Increased Serum Pyridoxal-5′-Phosphate in Pseudohypophosphatasia

De, Cole; Ra, Stinson; Sp, Coburn; Lm, Ryan; Whyte, Mkb

doi:10.1056/nejm198604103141515

Cited by 20 publications

(1 citation statement)

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“…The nomenclature of pseudo-HPP has sometimes been used to describe apparent cases of HPP wherein clinical presentation overlaps with manifestations of HPP, but where ALP levels are within the normal range (23,24,26,27,(48)(49)(50). Many studies also report cases where clinical signs of HPP are present and ALP is low or normal, and no genetic variant in ALPL can be identified (51)(52)(53)(54)(55).…”

Section: Predicting Dental Manifestations In Patients With Pseudo-hpp...mentioning

confidence: 99%

Perspective on Dentoalveolar Manifestations Resulting From PHOSPHO1 Loss-of-Function: A Form of Pseudohypophosphatasia?

et al. 2022

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Mineralization of the skeleton occurs by several physicochemical and biochemical processes and mechanisms that facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Two key phosphatases, phosphatase, orphan 1 (PHOSPHO1) and tissue-non-specific alkaline phosphatase (TNAP), play complementary roles in the mineralization process. The actions of PHOSPHO1 on phosphocholine and phosphoethanolamine in matrix vesicles (MVs) produce inorganic phosphate (Pi) for the initiation of HA mineral formation within MVs. TNAP hydrolyzes adenosine triphosphate (ATP) and the mineralization inhibitor, inorganic pyrophosphate (PPi), to generate Pi that is incorporated into MVs. Genetic mutations in the ALPL gene-encoding TNAP lead to hypophosphatasia (HPP), characterized by low circulating TNAP levels (ALP), rickets in children and/or osteomalacia in adults, and a spectrum of dentoalveolar defects, the most prevalent being lack of acellular cementum leading to premature tooth loss. Given that the skeletal manifestations of genetic ablation of the Phospho1 gene in mice resemble many of the manifestations of HPP, we propose that Phospho1 gene mutations may underlie some cases of “pseudo-HPP” where ALP may be normal to subnormal, but ALPL mutation(s) have not been identified. The goal of this perspective article is to compare and contrast the loss-of-function effects of TNAP and PHOSPHO1 on the dentoalveolar complex to predict the likely dental phenotype in humans that may result from PHOSPHO1 mutations. Potential cases of pseudo-HPP associated with PHOSPHO1 mutations may resist diagnosis, and the dental manifestations could be a key criterion for consideration.

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