Skip to main content

Advertisement

SpringerLink
Log in

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts

  • Pediatrics (L Ward and E Imel, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.

Recent Findings

Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC.

Summary

Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol. 2002;39(2):225–30.

    Article  PubMed  Google Scholar 

  2. Wilson PW, Kauppila LI, O’Donnell CJ, Kiel DP, Hannan M, Polak JM, et al. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation. 2001;103(11):1529–34.

    Article  CAS  PubMed  Google Scholar 

  3. Niskanen LK, Suhonen M, Siitonen O, Lehtinen JM, Uusitupa MI. Aortic and lower limb artery calcification in type 2 (non-insulin-dependent) diabetic patients and non-diabetic control subjects. A five year follow-up study. Atherosclerosis. 1990;84(1):61–71.

    Article  CAS  PubMed  Google Scholar 

  4. Kalra SS, Shanahan CM. Vascular calcification and hypertension: cause and effect. Ann Med. 2012;44(Suppl 1):S85–92. doi:10.3109/07853890.2012.660498.

    Article  CAS  PubMed  Google Scholar 

  5. Weissen-Plenz G, Nitschke Y, Rutsch F. Mechanisms of arterial calcification: spotlight on the inhibitors. Adv Clin Chem. 2008;46:263–93.

    Article  CAS  PubMed  Google Scholar 

  6. Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers. 2016;2:16006. doi:10.1038/nrdp.2016.6.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kirsch T. Biomineralization—an active or passive process? Connect Tissue Res. 2012;53(6):438–45. doi:10.3109/03008207.2012.730081.

    Article  CAS  PubMed  Google Scholar 

  8. Proudfoot D, Shanahan CM, Weissberg PL. Vascular calcification: new insights into an old problem. J Pathol. 1998;185(1):1–3. doi:10.1002/(SICI)1096-9896(199805)185:1<1::AID-PATH89>3.0.CO;2-J.

    Article  CAS  PubMed  Google Scholar 

  9. Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, et al. Multilineage potential of cells from the artery wall. Circulation. 2003;108(20):2505–10. doi:10.1161/01.CIR.0000096485.64373.C5.

    Article  PubMed  Google Scholar 

  10. Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation. 2000;102(21):2636–42.

    Article  CAS  PubMed  Google Scholar 

  11. Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003;23(3):489–94. doi:10.1161/01.ATV.0000059406.92165.31.

    Article  CAS  PubMed  Google Scholar 

  12. Bini A, Mann KG, Kudryk BJ, Schoen FJ. Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1999;19(8):1852–61.

    Article  CAS  PubMed  Google Scholar 

  13. Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21(12):1998–2003.

    Article  CAS  PubMed  Google Scholar 

  14. Nitschke Y, Rutsch F. Modulators of networks: molecular targets of arterial calcification identified in man and mice. Curr Pharm Des. 2014;20(37):5839–52.

    Article  CAS  PubMed  Google Scholar 

  15. • Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):275–82. doi:10.1016/j.ajhg.2014.12.014. This paper for the first time links a gain of function mutation in a RIG-I like intracellular receptor for double stranded RNA to arterial and cardiac valve calcification

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abrahamov A, Elstein D, Gross-Tsur V, Farber B, Glaser Y, Hadas-Halpern I, et al. Gaucher’s disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet. 1995;346(8981):1000–3.

    Article  CAS  PubMed  Google Scholar 

  17. Kirsch T. Determinants of pathological mineralization. Curr Opin Rheumatol. 2006;18(2):174–80. doi:10.1097/01.bor.0000209431.59226.46.

    Article  CAS  PubMed  Google Scholar 

  18. • Feigenbaum A, Muller C, Yale C, Kleinheinz J, Jezewski P, Kehl HG, et al. Singleton-Merten syndrome: an autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A(2):360–70. doi:10.1002/ajmg.a.35732. This case series describes the multi-faceted clinical picture of Singleton-Merten syndrome

    Article  PubMed  Google Scholar 

  19. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification. Nat Genet. 2003;34(4):379–81. doi:10.1038/ng1221.

    Article  CAS  PubMed  Google Scholar 

  20. Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1(2):133–40. doi:10.1161/CIRCGENETICS.108.797704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mastrolia SA, Weintraub AY, Baron J, Sciaky-Tamir Y, Koifman A, Loverro G, et al. Antenatal diagnosis of idiopathic arterial calcification: a systematic review with a report of two cases. Arch Gynecol Obstet. 2015;291(5):977–86. doi:10.1007/s00404-014-3567-z.

