The ALPL gene contains the blueprint for an enzyme fundamental to building a healthy skeletal system. This gene’s primary role is to ensure the development of strong bones and teeth, a process that begins before birth and continues throughout life. Its proper function is a basic requirement for a durable and resilient skeleton.
The Function of the ALPL Gene
The ALPL gene provides instructions for creating the enzyme tissue-nonspecific alkaline phosphatase (TNSALP). While active in the liver and kidneys, its primary actions relate to the skeleton. As a phosphatase, TNSALP removes phosphate groups from various molecules, a chemical activity that supports bone development and vitamin processing.
A primary responsibility of TNSALP is to enable mineralization, the process of depositing calcium and phosphorus into bones and teeth. The enzyme achieves this by breaking down inorganic pyrophosphate (PPi), a compound that naturally acts as an inhibitor, preventing minerals from hardening into bone tissue. By clearing away PPi, TNSALP allows calcium and phosphate to integrate into the structural matrix, making bones and teeth hard and robust.
The enzyme also participates in vitamin B6 metabolism. It converts pyridoxal 5′-phosphate (PLP) into a form usable by the body’s cells, particularly nerve cells. This function demonstrates the enzyme’s broader involvement in maintaining the body’s chemical balance.
ALPL Gene Mutations and Hypophosphatasia
Mutations in the ALPL gene can alter the instructions for building the TNSALP enzyme, leading to a defective or insufficient supply. When TNSALP activity is reduced, the body’s ability to mineralize bones and teeth is impaired. This metabolic condition is known as hypophosphatasia (HPP).
The severity of HPP is directly linked to the level of enzyme dysfunction. Mutations that almost completely eliminate TNSALP activity cause the most severe forms, while those that only partially reduce its function lead to milder conditions. Over 300 different ALPL gene mutations have been identified in individuals with HPP, most of which involve a change to a single amino acid in the enzyme’s structure.
Hypophosphatasia is an inherited disorder. Severe forms that appear at birth or in infancy are inherited in an autosomal recessive pattern, meaning an individual must receive two copies of the mutated gene—one from each parent. Milder forms can be passed down in either an autosomal recessive or an autosomal dominant pattern, where inheriting just one copy is enough to cause the condition.
Symptoms and Forms of Hypophosphatasia
The signs and symptoms of hypophosphatasia vary widely, reflecting the spectrum of enzyme deficiency. The disorder is classified into several forms based on the age of onset and severity. These forms range from a lethal condition detected before birth to a version that only affects the teeth in adulthood.
The most severe types are perinatal and infantile HPP. Infants with perinatal HPP are born with profound skeletal defects, including a soft skull, underdeveloped ribs that compromise breathing, and shortened limbs. Infantile HPP presents within the first six months of life with symptoms like poor feeding, respiratory complications, and high blood calcium levels because the mineral cannot enter the bones.
Childhood HPP becomes apparent after six months of age and is characterized by several signs:
- Premature loss of baby teeth before age five, often with the roots intact
- Short stature
- A waddling gait due to bone malformations
- Delayed walking
- Pain in the bones and joints
Adult hypophosphatasia is typically milder and may not be diagnosed until middle age. Individuals experience recurrent stress fractures, particularly in the feet, chronic joint pain, and the early loss of permanent teeth. A distinct form, odontohypophosphatasia, is the mildest version where symptoms are exclusively dental. People with this form have premature tooth loss or severe cavities but no other skeletal abnormalities.
Diagnosing and Treating Hypophosphatasia
Diagnosing hypophosphatasia begins with a blood test to measure alkaline phosphatase (ALP) activity, as persistently low levels are a primary indicator. This finding prompts further investigation, including blood tests for elevated TNSALP substrates like pyridoxal 5′-phosphate (PLP). X-rays are also used to identify bone abnormalities, such as rickets in children or bone softening in adults. A definitive diagnosis is typically confirmed through genetic testing to identify causative mutations in the ALPL gene.
The primary treatment for hypophosphatasia is enzyme replacement therapy (ERT) with a medication called asfotase alfa. This therapy supplies the body with a manufactured version of the TNSALP enzyme, directly addressing the disorder’s root cause. ERT improves bone mineralization, reduces skeletal deformities, and enhances physical function, particularly in infants and children with severe forms of HPP.
Due to the condition’s wide-ranging effects, management involves a multidisciplinary approach. This includes specialized dental care for premature tooth loss and other oral health issues. Physical and occupational therapy can help address muscle weakness and improve mobility. For adults, pain management and orthopedic care for fractures are also components of a comprehensive treatment plan.