Hypophosphatasia and the Extracellular Metabolism of Inorganic Pyrophosphate: Clinical and Laboratory Aspects

Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate. Substrate accumulation in carriers of hypophosphatasia corrects during pregnancy.

“…Subject (26). Failure of TNSALP to hydrolyze PPi, an inhibitor of biomineralization, offers a plausible explanation for the associated skeletal disease (8,10). Hypophosphatasia, however, raises intriguing questions about the physiological role of TNSALP elsewhere in the body, because organs other than the skeleton that are also TNSALP-rich (e.g., liver, kidney, adrenal glands) do not significantly malfunction (2,8).…”

“…In hypophosphatasia, three phosphocompounds (phosphoethanolamine [PEA], inorganic pyrophosphate [PPi], and pyridoxal 5'-phosphate [PLP]) accumulate endogenously and appear, therefore, to be natural substrates for TNSALP (8,9). PPi is an inhibitor of calcification and, accordingly, increased levels could account for the skeletal disease (8,10). Identification of 12 missense mutations to date within the TNSALP gene (11)(12)(13) and Henthom, P. S., M. Raducha, V. Fimiani, K. N. Fedde, and M. P. Whyte, manuscript in preparation) associated with hypophosphatasia and a transfection study, which showed that-one of these nucleotide changes destroyed the enzyme's catalytic action ( 11) (8).…”

Hypophosphatasia: an overview of the disease and its treatment

“…There are at least four ALP isoenzymes, encoded by four separate genes: three tissue-specific ALPs (Bintestinal,^Bplacental,^and Bgerm cell^) and the ubiquitous TNSALP, especially abundant in the liver, bone, and kidney [2,6,8,9], but also expressed in the brain, particularly in the cortical sensory areas [10]. TNSALP accounts for approximately 95 % of the total serum ALP activity, and PPi and PLP are currently considered its main physiological substrates.…”

“…The main clinical signs are related to defective bone and teeth mineralization (rickets, osteomalacia, fractures, teeth loss), but other systemic manifestations can be present in the severe forms (seizures, respiratory and kidney problems, chronic pain, weakness, etc.). The main diagnostic laboratory abnormalities are low serum ALP and TNSALP activity (hypophosphatasemia) and increased levels of ALP substrates (inorganic pyrophosphate (PPi), pyridoxal-5'-phosphate (PLP, the active metabolite of vitamin B6), and phosphoethanolamine (PEA)) [2][3][4][5][6][7].…”

Surgical management for tibial shaft fractures using flexible nailing in adult hypophosphatasia

“…Decreased production of ALP leads to the endogenous accumulation and toxicity of PPi. The PPi accumulation causes defective skeletal mineralization manifesting as osteomalacia and development of articular chondrocalcinosis in affected adults [2,3].…”