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Hypophosphatasia Inherited Metabolic Disease in Newborns and Adults

Hypophosphatasis a rare genetic metabolic (chemical) disorder (disease) characterized by defective bone and teeth mineralization (During normal process of mineralization calcium and phoshorus deposited during normal development of bones and teeth. When mineralization does occur normally, bones will not become strong and rigid and teeth will no able to withstand chewing and grinding. 1), result from low levels of an enzyme called alkaline phosphatase (gene – ALPL 3). 2 “Enzymes are proteins that break down other chemicals in the body so the body can use them”. Mutations of the ALPL (gene) prohibit normal mineralization create health bones and teeth. 4 Subsequently several chemicals including hypophosphatasia and inorganic pyrophosphate, increased amounts found in blood and urine. Inorganic pyrophosphate link to defective calcification of bone, basis for the diagnosis of rickets (“Rickets is a softening of the bones in children potentially leading to fractures and deformity” 5) (infants and adults) and osteomalacia (“Osteomalacia is the general term for the softening of the bones due to defective bone mineralization” 6) (adults).

Characteristic symptoms of Hypophosphatasis include: Deformity of the limbs and chest depending upon the degree of skeletal disease. If Chest distortion severe not uncommon for pheumonia to develop. Teeth maybe lost prematurely and fractures occur frequently. 7

Hypophosphatasia categorized one of five stages: Perintal, infantile, childhood, adult and odontohypophosphatasia. Perintal stage inevitably fatal (“The most severely affected fail to form a skeleton in the womb and are stillborn” 4). Infantile stage symptoms appear six months after birth, and approximately fifty percent mortality (Description of short limbs, abnormal chest, and soft skull bones. During infancy stage poor feeding, failure to gain weight, breathing or respiratory problems and increase level of calcium in blood (hypercalcemia), linked to frequent kidney problems and vomiting. 1 Also, Increased susceptibility to fractures incur development of pneumonia. 10). 8 More common and milder stage of hypophosphatasia develop during childhood and adult (7) :Children prematurely lose their baby teeth, result of abnormal dental cementum (10): Loss of calcified substance covering the root of a tooth. 11 Also symptoms include: Height shortened, bowed legs or knock knees, enlarged wrist and ankle joints, and abnormally size skull. Adults develop osteomalacia, premature loss of adult teeth or secondary teeth, increase risk of joint pain & inflammation, frequent fractures in the foot and thigh and bones may cause chronic pain. The mildest form of hypophosphatasia is odontohypoposphatasia: Symptoms are abnormal teeth development and premature loss of teeth. 1

Most severe stage of hypophosphatasia occur (estimated) one in 100,000 newborns and milder cases occur more frequently. Hypophosphatasia diagnoses often among Caucasian (white) population. Residence of Menonite population in Manitoba, Canada reported most frequent number of hypophosphatasia cases (where mating among blood relatives is not unusual 10), about one in 2,500 newborns, most severe stage.1

In 1948, Canadian pediatrician Dr. J.C. Rathbun first described hypophosphatsia development, male infant born and died of the disease. In 1953, further clinical study of ALPL, redefined the disease include the loss of permanent teeth in adulthood. 10 Severe form of hypophosphatasia is an autosomal recessive disorder (1): “Means two copies of an abnormal gene (mother and father) must be present in order for the disease or trait to develop. 9 Twenty-five percent risk a newborn inherit hypophosphatasia both parents have the defective gene. 10 Milder stages of ALPL occur when altered gene is present from one parent. 1

Diagnosis of Hypophosphatasia confirmed by physical examination and variety of tests, including X-ray of bone structure (Evaluating stage of hypophosphatasia development), and biochemical studies (blood test to evaluate the level of alkaline phosphatase activity). During the late stage of pregnancy, trained specialist could identify through ultrasound severe bone abnormalities attributed to hypophosphatasia disease. Amniocentesis test (Examine amniotic fluid surrounding the fetus in the womb) technically not reliable test for ALPL. 10

There is no current available cure for hypophosphatasia disorder. Treatment options include trying to prevent the disease, correct symptoms and complications. “Why the disease can present late in life (or even return in adults who seem to recover for childhood hypophosphatasia) is unexplained”. Dr. Michael Whyte stated on the website Canadian Hypophosphatasia Society: “Since the gene defects are currently being uncovered for hypophosphatasis there is promise for a precise genetic nosology in the near future”. Further information regarding Hypophosphatasia E-mail: hypophosphatasia@yahoo.ca (Canadian Hypophosphatasia – R.R. #2 – Clayton, Ontario KOA 1P0 – Telephone: (613) 256 – 8532)). 12

Enobia Pharma Incorporated (Montreal – Canada) reported in September 2007, raised $40.1 Million (Canadian dollars) financing fund novel hypophosphatasia drug development program (Enzyme replacement Therapy for hypophosphatasia. Laureate Pharma, Incorporated entered a contract manufacturing agreement to produce Enobia’s Pharma’s fusion protein for the treatment of hypophosphatasia.14) through Phase two clinical trials. 13


1.) What is hypophosphatasia? – http://ghr.nlm.nih.gov/condition=hypophosphatasia

2,) Hypophosphatasia – http://www.ojrd.com/content/2/1/40/abstract

3.) ALPL – http://ghr.nlm.nih.gov/gene=alpl

4.) OI Issues: Hypophosphatasia – http://www.oif.org/site/PageServer?pagename=Hypophosphatasia

5.) Rickets – http://en.wikipedia.org/wiki/Rickets

6.) Osteomalacia – http://en.wikipedia.org/wiki/Osteomalacia

7.) HYPOPHOSPHATASIA – http://www.magicfoundation.org/www/docs/175.140/hypophosphatasia_general_info.html

8.) Hypophosphatasia – http://en.wikipedia.org/wiki/Hypophosphatasia

9.) Autosmal recessive – http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm

10.) Hypophosphatasia – http://www.healthline.com/galecontent/hypophosphatasia#hypophosphatasia

11.) Cementum – http://en.wikipedia.org/wiki/Cementum

12.) Canadian Hypophosphatasia Society – http://hypophosphatasia.homestead.com/

13.) Health News Press Release – http://www.medindia.net/health-press-release/Enobia-Pharma-Raises-401-Million-Series-B-Financing-3528-1.htm

14.) Laureate Pharma Announces Agreement with Enobia Pharma, Inc. – http://www.pharmafocusasia.com/press_releases/laureatepharma_enobiapharma.htm