Hypophosphatasia: A Unique Disorder of Bone Mineralization

Abstract

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5′-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

Hypophosphatasia

“…HPP is most commonly caused by heterozygous or compound heterozygous mostly missense (about 74%) mutations at the ALPL gene [ 65 ]. The mode of inheritance refers to an autosomal dominant or recessive manner, with the most severe phenotypes being transmitted with the autosomal recessive trait, whereas the milder forms are transmitted with either the dominant or recessive trait [ 19 ].…”

“…In general, the severe phenotypes of HPP are usually caused by homozygous or compound heterozygous mutations [ 66 ] and manifest as a recessive disease. In cases of mild or moderate forms with autosomal dominant inheritance the underlying mechanisms involve either a dominant negative effect of a single heterozygous mutation, intronic mutations, or mutations in the regulatory sequence [ 65 , 67 ]. In European patients it has been shown that 13.4% of the HPP-affected chromosome alleles have a dominant negative effect [ 3 ].…”

“…Other authors have used bone marrow transplantation in infants or growth hormone therapy in children with HPP with reportedly satisfactory results [ 65 ]. However, until more data are available, their use should be carefully considered on an individual basis.…”

Tissue-Nonspecific Alkaline Phosphatase, a Possible Mediator of Cell Maturation: Towards a New Paradigm

“…Clinically, a mutation in the gene coding for TNSALP has been closely associated with a severe skeletal deformity disease termed “hypophosphatasia (HPP),” which is characterized by several pathological abnormalities, including rickets, osteomalacia, epilepsy-like seizures associated with vitamin B6 deficiency, muscle weakness, and respiratory disturbance [ 14 , 15 ].…”

Young woman with hypophosphatasia: A case report

“…4 Generally, teeth and skeletal mineralization disorders are the most common symptoms of HPP patients and less common clinical presentations include musculoskeletal abnormalities, multiple fractures, fatigue, and migraine. 5 HPP is classified into the following groups based on severe to mild symptoms since before birth to adulthood: perinatal lethal HPP, prenatal benign HPP, infantile HPP, childhood HPP, adult HPP, and ordontohypophosphatasia. 6 Lethal perinatal is the most severe subtype of HPP characterized by deformed and shorted arms and legs, deformity of the chest during delivery because of skeletal mineralization blocking due to low alkaline phosphatase level.…”