    Article  PubMed  Google Scholar 

  22. Felix R, Monod A, Broge L, Hansen NM, Fleisch H. Aggregation of calcium oxalate crystals: effect of urine and various inhibitors. Urol Res. 1977;5(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  23. Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. 2002;71(4):933–40. doi:10.1086/343054.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cheng KS, Chen MR, Ruf N, Lin SP, Rutsch F. Generalized arterial calcification of infancy: different clinical courses in two affected siblings. Am J Med Genet A. 2005;136(2):210–3. doi:10.1002/ajmg.a.30800.

    Article  PubMed  Google Scholar 

  25. Ciana G, Trappan A, Bembi B, Benettoni A, Maso G, Zennaro F, et al. Generalized arterial calcification of infancy: two siblings with prolonged survival. Eur J Pediatr. 2006;165(4):258–63. doi:10.1007/s00431-005-0035-6.

    Article  PubMed  Google Scholar 

  26. Dlamini N, Splitt M, Durkan A, Siddiqui A, Padayachee S, Hobbins S, et al. Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications. Am J Med Genet A. 2009;149A(3):456–60. doi:10.1002/ajmg.a.32646.

    Article  CAS  PubMed  Google Scholar 

  27. Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86(2):267–72. doi:10.1016/j.ajhg.2010.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86(2):273–8. doi:10.1016/j.ajhg.2010.01.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Meradji M, de Villeneuve VH, Huber J, de Bruijn WC, Pearse RG. Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J Pediatr. 1978;92(3):401–5.

    Article  CAS  PubMed  Google Scholar 

  30. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest. 1996;97(12):2692–6. doi:10.1172/JCI118722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ferreira C, Ziegler S, Gahl W. Generalized arterial calcification of infancy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al., editors. GeneReviews® [Internet]. Seattle (WA) 1993.

  32. Ramjan KA, Roscioli T, Rutsch F, Sillence D, Munns CF. Generalized arterial calcification of infancy: treatment with bisphosphonates. Nat Clin Pract Endocrinol Metab. 2009;5(3):167–72. doi:10.1038/ncpendmet1067.

    Article  CAS  PubMed  Google Scholar 

  33. •• Otero JE, Gottesman GS, WH MA, Mumm S, Madson KL, Kiffer-Moreira T, et al. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res : Off J Am Soc Bone Miner Res. 2013;28(2):419–30. doi:10.1002/jbmr.1752. This paper for the first time describe serious side effects associated with prolonged bisphosphonate therapy in a child with GACI

    Article  CAS  Google Scholar 

  34. Thomas P, Chandra M, Kahn E, McVicar M, Naidich J, LaCorte M. Idiopathic arterial calcification of infancy: a case with prolonged survival. Pediatr Nephrol. 1990;4(3):233–5.

    Article  CAS  PubMed  Google Scholar 

  35. •• Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, et al. ENPP1-FC prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015;6:10006. doi:10.1038/ncomms10006. In this study, enzyme therapy using recombinant ENPP1 protein coupled to the FC-portion of the IgG protein successfully prevents ectopic calcification in Enpp1 deficient mice

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ringpfeil F, Pulkkinen L, Uitto J. Molecular genetics of pseudoxanthoma elasticum. Exp Dermatol. 2001;10(4):221–8.

    Article  CAS  PubMed  Google Scholar 

  37. Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, et al. Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum Mutat. 2005;26(3):235–48. doi:10.1002/humu.20206.

    Article  CAS  PubMed  Google Scholar 

  38. Bercovitch L, Terry P. Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. 2004;51(1 Suppl):S13–4. doi:10.1016/j.jaad.2004.01.015.

    Article  PubMed  Google Scholar 

  39. Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25(2):228–31. doi:10.1038/76109.

    Article  CAS  PubMed  Google Scholar 

  40. Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, et al. A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Am J Hum Genet. 2001;69(4):749–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci U S A. 2000;97(11):6001–6. doi:10.1073/pnas.100041297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Struk B, Cai L, Zach S, Ji W, Chung J, Lumsden A, et al. Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum. J Mol Med. 2000;78(5):282–6.

    Article  CAS  PubMed  Google Scholar 

  43. Aherrahrou Z, Doehring LC, Ehlers EM, Liptau H, Depping R, Linsel-Nitschke P, et al. An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H/He mice. J Biol Chem. 2008;283(12):7608–15. doi:10.1074/jbc.M708290200.

    Article  CAS  PubMed  Google Scholar 

  44. Doehring LC, Kaczmarek PM, Ehlers E, Mayer B, Erdmann J, Schunkert H, et al. Arterial calcification in mice after freeze-thaw injury. Ann Anat = Anatomischer Anzeiger : Off Organ Anatomische Gesellschaft. 2006;188(3):235–42.

    Article  Google Scholar 

  45. Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, et al. Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum. J Med Genet. 2007;44(10):621–8. doi:10.1136/jmg.2007.051094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li Q, Jiang Q, Pfendner E, Varadi A, Uitto J. Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms. Exp Dermatol. 2009;18(1):1–11. doi:10.1111/j.1600-0625.2008.00795.x.

