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Hypophosphatasia (HPP) is a life-threatening, progressive, systemic, inherited metabolic disorder.1-3

Hypophosphatasia is a lifelong disease caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP).1,4-6

The resulting low alkaline phosphatase (ALP) activity inhibits bone mineralization, which can lead to premature death, progressive physical disability, and poor quality of life in children.1,4,7,8

In hypophosphatasia, low alkaline phosphatase ruins bones, bodies, and lives.1,8-13

Low alkaline phosphatase activity is the biological hallmark of hypophosphatasia.1,4

Low alkaline phosphatase activity is caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase.4,6
As a result, alkaline phosphate substrates accumulate, leading to life-threatening and debilitating consequences.1,4,5

Alkaline phosphatase is critical for metabolizing 3 substrates5,14

Pyridoxal 5'-phosphate (PLP—or vitamin B6) - alkaline phosphatase substrate

Pyridoxal 5'-phosphate

(PLP—or vitamin B6)

Inorganic pyrophosphate (PPi) - alkaline phosphatase substrate

Inorganic pyrophosphate

(PPi)

Phosphoethanolamine (PEA) - alkaline phosphatase substrate

Phosphoethanolamine

(PEA)

Low alkaline phosphatase activity is the underlying cause of morbidities and mortality in hypophosphatasia.1,4,5

In hypophosphatasia, low alkaline phosphatase ruins bones, bodies, and lives.1,8-13


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In addition to its role in bone mineralization, alkaline phosphatase dephosphorylates PLP (vitamin B6) into pyridoxal (PL), allowing it to cross the plasma membrane into the central nervous system (CNS). Within the CNS, PL is rephosphorylated into PLP. Intracellular PLP is involved in neurotransmitter synthesis (e.g., gamma aminobutyric acid [GABA], dopamine, serotonin).1,21

In patients with hypophosphatasia, PLP deficiency in the CNS can cause fatal vitamin B6–responsive seizures.1,4,5

Clinical symptoms

Prominent clinical symptoms of hypophosphatasia

Avoid misdiagnoses

Hypophosphatasia is often misdiagnosed, because the signs and symptoms can overlap with those of other disorders.1,14

Low alkaline phosphatase —the biological hallmark of hypophosphatasia1,5

Growth and development profoundly affect the normal interval for alkaline phosphatase24,25
Assess your patient’s
alkaline phosphatase
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References: 1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 2. Fraser D. Hypophosphatasia. Am J Med. 1957;22(5):730-746. 3. Whyte MP, Leung E, Wilcox W, et al. for Study 011-10 Investigators. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at: 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; May 3-6, 2014; Vancouver, BC. 2014. 4. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 1. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598. 5. Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 4. 8th ed. New York, NY: McGraw-Hill; 2001:5313-5329. 6. Greenberg CR, Taylor CLD, Haworth JC, et al. A homoallelic Gly317 → Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites. Genomics. 1993;17(1):215-217. 7. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from patient-reported outcome surveys [abstract FRI-240]. Endocrine Society’s 97th Annual Meeting and Expo website. https://endo.confex.com/endo/2015endo/webprogram/Paper20871.html. Accessed July 13, 2015. 8. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661. 9. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170. 10. Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5-phosphate availability. J Inherit Metab Dis. 2010;33(3):25-33. 11. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990;65(1):130-131. 12. Whyte MP, Murphy WA, Fallon MD. Adult hypophosphatasia with chondrocalcinosis and arthropathy: variable penetrance of hypophosphatasemia in a large Oklahoma kindred. Am J Med. 1982;72(4):631-641. 13. Fallon MD, Teitelbaum SL, Weinstein RS, Goldfischer S, Brown DM, Whyte MP. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine. 1984;63(1):12-24. 14. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Bird TD, Dolan CR, Stephen K, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated August 5, 2010. Accessed March 27, 2015. 15. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4-12. 16. Beck C, Morbach H, Wirth C, Beer M, Girschick HJ. Whole-body MRI in the childhood form of hypophosphatasia. Rheumatol Int. 2011;31(10):1315-20. 17. Whyte MP. Hypophosphatasia. In: Glorieux FH PJ, Jüppner H, editor. Pediatric Bone. 2nd ed. London, UK: Academic Press; 2012: 771-94. 18. Coe JD, Murphy WA, Whyte MP. Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am. 1986;68(7):981-90. 19. Gagnon C, Sims NA, Mumm S, et al. Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(3):1007-12. 20. Schalin-Jantti C, Mornet E, Lamminen A, Valimaki MJ. Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(12):5174-9. 21. Sebastián-Serrano Á, de Diego-García L, Martínez-Frailes C, et al. Tissue-nonspecific alkaline phosphatase regulates purinergic transmission in the central nervous system during development and disease. Comput Struct Biotechnol J. 2015;13:95-100. 22. Moulin P, Vaysse F, Bieth E, et al. Hypophosphatasia may lead to bone fragility: don't miss it. Eur J Pediatr. 2009 Jul;168(7):783-8. 23. Sutton RAL, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994. 24. Colantonio DA, Kyriakopoulou L, Chan MK, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012 May;58(5):854-68. 25. Turan S, Topcu B, Gokce I, et al. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol. 2011;3(1):7-11.