Hypophosphatasia (HPP) is a rare genetic disorder characterized by the abnormal development of bones and teeth due to a deficiency of an enzyme called alkaline phosphatase (ALP). Alkaline phosphatase is essential for the normal mineralization of bones and teeth. The severity of symptoms can vary widely, and HPP can affect individuals of all ages. Exact data on its prevalence are not available, although, in Europe, there is an estimated one severe case per 300.000 births.
Hypophosphatasia genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Hypophosphatasia include:
- Bone Abnormalities: HPP can lead to various bone abnormalities, including soft or weakened bones. These can result in skeletal deformities, fractures, and poor growth. In severe cases, infants with HPP may exhibit signs of rickets characterized by soft and deformed bones.
- Dental Issues: Individuals with HPP may experience dental problems, including premature loss of teeth, delayed tooth eruption, and poorly mineralized teeth.
- Muscle Weakness: Some individuals with HPP may experience muscle weakness, contributing to mobility issues.
- Respiratory Complications: Severe cases of HPP, especially in infants, may be associated with respiratory complications due to chest deformities or weakened ribcages.
- Joint Pain: Adults with HPP may experience joint pain and stiffness.
- Age of Onset: The age of onset and the severity of symptoms can vary. There are different forms of HPP, including perinatal (severe), infantile (severe), childhood (moderate), and adult (mild) forms.
Hypophosphatasia is caused by mutations in the ALPL gene, which provides instructions for making alkaline phosphatase. Depending on the specific mutation and its effect on enzyme activity, the severity of HPP can vary.
There is no cure for Hypophosphatasia, and management focuses on supportive care and addressing symptoms. Treatment may involve multidisciplinary care, including orthopedic management of fractures and deformities, dental care, and physical therapy. In some cases, enzyme replacement therapy may be considered to help restore alkaline phosphatase activity.
Genetic counseling is essential for individuals with Hypophosphatasia and their families to understand the inheritance pattern and assess the risk of having affected children. Early diagnosis and intervention are crucial for optimizing outcomes, especially in severe forms of the condition.
More Information
The clinical heterogeneity of hypophosphatasia is due to the tremendous allelic heterogeneity in the ALPL gene. Depending on the effect of the ALPL allele on phosphatase activity and enzyme levels, symptoms will be more or less severe, and the time at which they appear will vary. We find alleles that cause the enzyme to lose function and alleles that reduce its activity. The inheritance pattern is also variable; it can be autosomal recessive or autosomal dominant.
The most common pathogenic variant in the Caucasian population is c.571G>A (p.Glu191Lys). This variant has been found both in homozygosis (two copies of this variant) and compound heterozygosis (in combination with another pathogenic variant in ALPL). This variant has been observed in approximately 31% of patients with mild hypophosphatasia.
Hypophosphatasia genetic testing analyzes the 10 most frequent pathogenic mutations of the ALPL gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