    Article  CAS  PubMed  Google Scholar 

  47. Le Saux O, Fulop K, Yamaguchi Y, Ilias A, Szabo Z, Brampton CN, et al. Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS One. 2011;6(9):e24738. doi:10.1371/journal.pone.0024738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Le Boulanger G, Labreze C, Croue A, Schurgers LJ, Chassaing N, Wittkampf T, et al. An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy. Am J Med Genet A. 2010;152A(1):118–23. doi:10.1002/ajmg.a.33162.

    Article  CAS  PubMed  Google Scholar 

  49. •• Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90(1):25–39. doi:10.1016/j.ajhg.2011.11.020. This paper demonstrates the genotypic and phenotypic overlap of GACI and PXE and points to disordered pyrophosphate metabolism as the common pathophysiologic pathway of both disorders

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. •• Jansen RS, Kucukosmanoglu A, de Haas M, Sapthu S, Otero JA, IEM H, et al. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013;110(50):20206–11. doi:10.1073/pnas.1319582110. This study for the first time directly links PXE to disordered ATP and pyrophosphate metabolism

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Varadi A, et al. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol. 2014;34(9):1985–9. doi:10.1161/ATVBAHA.114.304017.

    Article  CAS  PubMed  Google Scholar 

  52. Jiang Q, Uitto J. Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(−/−)). Exp Dermatol. 2012;21(9):694–9. doi:10.1111/j.1600-0625.2012.01553.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kupetsky-Rincon EA, Li Q, Uitto J. Magnesium reduces carotid intima-media thickness in a mouse model of pseudoxanthoma elasticum: a novel treatment biomarker. Clin Transl Sci. 2012;5(3):259–64. doi:10.1111/j.1752-8062.2011.00390.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. LaRusso J, Li Q, Jiang Q, Uitto J. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(−/−)). J Investig Dermatol. 2009;129(6):1388–94. doi:10.1038/jid.2008.391.

    Article  CAS  PubMed  Google Scholar 

  55. •• Li Q, Sundberg JP, Levine MA, Terry SF, Uitto J. The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene. Cell Cycle. 2015;14(7):1082–9. doi:10.1080/15384101.2015.1007809. Based on the observation of low extracellular PP i levels in Abcc−/− mice, the authors successfully used synthetic PP i analogs to prevent ectopic mineralization in this animal model

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Li Q, Kingman J, Sundberg JP, Levine MA, Uitto J. Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6−/−). Oncotarget. 2016; doi:10.18632/oncotarget.10738.

  57. •• Pomozi V, Brampton C, Szeri F, Dedinszki D, Kozak E, van de Wetering K, et al. Functional rescue of ABCC6 deficiency by 4-phenylbutyrate therapy reduces dystrophic calcification in Abcc6−/− mice. J Investig Dermatol. 2016; doi:10.1016/j.jid.2016.10.035. This study describes the successful use of 4-PBA, a pharmacological chaperone as an allele specific therapy to treat dystrophic calcification in a mouse model of PXE

    Article  CAS  PubMed  Google Scholar 

  58. •• St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364(5):432–42. doi:10.1056/NEJMoa0912923. This study for the first time links the rare disorder calcification of joint and arteries (CALJA) to mutations in NT5E encoding CD73, a protein which by degrading AMP generates adenosine

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang Z, He JW, Fu WZ, Zhang CQ, Zhang ZL. Calcification of joints and arteries: second report with novel NT5E mutations and expansion of the phenotype. J Hum Genet. 2015;60(10):561–4. doi:10.1038/jhg.2015.85.

    Article  CAS  PubMed  Google Scholar 

  60. de Nijs T, Albuisson J, Ockeloen CW, Legrand A, Jeunemaitre X, Schultze Kool LJ, et al. Isolated arterial calcifications of the lower extremities: a clue for NT5E mutation. Int J Cardiol. 2016;212:248–50. doi:10.1016/j.ijcard.2016.03.068.

    Article  PubMed  Google Scholar 

  61. • Li Q, Price TP, Sundberg JP, Uitto J. Juxta-articular joint-capsule mineralization in CD73 deficient mice: similarities to patients with NT5E mutations. Cell Cycle. 2014;13(16):2609–15. doi:10.4161/15384101.2014.943567. This paper links CD73 deficiency to disordered pyrophosphate metabolism

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fausther M, Lavoie EG, Goree JR, Baldini G, Dranoff JA. NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PLoS One. 2014;9(6):e98568. doi:10.1371/journal.pone.0098568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Markello TC, Pak LK, St Hilaire C, Dorward H, Ziegler SG, Chen MY, et al. Vascular pathology of medial arterial calcifications in NT5E deficiency: implications for the role of adenosine in pseudoxanthoma elasticum. Mol Genet Metab. 2011;103(1):44–50. doi:10.1016/j.ymgme.2011.01.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sheen CR, Kuss P, Narisawa S, Yadav MC, Nigro J, Wang W, et al. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J Bone Miner Res : Off J Am Soc Bone Miner Res. 2015;30(5):824–36. doi:10.1002/jbmr.2420.

