**3.5 Hypophosphatasia**

Hypophosphatasia (HPP) is a rare, systemic, genetic, metabolic disease with a deficiency in tissue nonspecific alkaline phosphatase (ALP) activity resulting in the extracellular accumulation of its substrates [71]. The clinical presentation of HPP can vary considerably between individuals and includes skeletal problems, muscle weakness, ambulatory difficulties, pain, and dental, neurologic, and renal manifestations. The first case of HPP was reported by the Canadian pediatrician John Campbell Rathbun in 1948 as a new developmental anomaly. The prevalence of HPP was estimated as 1 in 100,000 live births in the Toronto area in Canada; In Europe, the prevalence of severe cases is estimated as 1 in 300,000 [72].

## *3.5.1 Etiology and pathogenesis*

HPP is mainly caused by alkaline phosphatase, biomineralization associated (*ALPL*) gene mutations. At least 300 *ALPL* gene mutations have been reported. The gene encoding tissue non-specific alkaline phosphatase (TNSALP) or the alkaline phosphatase expressed in bone/kidney/liver is located on chromosome 1. The HPP mutation sites are heterogenous and the disease can be inherited in an autosomal dominant or recessive manner. Inactivating mutation of *ALPL* gene leads to decrease TNSALP, which in turn causes accumulation of extracellular TNSALP substrates like phosphoethanolamine, pyridoxal-5<sup>0</sup> -phosphate and pyrophosphate hence inhibiting hydroxyapatite formation in physicochemical fashion. At the same time, extracellular pyrophosphate induces osteopontin production and the latter inhibits formation of hydroxyapatite. The aforementioned are the main mechanisms that causes early tooth loss and abnormal bone mineralization in HPP patients [73, 74].
