1923:
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Robert Robison discovers alkaline phosphatase1 and develops the hypothesis that this enzyme is critical for bone mineralization.2
1 Robison R. (1923) The possible significance of hexosephosphoric esters in ossification. Biochem J, 17:286 – 293.
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2 Robison R. (1932) The Significance of Phosphoric Esters in Metabolism. New York University Press, New York.
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1936:
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A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency rickets (a kidney dysfunction which causes soft bones) who die at three and six months of age.3
3 Chown B. (1936) Renal rickets and dwarfism: A pituitary disease. Br J Surg 23(91):552-566.
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1948:
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Canadian pediatrician John C. Rathbun names the disease "hypophosphatasia" (HPP) following the first official case report.4
4 Rathbun J.C. (1948) Hypophosphatasia, a new developmental anomaly. Am J Dis Child, 75:822- 831.
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1955:
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Elevated level of phosphoethanolamine (PEA) in urine of patients proves to be a useful marker for HPP.5, 6, 7 This marker is still used for clinical testing today.
5 Fraser D., Yendt E.R. (1955) Metabolic abnormalities in hypophosphatasia. Am J Dis Child, 90:552-554.
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6Fraser D., Yendt E.R., Christie F.H.E. (1955) Metabolic abnormalities in hypophosphatasia. Lancet, 1: 286.
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7McCance R.A., Morrison A.B., Dent C.E. (1955) The excretion of phosphoethanolamine and hypophosphatasia. Lancet, 1:131.
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1965 & 1971:
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Elevated levels of inorganic pyrophosphate (Ppi) in the urine8 and blood9 of patients proves to be a useful marker for HPP, and is still used for clinical testing today. This observation also leads researchers to believe that defective bone mineralization is the cause of HPP.10
8 Russell R.G.G.(1965) Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet, 2:461- 464.
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9 Russell R.G., Bisaz S., Donath A., Morgan D.B., and Fleisch H. (1971) Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone. J Clin Invest, 50:961-969.
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10 Heinonen J.K. (2001)Biological Role of Inorganic Pyrophosphate. Kluwer Academic Publishers, Norwell, MA.
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1982:
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Enzyme replacement therapy in an HPP patient is attempted by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease.11
11 Whyte M.P., Valdes R. Jr., Ryan L.M., McAlister W.H. (1982) Infantile hypophosphatasia: enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease. J Peds, 101(3):379-386.
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1985:
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Elevated levels of pyridoxal 5’-phosphate (PLP) are found in HPP patients.12 This marker is still used for clinical testing today.
12 Whyte M.P., Vrabel L.A. (1985) Infantile hypophosphatasia: genetic complimentation analyses with skin fibroblast heterokaryons suggest a defect(s) at a single gene locus. Clin Res, 33: 332A.
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1986:
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Gene coding TNSALP is mapped to chromosome 1.13
13 Swallow D.M. (1986) Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1. Ann Hum Genet, 50(3):229-235.
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2003:
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First autologous bone marrow transplant is performed in an HPP patient.14
14 Whyte M.P., Kurtzberg J., McAlister W.H., Mumm S., Podgornik M.N., Coburn S.P., Ryan L.M., Miller C.R., Gottesman G.S., Smith A.K., Douville J., Waters-Pick B., Armstrong R.D., Martin P.L. (2003) Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 18(4):624-636.
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2005:
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Enobia begins preclinical studies of ENB-0040.
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2008:
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Enobia begins clinical trials investigating ENB-0040 in infants and adults with HPP.
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