What causes hypophosphatasia?

Hypophosphatasia (HPP) is a genetic condition caused by mutations in the ALPL gene. This gene gives the body instructions to make an enzyme called alkaline phosphatase, which is needed for mineralization of the bones and teeth. Mutations in this gene lead to an abnormal version of the enzyme, thus affecting the mineralization process. A shortage of the enzyme also causes other substances to build up in the body. These abnormalities lead to the features of HPP.

ALPL mutations that almost completely eliminate alkaline phosphatase activity generally cause the more severe forms of HPP, while mutations that reduce activity to a lesser extent often cause the milder forms of HPP.

Last updated on 05-01-20

Can hypophosphatasia cause the early loss of adult (or secondary) teeth?

It may cause early loss of adult teeth. Hypophosphatasia is a disorder that disrupts a process called mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of teeth that can withstand chewing and grinding. Hypophosphatasia is characterized by the early loss of baby (or deciduous) teeth. While not as common, children and adults with hypophosphatasia may also have additional issues with their adult or permanent teeth. Problems may include cavity prone teeth and early loss of teeth. Children and adults with hypophosphatasia benefit from consultations with an appropriate specialist for care of dentition (tooth) complications.

Last updated on 05-01-20

How is hypophosphatasia inherited?

Perinatal (onset before birth) and infantile hypophosphatasia (HPP) are inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene ( ALPL ) in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

  • 25% (1 in 4) chance to be affected
  • 50% (1 in 2) chance to be an unaffected carrier like each parent
  • 25% chance to be unaffected and not be a carrier.

The milder forms, especially adult HPP and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner - depending on the effect the ALPL mutation has on enzyme activity. In autosomal dominant inheritance, having a mutation in only one copy of the ALPL gene in each cell is enough to cause features of the condition. When a person with a mutation that causes an autosomal dominant HPP has children, each child has a 50% (1 in 2) chance to inherit that mutation.

Most people with autosomal dominant HPP have inherited the mutation from a parent who may or may not have symptoms. Not all people with a mutation that causes autosomal dominant HPP develop symptoms of the condition. While it is possible to have autosomal dominant HPP due to a new mutation that was not inherited (a de novo mutation), this has never been reported in HPP.

Last updated on 05-01-20

How can I learn more about hypophosphatasia and/or osteoporosis?

You can find relevant journal articles on treatment of hypophosphatasia through a service called PubMed, a searchable database of medical literature. Information on finding an article and its title, authors, and publishing details is listed here. Some articles are available as a complete document, while information on other studies is available as a summary abstract. To obtain the full article, contact a medical/university library (or your local library for interlibrary loan), or order it online using the following link. Using "hypophosphatasia AND treatment" as your search term should locate articles. To narrow your search, click on the “Limits” tab under the search box and specify your criteria for locating more relevant articles. Click here to view a search.

The National Library of Medicine (NLM) Web site has a page for locating libraries in your area that can provide direct access to journals (print or online) or where you can get articles through interlibrary loan and Loansome Doc (an NLM document-ordering service). You can access this page at the following link. You can also contact the NLM toll-free at 888-346-3656 to locate libraries in your area.

To learn more about traditional therapies for osteoporosis you can visit the following link from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): which sponsors the NIH Osteoporosis and Related Bone Diseases ~ National Resource Center. http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/Medicine/default.asp

The Osteoporosis and Related Bone Diseases ~ National Resource Center, a part of the U.S. Department of Health and Human Services' National Institutes of Health (NIH), provides patients, health professionals, and the public with an important link to resources and information on metabolic bone diseases, including osteoporosis and hypophosphatasia.

NIH Osteoporosis and Related Bone Diseases ~ National Resource Center
National Institute of Health
2 AMS Circle
Bethesda, MD 20892-3676
Toll-free: 800-624-2663
Phone: 202-223-0344
TTY: 202-466-4315
Fax: 202-293-2356
E-mail: NIAMSBoneInfo@mail.nih.gov
Web site: http://www.osteo.org

More information on osteoporosis can be found at the following link from MedlinePlus, the National Library of Medicine Web site designed to help you research your health questions.