    Article  CAS  Google Scholar 

  65. Savinov AY, Salehi M, Yadav MC, Radichev I, Millan JL, Savinova OV. Transgenic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in vascular endothelium results in generalized arterial calcification. J Am Heart Assoc. 2015;4(12). doi:10.1161/JAHA.115.002499.

  66. Gutierrez LB, Link T, Chaganti K, Motamedi D. Arterial calcification due to CD73 deficiency (ACDC): imaging manifestations of ectopic mineralization. Skelet Radiol. 2016;45(11):1583–7. doi:10.1007/s00256-016-2465-9.

    Article  Google Scholar 

  67. Kimura T, Miura T, Aoki K, Saito S, Hondo H, Konno T, et al. Familial idiopathic basal ganglia calcification: histopathologic features of an autopsied patient with an SLC20A2 mutation. Neuropathol Off J Jpn Soc Neuropathol. 2016;36(4):365–71. doi:10.1111/neup.12280.

    Article  CAS  Google Scholar 

  68. Hozumi I, Kohmura A, Kimura A, Hasegawa T, Honda A, Hayashi Y, et al. High levels of copper, zinc, iron and magnesium, but not calcium, in the cerebrospinal fluid of patients with Fahr’s disease. Case Rep Neurol. 2010;2(2):46–51. doi:10.1159/000313920.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet. 2012;44(3):254–6. doi:10.1038/ng.1077.

    Article  CAS  PubMed  Google Scholar 

  70. Jensen N, Schroder HD, Hejbol EK, Fuchtbauer EM, de Oliveira JR, Pedersen L. Loss of function of Slc20a2 associated with familial idiopathic basal ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci : MN. 2013;51(3):994–9. doi:10.1007/s12031-013-0085-6.

    Article  CAS  PubMed  Google Scholar 

  71. Wallingford MC, Chia JJ, Leaf EM, Borgeia S, Chavkin NW, Sawangmake C, et al. SLC20A2 deficiency in mice leads to elevated phosphate levels in cerebrospinal fluid and glymphatic pathway-associated arteriolar calcification, and recapitulates human idiopathic basal ganglia calcification. Brain Pathol. 2017;27(1):64–76. doi:10.1111/bpa.12362.

    Article  CAS  PubMed  Google Scholar 

  72. •• Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, et al. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet. 2015;47(6):579–81. doi:10.1038/ng.3289. This study for the first time links the rare disorder IBGC to mutations in XPR1, encoding a phosphate exporter involved in phosphate homeostasis

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Giovannini D, Touhami J, Charnet P, Sitbon M, Battini JL. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep. 2013;3(6):1866–73. doi:10.1016/j.celrep.2013.05.035.

    Article  CAS  PubMed  Google Scholar 

  74. Anheim M, Lopez-Sanchez U, Giovannini D, Richard AC, Touhami J, N’Guyen L, et al. XPR1 mutations are a rare cause of primary familial brain calcification. J Neurol. 2016;263(8):1559–64. doi:10.1007/s00415-016-8166-4.

    Article  CAS  PubMed  Google Scholar 

  75. •• Nicolas G, Pottier C, Maltete D, Coutant S, Rovelet-Lecrux A, Legallic S, et al. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. 2013;80(2):181–7. doi:10.1212/WNL.0b013e31827ccf34. This study for the first time links mutations in PDGFRB to the rare disease IBGC

    Article  CAS  PubMed  Google Scholar 

  76. Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 2004;15(4):197–204. doi:10.1016/j.cytogfr.2004.03.007.

    Article  CAS  PubMed  Google Scholar 

  77. Sanchez-Contreras M, Baker MC, Finch NA, Nicholson A, Wojtas A, Wszolek ZK, et al. Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology. Hum Mutat. 2014;35(8):964–71. doi:10.1002/humu.22582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Arts FA, Velghe AI, Stevens M, Renauld JC, Essaghir A, Demoulin JB. Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. J Cell Mol Med. 2015;19(1):239–48. doi:10.1111/jcmm.12443.

    Article  CAS  PubMed  Google Scholar 

  79. •• Keller A, Westenberger A, Sobrido MJ, Garcia-Murias M, Domingo A, Sears RL, et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013;45(9):1077–82. doi:10.1038/ng.2723. Mutations in the gene encoding PDGF-B, the main ligand for PDGF-RB, were found to cause IBGC. Loss of PDGFB was found to correlate with pericyte and blood-brain barrier deficiency, leading to calcification

    Article  CAS  PubMed  Google Scholar 

  80. Villa-Bellosta R, Levi M, Sorribas V. Vascular smooth muscle cell calcification and SLC20 inorganic phosphate transporters: effects of PDGF, TNF-alpha, and pi. Pflugers Archiv : Eur J Physiol. 2009;458(6):1151–61. doi:10.1007/s00424-009-0688-5.

