Hypophosphatasia

Hypophosphatasia is a rare and sometimes fatal metabolic bone disease. Clinical symptoms are heterogeneous, ranging from the rapidly fatal perinatal variant, with profound skeletal hypomineralization and respiratory compromise, to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 200 genetic mutations identified to date in the gene encoding Tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an ectoenzyme tethered to the outer surface of osteoblast and chondrocyte cell membranes. TNSALP normally hydrolyzes several substances, including inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP) a major form of vitamin B6.

When TSNALP is low, inorganic pyrophosphate (PPi) accumulates extracellularly and potently inhibits formation of hydroxyapatite (mineralization) causing rickets in infants and children and osteomalacia (soft bones) in adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP for PLP to cross over the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the joint can cause pseudogout.

Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in milder forms. The prevalence of hypophosphatasia is not known. One study estimated the live birth incidence of severe forms to be 1:100,000.