Last updated on 05-01-20

Can the type or severity of hypophosphatasia vary among affected family members?

Yes. In general, the perinatal and infantile forms of hypophosphatasia (HPP) are inherited in an autosomal recessive manner. The childhood form can be autosomal recessive or autosomal dominant. The adult form and odontohypophosphatasia usually are autosomal dominant, but can also be inherited in an autosomal recessive manner. However, significant variability among family members with HPP has been reported. For example, one author reported a 15-month-old girl with symptoms suggestive of childhood HPP, who had a father with symptoms suggestive of odontohypophosphatasia, and a paternal aunt who died at 7 days old of apparent neonatal HPP.

Autosomal dominant HPP has shown reduced penetrance. This means that not all people with a mutation that can cause autosomal dominant HPP will develop symptoms of HPP.

In families with recessive HPP, the severity of symptoms mostly has been reported to be comparable, or to differ only moderately, from one child to another. However, families with AR inheritance and larger variations among family members have been reported.

It is possible that other genetic, epigenetic or environmental factors may explain the clinical variability among families and between families with HPP. People with questions about potential risks to children or other family members are strongly encouraged to speak with a genetics professional to discuss family history and what may be known about the specific mutation(s) in the family. The genetics of HPP is complex, so predicting how a person will be affected can be difficult.

Last updated on 05-01-20

How might hypophosphatasia be treated?

Until recently, management of hypophosphatasia (HPP) has mostly been aimed at addressing symptoms of the condition. For example:

  • Hydration, restriction of dietary calcium, vitamin D, and sometimes thiazide diuretics for hypercalcemia
  • Ventilatory support for severely affected infants, some of which need a tracheostomy, which can lead to problems with speech and language development and tolerance of oral feeds
  • Physiotherapy, occupational therapy and chronic pain management for pain and motor difficulty
  • Surgery for fractures that fail to heal

More recently, research has shown positive effects of human recombinant enzyme replacement therapy (ERT), called asfotase alfa, on people who began having symptoms before 6 months of age. There reportedly have been significant improvements in the X-ray appearances of bone tissue, along with improvements in growth, respiratory function, motor development and calcium homeostasis after 6–12 months of treatment. The children in the original study have now received more than three years of treatment, without apparent major side effects, and with continuing improvement in affected systems. Asfotase alfa appears to be a valuable emerging therapy for the treatment of bone manifestations in people with pediatric-onset HPP. In October of 2015 the FDA approved asfotase alfa, sold as Strensiq.

Bone marrow and stem cell transplantation in infancy and childhood have improved the severity of the disease, but have not provided long term improvement.

Last updated on 05-01-20

Is hypophosphatasia treated differently if you have osteoporosis?

Having hypophosphatasia as a confirmed diagnosis may help patients avoid therapies for osteoporosis or osteomalacia that could be either ineffective or possibly harmful to them. To learn more about a potential treatment which has shown success for individuals with hypophosphatasia and reduced bone density, click here.

Last updated on 05-01-20

Name: The MAGIC Foundation 4200 Cantera Dr. #106
Warrenville, IL, 60555, United States
Phone: 630-836-8200 Toll Free: 800-362-4423 Fax : 630-836-8181 Email: contactus@magicfoundation.org Url: https://www.magicfoundation.org/
Name: Soft Bones Inc. 121 Hawkins Place #267
Boonton, NJ, 07005,
Phone: +1 (201) 317-1818 Toll Free: (866) 827-9937 Email: info@softbones.org Url: http://www.softbones.org
Name: Soft Bones Canada PO Box 23520 Prairie Mall Grande Prairie, AB
T8V 7G7
Phone: 1-844-255-8477 Email: contactus@softbonescanada.ca Url: http://softbonescanada.ca/
Name: The Avalon Foundation Ottawa Hills, OH, 43606, Phone: 1(419)841-2059 Email: team@kidscaringforkids.org Url: https://kidscaringforkids.org/ The Avalon Foundation provides emotional and educational support to families receiving care for hypophosphatasia.

Note, these links are external searches against the National Laboratory of Medicine's drug database. You may need to adjust the search if there are no results found.

Drug Name Generic Name
Strensiq Asfotase alfa

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