Abstract
Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to CTNS mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven.
Highlights
Infantile nephropathic cystinosis (INC) is a rare autosomal recessive storage disease, due to mutations in the CTNS gene encoding for the lysosomal cystine transporter cystinosin [1]
INC patients develop an insensitivity to the actions of growth hormone (GH) and insulin-like growth factor 1 (IGF1), as noted in other patients suffering from advanced chronic kidney disease (CKD), which further hinders growth and can be overcome by treatment with recombinant human GH [22,32,33]
Recent studies show that INC is characterized by distinct CKD stage-dependent abnormalities in bone metabolism, including sclerostin and FGF23, which differs markedly to that observed in patients with other underlying causes of CKD as outlined below [13,14]
Summary
Infantile nephropathic cystinosis (INC) is a rare autosomal recessive storage disease, due to mutations in the CTNS gene encoding for the lysosomal cystine transporter cystinosin [1]. Initial studies suggest that bone and muscle impairment in INC are the primary consequences of Fanconi syndrome, and later, of mineral and bone disorder associated with CKD (CKD-MBD) [8,9]. The former results in impairment of calcium and phosphate homeostasis, with the clinical consequences of hypophosphatemic rickets and muscle weakness, whereas the latter describes the complexity of renal osteodystrophy, alterations in mineral and vitamin D metabolism, and cardiovascular complications, as seen in CKD patients with other underlying causes of 2 of 12 2 of 11 derlying causes of CKD [2,10]. Telheevateterdmlecpystitninsoigsinsamlinegta,bporloimc bootinnegdmisuesacslee w(CaMstBinDg)[w11a–s17co].inTehde bteyrmanciynstteinrnoasitsiomnaeltagbuoildicelbinoeneinditiisaetaivsee (tCoMdBesDcr)iwbeasthciosincoemd pbyleaxnbionnteerpnhaetinoontaylpgeuiindeIlNinCe pinaittiieantitvse(Ftoigduersec1ri)b[e18th].isTchoismrpevleixewbohnieghplhigehntostythpee riencIeNntCinpsaitgiehntstsin(Ftihgeurpea1th) o[1p8h]y. sTiholisogreyovfiemwuhsicglehlaignhdtsbothneeriemcepnatirinmseignhttasnidn tthheeipr ainthteorpphlyaysioinloIgNyCo.f muscle and bone impairment and their interplay in INC
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