Hypophosphatasia

Abstract

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

Dental manifestation and management of hypophosphatasia

“…HPP is a rare inherited disease caused by inactivating mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP) [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . More than 400 ALPL gene mutations have been reported in The ALPL Gene Variant Database ( https://alplmutationdatabase.jku.at ).…”

“…More than 400 ALPL gene mutations have been reported in The ALPL Gene Variant Database ( https://alplmutationdatabase.jku.at ). Such mutations lead to a reduction of alkaline phosphatase (ALP) enzyme activity, which impairs bone mineralization [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . TNSALP, which is abundant in bone, liver, kidney, and developing teeth, produces inorganic phosphate by degrading inorganic pyrophosphate, a mineralization inhibitor, and the phosphate and calcium form hydroxyapatite, leading to the progression of mineralization [3] , [4] , [5] , [7] , [8] , [10] , [11] , [13] , [17] .…”

“…Then, gene testing should be performed for a definitive diagnosis. The phenotype of HPP is classified into six types based on the age at onset and severity of clinical features: perinatal, prenatal benign, infantile, childhood, adult, and odonto types ( Table 1 ) [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [41] . In general, an earlier onset is associated with more severe systemic symptoms.…”

“…Early exfoliation of primary teeth was soon after reported as a characteristic clinical finding of this disorder [2] . HPP is a rare genetic disease characterized by defective mineralization of bones and teeth [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . Patients with HPP show a wide range of manifestations, ranging from stillbirths and severe skeletal hypomineralization with dental symptoms in severe cases to early exfoliation of primary teeth without bone symptoms in mildest cases.…”

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism

“…The cells genetically determined to express TNSALP are found mainly in bone (hypertrophic chondrocytes and osteoblasts), liver and kidney. TNSALP is also found in teeth (odontoblasts), central nervous system, fibroblasts, and other cell types [41]. It is anchored to the plasma membrane, in a way that follows membrane's fluidity [40].…”