    Article  CAS  Google Scholar 

  81. Betsholtz C, Keller A. PDGF, pericytes and the pathogenesis of idiopathic basal ganglia calcification (IBGC). Brain Pathol. 2014;24(4):387–95. doi:10.1111/bpa.12158.

    Article  CAS  PubMed  Google Scholar 

  82. Lemos RR, Ferreira JB, Keasey MP, Oliveira JR. An update on primary familial brain calcification. Int Rev Neurobiol. 2013;110:349–71. doi:10.1016/B978-0-12-410502-7.00015-6.

    Article  CAS  PubMed  Google Scholar 

  83. Loeb JA. Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. Mov Disord Off J Mov Disord Soc. 1998;13(2):345–9. doi:10.1002/mds.870130225.

    Article  CAS  Google Scholar 

  84. Loeb JA, Sohrab SA, Huq M, Fuerst DR. Brain calcifications induce neurological dysfunction that can be reversed by a bone drug. J Neurol Sci. 2006;243(1–2):77–81. doi:10.1016/j.jns.2005.11.033.

    Article  CAS  PubMed  Google Scholar 

  85. Oliveira JR, Oliveira MF. Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate. Sci Rep. 2016;6:22961. doi:10.1038/srep22961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. • Keasey MP, Lemos RR, Hagg T, Oliveira JR. Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1. Sci Rep. 2016;6:25802. doi:10.1038/srep25802. Incubation of calcifying SaOs2 cells with vitamin D increased SLC20A expression and maybe thereby reduced calcification.This in vitro study presents a new attractive option for treatment of IBGC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, et al. Lamin a truncation in Hutchinson-Gilford progeria. Science. 2003;300(5628):2055. doi:10.1126/science.1084125.

    Article  CAS  PubMed  Google Scholar 

  88. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423(6937):293–8. doi:10.1038/nature01629.

    Article  CAS  PubMed  Google Scholar 

  89. Nair K, Ramachandran P, Krishnamoorthy KM, Dora S, Achuthan TJ. Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis and calcific mitral valve. J Heart Valve Dis. 2004;13(5):866–9.

    PubMed  Google Scholar 

  90. Salamat M, Dhar PK, Neagu DL, Lyon JB. Aortic calcification in a patient with Hutchinson-Gilford progeria syndrome. Pediatr Cardiol. 2010;31(6):925–6. doi:10.1007/s00246-010-9711-z.

    Article  PubMed  Google Scholar 

  91. Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006;140(23):2603–24. doi:10.1002/ajmg.a.31346.

    Article  CAS  PubMed  Google Scholar 

  92. Andres V, Gonzalez JM. Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol. 2009;187(7):945–57. doi:10.1083/jcb.200904124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schreiber KH, Kennedy BK. When lamins go bad: nuclear structure and disease. Cell. 2013;152(6):1365–75. doi:10.1016/j.cell.2013.02.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nakano-Kurimoto R, Ikeda K, Uraoka M, Nakagawa Y, Yutaka K, Koide M, et al. Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol. 2009;297(5):H1673–84. doi:10.1152/ajpheart.00455.2009.

    Article  CAS  PubMed  Google Scholar 

  95. Liu Y, Drozdov I, Shroff R, Beltran LE, Shanahan CM. Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells. Circ Res. 2013;112(10):e99–109. doi:10.1161/CIRCRESAHA.111.300543.

    Article  CAS  PubMed  Google Scholar 

  96. •• Villa-Bellosta R, Rivera-Torres J, Osorio FG, Acin-Perez R, Enriquez JA, Lopez-Otin C, et al. Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment. Circulation. 2013;127(24):2442–51. doi:10.1161/CIRCULATIONAHA.112.000571. This study for the first time directly links HGPS to disordered PP i metabolism. The authors successfully used PP i to prevent ectopic mineralization in HGPS animal model

    Article  CAS  PubMed  Google Scholar 

  97. Glynn MW, Glover TW. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet. 2005;14(20):2959–69. doi:10.1093/hmg/ddi326.

    Article  CAS  PubMed  Google Scholar 

  98. Varga R, Eriksson M, Erdos MR, Olive M, Harten I, Kolodgie F, et al. Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2006;103(9):3250–5. doi:10.1073/pnas.0600012103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, et al. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc Natl Acad Sci U S A. 2008;105(41):15902–7. doi:10.1073/pnas.0807840105.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109(41):16666–71. doi:10.1073/pnas.1202529109.

