Causes of Hypophosphatasia

About Gene Mutations and TNSALP

Gene mutations that completely eliminate TNSALP activity result in the more severe forms of HPP seen in infants. Milder mutations, those that reduce but do not eliminate the enzyme’s activity, are typically responsible for milder forms of the disease. Approximately 204 distinct mutations have been identified in the ALPL gene.

In HPP, substances that are normally processed by TNSALP, such as inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP; the active form of vitamin B6), accumulate in the body, producing clinical symptoms associated with the disease.

The buildup of PPi underlies the defective mineralization of bones and teeth by preventing the formation of hydroxyapatite bone crystals, which are are required for bone building. Low PLP in the brain can cause seizures.

Inheritance of HPP

The most severe forms of HPP, those that appear before birth and in early infancy, are inherited in an autosomal recessive pattern, meaning that affected individuals have inherited two copies of the altered gene. Males and females are affected equally.

Autosomal Recessive Inheritance In autosomal recessive inheritance, each parent carries one copy of the altered gene but do not have symptoms themselves. They are referred to as carriers. In most instances, each sibling of an individual with HPP has a 25% chance of having HPP, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.	Autosomal recessive inheritance
Autosomal Dominant Inheritance The milder forms of HPP (childhood, adult, odonto, benign in utero HPP) are inherited in either an autosomal recessive or dominant pattern depending on the effect that the ALPL mutation has on TNSALP activity. Autosomal dominant inheritance means that just one copy of the altered gene is sufficient to cause disease.	Autosomal dominant inheritance