Hypophosphatasia (HPP) is caused by inactivating mutations in the ALPL gene, which is located on the short arm of chromosome 1 (1p36.1-34). This gene has the designation TNSALP (tissue-nonspecific alkaline phosphatase) or ALPL (bone/liver/kidney ALP) and more than 300 different mutations have been described:  2015 TNSALP Gene Mutations Database

 

The TNSALP gene codes for the tissue-specific isoenzyme of alkaline phosphatase (ALP). The consequences of low ALP activity and accumulation of ALP substrate can be life-threatening or lead to serious disease complications.

 

As with many genetic diseases, the underlying pathological processes linked to HPP are permanent throughout life – even though sometimes symptoms do not appear until later in life.

 

ALP is needed to metabolise 3 ALP-related substrates:
  • Pyridoxal 5’ phosphate (PLP – or vitamin B6)
  • Inorganic pyrophosphate (PPi)
  • Phosphoethanolamine (PEA)

Disease mechanism

Low ALP activity and subsequent biochemical deviations have systemic consequences
Low ALP activity results in extracellular accumulation of PLP, the active form of vitamin B6. Without dephosphorylation via ALP, vitamin B6 cannot pass into the central nervous system, which can result in a PLP deficiency in the central nervous system and associated vitamin B6-related seizures. The neurological symptoms can also be caused and worsened by craniosynostosis and accompanying raised intracranial pressure.
PPi is a natural inhibitor of bone mineralisation. When ALP activity is too low, PPi accumulates, disrupting bone mineralisation. This severely impairs bone formation and stability and calcium deposits to bone. This results in skeletal deformities and other pathological consequences, and can also produce other systemic consequences:
  • Atypical, repeated and/or slow-healing fractures
  • Nephrocalcinosis and kidney disorders
  • Craniosynostosis and accompanying raised intracranial pressure
  • Severe hypomineralisation of the ribs that can lead to pulmonary hypoplasia and respiratory failure
  • Chondrocalcinosis and rheumatological problems, with chronic pain and inflammation
PEA is an amino acid derivative used in the formation of certain phospholipids. Accumulation of PEA in urine is a diagnostic marker for HPP, but its significance in the disease’s pathology is unclear.

 

Film on the disease mechanism behind hypophosphatasia

 

Greenberg CR et al. Am J Hum Genet. 1990; 46: 286-292.

Millán JL & Plotkin H. Actual osteol. 2012; 8: 164-182

Mornet E. Best Pract Res Clin Rheum 2008; 22: 113-127. 

Mornet E. Clinic Rev Bone Miner Metab 2013; 11:71–77. 

Mornet E. 2015 The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. 

http://www.sesep.uvsq.fr/03_hypo_mutations.php 

Orimo H. J Nippon Med Sch 2010; 77: 4-12

Whyte MP et al. J Clin Invest 1985; 76: 752-756

Whyte MP. Ann N Y Acad Sci 2010;1192: 190-200.

SYMPTOMS AND CONDITIONS
ASSOCIATED WITH HYPOPHOSPHATASIA

COMMON SYMPTOMS AND CONDITIONS THAT
CAN BE CAUSED BY HYPOPHOSPHATASIA READ MORE

THE ALP CALCULATOR
– DIAGNOSTIC TOOL

LOW ALP ACTIVITY KEY TO DIAGNOSIS READ MORE


IMPORTANT DIFFERENTIAL DIAGNOSES

IMPORTANT DIFFERENTIAL 
DIAGNOSES/CONDITIONS READ MORE
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