    Article  PubMed  PubMed Central  Google Scholar 

  101. •• Gordon LB, Kleinman ME, Massaro J, RB D’A Sr, Shappell H, Gerhard-Herman M, et al. Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation. 2016;134(2):114–25. doi:10.1161/CIRCULATIONAHA.116.022188. This study present data on a clinical trial on HGPS patient, treated with lonafarnib, pravastatin and zoledronate. The data impressively demonstrate the benefit of lonafarnib on cardiovascular calcification in HGPS patients, but clearify that addition of pravastatin and zoledronate have no added effect on arterial calcification

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Najjar SS, Farah FS, Kurban AK, Melhem RE, Khatchadourian AK. Tumoral calcinosis and pseudoxanthoma elasticum. J Pediatr. 1968;72(2):243–7.

    Article  CAS  PubMed  Google Scholar 

  103. Rafaelsen S, Johansson S, Raeder H, Bjerknes R. Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. BMC Genet. 2014;15:98. doi:10.1186/s12863-014-0098-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shah A, Miller CJ, Nast CC, Adams MD, Truitt B, Tayek JA, et al. Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing. Nephrol Dial Transplant Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc. 2014;29(12):2235–43. doi:10.1093/ndt/gfu324.

    Article  CAS  Google Scholar 

  105. Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005;14(3):385–90. doi:10.1093/hmg/ddi034.

    Article  CAS  PubMed  Google Scholar 

  106. Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007;117(9):2684–91. doi:10.1172/JCI31330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004;36(6):579–81. doi:10.1038/ng1358.

    Article  CAS  PubMed  Google Scholar 

  108. Imel EA, Econs MJ. Fibroblast growth factor 23: roles in health and disease. J Am Soc Nephrol JASN. 2005;16(9):2565–75. doi:10.1681/ASN.2005050573.

    Article  CAS  PubMed  Google Scholar 

  109. Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281(27):18370–7. doi:10.1074/jbc.M602469200.

    Article  CAS  PubMed  Google Scholar 

  110. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281(10):6120–3. doi:10.1074/jbc.C500457200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770–4. doi:10.1038/nature05315.

    Article  CAS  PubMed  Google Scholar 

  112. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51. doi:10.1038/36285.

    Article  CAS  PubMed  Google Scholar 

  113. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone klotho. Science. 2005;309(5742):1829–33. doi:10.1126/science.1112766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology. 2002;143(2):683–9. doi:10.1210/endo.143.2.8657.

    Article  CAS  PubMed  Google Scholar 

  115. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113(4):561–8. doi:10.1172/JCI19081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Esapa CT, Head RA, Jeyabalan J, Evans H, Hough TA, Cheeseman MT, et al. A mouse with an N-ethyl-N-nitrosourea (ENU) induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis. PLoS One. 2012;7(8):e43205. doi:10.1371/journal.pone.0043205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Fathi I, Sakr M. Review of tumoral calcinosis: a rare clinico-pathological entity. World J Clin Cases. 2014;2(9):409–14. doi:10.12998/wjcc.v2.i9.409.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Chefetz I, Sprecher E. Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis. Biochim Biophys Acta. 2009;1792(9):847–52. doi:10.1016/j.bbadis.2008.10.008.

    Article  CAS  PubMed  Google Scholar 

  119. Lammoglia JJ, Mericq V. Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. Horm Res. 2009;71(3):178–84. doi:10.1159/000197876.

    Article  CAS  PubMed  Google Scholar 

  120. •• Chen TH, Kuro OM, Chen CH, Sue YM, Chen YC, Wu HH, et al. The secreted klotho protein restores phosphate retention and suppresses accelerated aging in klotho mutant mice. Eur J Pharmacol. 2013;698(1–3):67–73. doi:10.1016/j.ejphar.2012.09.032. In this study, recombinant soluble Klotho protein successfully prevents ectopic calcification and accelerated aging in Klotho deficient mice

    Article  CAS  PubMed  Google Scholar 

  121. •• Hum JM, O, Bryan LM, Tatiparthi AK, Cass TA, Clinkenbeard EL, Cramer MS, et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho. J Am Soc Nephrol JASN. 2016; doi:10.1681/ASN.2015111266. In this study, stable delivery of adeno-associated virus expressing soluble Klotho protein successfully prevents aortic calcification in Klotho deficient mice

    Article  PubMed  PubMed Central  Google Scholar 

  122. Leibrock CB, Feger M, Voelkl J, Kohlhofer U, Quintanilla-Martinez L, Kuro-o M, et al. Partial reversal of tissue calcification and extension of life span following ammonium nitrate treatment of klotho-deficient mice. Kidney Blood Press Res. 2016;41(1):99–107. doi:10.1159/000443411.

