of phosphate through regulation of sodium/phosphate cotransporters in the renal proximal tubules. In addition, FGF23 inhibits 1,25-dihydroxyvitamin D production in the proximal renal tubules by downregulating 1α-hydroxylase (CYP27B1) and upregulating CYP24A1 (24-hydroxylase), leading to decreased phosphate absorption in the intestine.

Figure 2

Effects of hypo- and hyper-phosphatemia and FGF23 on skeletal muscle.