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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

ALPL mutations result in low alkaline phosphatase (ALP) activity, which causes the severe systemic manifestations of hypophosphatasia1,4,7

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In hypophosphatasia, low alkaline phosphatase ruins bones, bodies, and lives.1,7-12

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

Low alkaline phosphatase—and the resulting elevated substrate levels—can lead to morbidities and premature mortality in patients with hypophosphatasia.13

Alkaline phosphatase is critical for metabolising 3 substrates5,14


Biochemical and clinical impact of low ALP activity5

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.1,7-12


Low alkaline phosphatase activity disrupts bone mineralization and calcium/phosphate homeostasis throughout life.1,4

Lifelong bone health depends on healthy bone growth in childhood and adolescence and on bone mass turnover throughout adulthood.16-18

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 (eg, gamma aminobutyric acid [GABA], dopamine, serotonin).1,19

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 phosphatase22,23
Assess your patient’s alkaline phosphatase

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  2. Fraser D. Hypophosphatasia. Am J Med. 1957;22(5):730-746.
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  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 2. 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. 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.
  8. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170.
  9. 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.
  10. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990;65(1):130-131.
  11. 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.
  12. 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.
  13. Whyte MP, Zhang F, Wenkert D, et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015;75:229-239.
  14. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. Published November 20, 2007. Updated February 4, 2016. Accessed October 26, 2017.
  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.
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  17. Wüster C, Ziegler R. Reduced bone mineral density and low parathyroid hormone levels in patients with the adult form of hypophosphatasia. Clin Investig. 1992;70(7):560-565.
  18. Kini U, Nandeesh BN. Physiology of bone formation, remodeling, and metabolism. In: Fogelman I, Gnanasegaran G, van der Wall H, eds. Radionuclide and Hybrid Bone Imaging. Berlin, Germany: Springer-Verlag Berlin Heidelberg; 2012:29-57.
  19. 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.
  20. Moulin P, Vaysse F, Bieth E, et al. Hypophosphatasia may lead to bone fragility: don't miss it. Eur J Pediatr. 2009;168(7):783-788.
  21. 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.
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  23. Turan S, Topcu B, Gökçe 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.