    Article  CAS  PubMed  Google Scholar 

  123. Leibrock CB, Voelkl J, Kohlhofer U, Quintanilla-Martinez L, Kuro OM, Lang F. Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice. Am J Physiol Ren Physiol. 2016;310(1):F102–8. doi:10.1152/ajprenal.00037.2015.

    Article  CAS  Google Scholar 

  124. Leibrock CB, Alesutan I, Voelkl J, Pakladok T, Michael D, Schleicher E, et al. NH4Cl treatment prevents tissue calcification in klotho deficiency. J Am Soc Nephrol JASN. 2015;26(10):2423–33. doi:10.1681/ASN.2014030230.

    Article  CAS  PubMed  Google Scholar 

  125. •• Leibrock CB, Alesutan I, Voelkl J, Michael D, Castor T, Kohlhofer U, et al. Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice. J Mol Med. 2016;94(1):95–106. doi:10.1007/s00109-015-1331-x. The study revealed a powerful effect of acetazolamide on arterial calcification, including osteoinductive signaling, in Klotho deficient mice

    Article  CAS  PubMed  Google Scholar 

  126. •• Jost J, Bahans C, Courbebaisse M, Tran TA, Linglart A, Benistan K, et al. Topical sodium thiosulfate: a treatment for calcifications in hyperphosphatemic familial tumoral calcinosis? J Clin Endocrinol Metab. 2016;101(7):2810–5. doi:10.1210/jc.2016-1087. The authors presented an interesting study on a very effective topical treatment of ectopic calcification in HFTC with sodium thiosulfate

    Article  CAS  PubMed  Google Scholar 

  127. Pasch A, Schaffner T, Huynh-Do U, Frey BM, Frey FJ, Farese S. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int. 2008;74(11):1444–53. doi:10.1038/ki.2008.455.

    Article  CAS  PubMed  Google Scholar 

  128. Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant Off Publ Eur Dial Transplant Assoc - Eur Ren Assoc. 2010;25(6):1923–9. doi:10.1093/ndt/gfp755.

    Article  CAS  Google Scholar 

  129. Buers I, Nitschke Y, Rutsch F. Novel interferonopathies associated with mutations in RIG-I like receptors. Cytokine Growth Factor Rev. 2016;29:101–7. doi:10.1016/j.cytogfr.2016.03.005.

    Article  CAS  PubMed  Google Scholar 

  130. Hall MC, Matson SW. Helicase motifs: the engine that powers DNA unwinding. Mol Microbiol. 1999;34(5):867–77.

    Article  CAS  PubMed  Google Scholar 

  131. •• Funabiki M, Kato H, Miyachi Y, Toki H, Motegi H, Inoue M, et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity. 2014;40(2):199–212. doi:10.1016/j.immuni.2013.12.014. In this elegant study, the authors show how a gain of function mutation in MDA5, an intracellular receptor for viral RNA through elevated type I interferon signaling leads to a lupus-like phenotype including ectopic calcifications in an animal model

    Article  CAS  PubMed  Google Scholar 

  132. Rice GI, del Toro DY, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503–9. doi:10.1038/ng.2933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bursztejn AC, Briggs TA, del Toro Duany Y, Anderson BH, O’Sullivan J, Williams SG, et al. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutieres and Singleton-Merten syndromes. Br J Dermatol. 2015;173(6):1505–13. doi:10.1111/bjd.14073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. •• Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ, Yoo JY, et al. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):266–74. doi:10.1016/j.ajhg.2014.11.019. Here, the authors for the first time provide a link of a familiar syndrome consisting of glaucoma, aortic calcification and skeletal abnormalities to gain of function mutations in DDX58 encoding RIG-I, an intracellular receptor for double stranded RNA

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lassig C, Matheisl S, Sparrer KM, de Oliveira Mann CC, Moldt M, Patel JR et al. ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. eLife. 2015;4. doi:10.7554/eLife.10859.

  136. Takahasi K, Yoneyama M, Nishihori T, Hirai R, Kumeta H, Narita R, et al. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell. 2008;29(4):428–40. doi:10.1016/j.molcel.2007.11.028.

    Article  CAS  PubMed  Google Scholar 

  137. Barral PM, Sarkar D, Su ZZ, Barber GN, DeSalle R, Racaniello VR, et al. Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacol Ther. 2009;124(2):219–34. doi:10.1016/j.pharmthera.2009.06.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet. 1999;21(1):142–4. doi:10.1038/5102.

    Article  CAS  PubMed  Google Scholar 

  139. Meier M, Weng LP, Alexandrakis E, Ruschoff J, Goeckenjan G. Tracheobronchial stenosis in Keutel syndrome. Eur Respir J. 2001;17(3):566–9.

    Article  CAS  PubMed  Google Scholar 

  140. Khosroshahi HE, Sahin SC, Akyuz Y, Ede H. Long term follow-up of four patients with Keutel syndrome. Am J Med Genet A. 2014;164A(11):2849–56. doi:10.1002/ajmg.a.36699.

    Article  CAS  PubMed  Google Scholar 

  141. El-Maadawy S, Kaartinen MT, Schinke T, Murshed M, Karsenty G, McKee MD. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res. 2003;44(Suppl 1):272–8.

    Article  CAS  PubMed  Google Scholar 

  142. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78–81. doi:10.1038/386078a0.

    Article  CAS  PubMed  Google Scholar 

  143. Speer MY, Yang HY, Brabb T, Leaf E, Look A, Lin WL, et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res. 2009;104(6):733–41. doi:10.1161/CIRCRESAHA.108.183053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem. 2002;277(6):4388–94. doi:10.1074/jbc.M109683200.

    Article  CAS  PubMed  Google Scholar 

  145. Leroux-Berger M, Queguiner I, Maciel TT, Ho A, Relaix F, Kempf H. Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin. J Bone Miner Res Off J Am Soc Bone Miner Res. 2011;26(7):1543–53. doi:10.1002/jbmr.382.

    Article  CAS  Google Scholar 

  146. • Beazley KE, Reckard S, Nurminsky D, Lima F, Nurminskaya M. Two sides of MGP null arterial disease: chondrogenic lesions dependent on transglutaminase 2 and elastin fragmentation associated with induction of adipsin. J Biol Chem. 2013;288(43):31400–8. doi:10.1074/jbc.M113.495556. This paper demonstrates, that arterial calcification in MGP deficient mice is more than ectopic chondrogenesis. First elastin fragmentation takes place, which already enables calcification, and vascular SMC pass through chondrogenic transdifferentiation leading to formation of cartilaginous lesions in the arteries

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Khavandgar Z, Roman H, Li J, Lee S, Vali H, Brinckmann J, et al. Elastin haploinsufficiency impedes the progression of arterial calcification in MGP-deficient mice. J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29(2):327–37. doi:10.1002/jbmr.2039.

    Article  CAS  Google Scholar 

  148. Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18(9):1400–7.

    Article  CAS  PubMed  Google Scholar 

  149. •• Cranenburg EC, VANS-Z KY, Bonafe L, Mittaz Crettol L, Rodiger LA, Dikkers FG, et al. Circulating matrix gamma-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome. J Thromb Haemost JTH. 2011;9(6):1225–35. doi:10.1111/j.1538-7836.2011.04263.x. Very interesting case report, presenting a Keutel patient with uncarboxylated, but phosphorylated MGP, which is not sensitive to vitamin K. The authors speculate, that this phosphorylated MGP still has residual protein function and thereby prevented calcification in this patient

    Article  CAS  PubMed  Google Scholar 

  150. Sun LF, Chen X. Tracheobronchial stenosis in Keutel syndrome. Indian Pediatr. 2012;49(9):759.

    Article  PubMed  Google Scholar 

  151. Beutler E, Demina A, Gelbart T. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994;1(1):82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Schiffmann R, Heyes MP, Aerts JM, Dambrosia JM, Patterson MC, DeGraba T, et al. Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Ann Neurol. 1997;42(4):613–21. doi:10.1002/ana.410420412.

    Article  CAS  PubMed  Google Scholar 

  153. Bohlega S, Kambouris M, Shahid M, Al Homsi M, Al Sous W. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology. 2000;54(1):261–3.

    Article  CAS  PubMed  Google Scholar 

  154. George R, McMahon J, Lytle B, Clark B, Lichtin A. Severe valvular and aortic arch calcification in a patient with Gaucher’s disease homozygous for the D409H mutation. Clin Genet. 2001;59(5):360–3.

    Article  CAS  PubMed  Google Scholar 

  155. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab. 2017;120(1–2):47–56. doi:10.1016/j.ymgme.2016.12.001.

    Article  CAS  PubMed  Google Scholar 

  156. Spada M, Chiappa E, Ponzone A. Cardiac response to enzyme-replacement therapy in Gaucher’s disease. N Engl J Med. 1998;339(16):1165–6. doi:10.1056/NEJM199810153391615.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

F.R. and Y.N. were supported by a grant by the Deutsche Forschungsgemeinschaft. Both individuals listed as authors have contributed substantially to the design and writing of this review.

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Münster University Children’s Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany

    Yvonne Nitschke & Frank Rutsch

Authors
  1. Yvonne Nitschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank Rutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Rutsch.

Ethics declarations

Conflict of Interest

Yvonne Nitschke and Frank Rutsch declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pediatrics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nitschke, Y., Rutsch, F. Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts. Curr Osteoporos Rep 15, 255–270 (2017). https://doi.org/10.1007/s11914-017-0370-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-017-0370-3

Keywords

Search

Navigation