Biomarker for Hypophosphatasia Disease (BioHypophos)
Biomarker for Hypophosphatasia Disease (BioHypophos)
Development of a new MS-based biomarker for the early and sensitive diagnosis of
 Hypophosphatasia disease from plasma
Hypophosphatasia (HPP) is a rare genetic disorder characterized the abnormal development of
 bones and teeth. These abnormalities occur due to defective mineralization, the process by
 which bones and teeth take up minerals such as calcium and phosphorus. These minerals are
 required for proper hardness and strength. Defective mineralization results in bones that are
 soft and prone to fracture and deformity. Defective mineralization of teeth can lead to
 premature tooth loss. The specific symptoms can vary greatly from one person to another,
 sometimes even among members of the same family. There are five major clinical forms of HPP
 that range from an extremely severe form that can cause stillbirth to a form associated with
 only premature loss of baby (deciduous) teeth, but no bone abnormalities. Hypophosphatasia is
 caused by mutations in the tissue non-specific alkaline phosphatase (ALPL) gene. This gene is
 also known as the TNSALP gene. Such mutations lead to low levels of the tissue nonspecific
 alkaline phosphatase enzyme. Depending on the specific form, hypophosphatasia can be
 inherited in an autosomal recessive or autosomal dominant manner.

 Hypophosphatasia is an extremely variable disorder. Five major clinical forms have been
 identified based primarily upon the age of onset of symptoms and diagnosis. These are known
 as perinatal, infantile, childhood, adult, and odontohypophosphatasia. Generally, the
 severity of these different forms of hypophosphatasia correlates to the residual alkaline
 phosphate activity in the body, with less enzyme activity causing more severe dis- ease.
 Because hypophosphatasia is a highly variable disorder, it is important to note that affected
 individuals may not have all of the symptoms and that every individual case is unique. Some
 children will develop severe complications early in life; others have mild disease that may
 improve during young adult life.

 Perinatal hypophosphatasia is associated with profound inactivity of alkaline phosphatase and
 markedly impaired mineralization. Consequently, the skeleton fails to form properly in the
 womb. Specific skeletal malformations may vary, but short, bowed arms and legs and
 underdeveloped ribs often occur. Some pregnancies end in stillbirth. In other cases, affected
 newborns survive for several days, but pass away from respiratory failure due to deformities
 of the chest and underdeveloped lungs.

 Infantile hypophosphatasia may have no noticeable abnormalities at birth, but symptoms may
 become apparent at any time within the first six months. The initial symptom may be the
 failure to gain weight and grow at the expected rate for age and gender referred to as
 "failure to thrive." Some affected babies later exhibit early fusion of the bones of the
 skull (craniosynostosis), which can result in the head appearing disproportionately wide
 (brachycephaly). Craniosynostosis may be associated with increased pressure of the
 cerebrospinal fluid, a condition known as "intracranial hypertension." This complication can
 cause headaches, swelling of the optic disk (papilledema), and bulging of the eyes
 (proptosis). Affected infants have softened, weakened bones that lead to the skeletal
 malformations of rickets. Rickets is a bone disease that occurs during growth with softening
 of bone and characteristic bowing deformities of the legs from growth plate abnormalities.
 Enlarged wrist and ankle joints may occur. Affected infants may also have deformities in the
 chest and ribs and rib fractures, predisposing them to pneumonia. Varying degrees of
 pulmonary insufficiency and breathing difficulties may develop, potentially progressing to
 life-threatening respiratory failure. Episodes of fever and bone pain, or tender bones may
 occur. Some infants exhibit diminished muscle tone (hypotonia) so that a baby appears
 "floppy" as well as elevated levels of calcium in the blood (hypercalcemia). Hypercalcemia
 can cause vomiting, constipation, weakness, and poor feeding. In rare cases, vitamin
 B6-dependent seizures may occur. Increased excretion of calcium may lead to kidney (renal)
 damage. Sometimes there is spontaneous improvement in mineralization during early childhood,
 with the exception of craniosynostosis. Short stature and skeletal deformities may persist
 lifelong.

 Childhood hypophosphatasia is highly variable, but is less severe than the infantile form.
 Affected children may sometimes have craniosynostosis and exhibit signs of intra- cranial
 hypertension. Skeletal malformations that resemble rickets may become apparent at 2 to 3
 years of age. Bone and joint pain and fractures may occur. Baby teeth may fall out earlier
 than normal. Some children are weak and experience delays in walking, and when they do learn
 to walk may have a distinct, waddling gait. Spontaneous remission of bone symptoms has been
 reported in young adult life, but such symptoms can recur during middle age or late
 adulthood.

 Adult hypophosphatasia is characterized by a wide variety of symptoms. Affected individuals
 have osteomalacia, a softening of the bones in adults. Some individuals have a history of
 rickets during childhood, or have experienced premature loss of their baby teeth. Individuals
 with adult hypophosphatasia can experience fractures, especially stress fractures in the feet
 or pseudofractures of the thigh. Repeated fractures can result in chronic pain and debility.
 Fractures of the spine seem less common, but also occur. Bone pain is a common complication.
 Some affected adults develop joint inflammation and pain near or around certain joints due to
 the accumulation of calcium crystals (calcific periarthritis) or a condition called
 chondrocalcinosis, characterized by the accumulation of calcium crystals within the cartilage
 of joints, sometimes damaging the joint. Others have sudden, severe pain in the joint (pseudo
 gout). Affected adults may experience loss of adult teeth.

 Odontohypophosphatasia is characterized by the premature loss of teeth in childhood, or loss
 of teeth in adulthood. It is an isolated finding that does not occur along with the
 characteristic bone symptoms of other forms of hypophosphatasia.

 For hypophosphatasia, mutations in the ALPL gene can be inherited in an autosomal recessive
 or autosomal dominant manner. The perinatal and infantile forms of HPP are inherited in an
 autosomal recessive manner. The childhood form can be autosomal recessive or autosomal
 dominant. The adult form and odontohypophosphatasia typically are autosomal dominant
 disorders, but in rare cases can be inherited as an autosomal recessive trait.

 A diagnosis of hypophosphatasia is based upon identification of characteristic signs and
 symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of
 laboratory tests including x-ray studies. Proper diagnosis of hypophosphatasia is easy for
 physicians who are familiar or experienced with this disorder.

 New methods, like mass-spectrometry give a good chance to characterize specific metabolic
 alterations in the blood (plasma) of affected patients that allow diagnosing in the future
 the disease earlier, with a higher sensitivity and specificity.

 Therefore it is the goal of the study to identify and validate a new biochemical marker from
 the plasma of the affected patients helping to benefit other patients by an early diagnose
 and thereby with an earlier treatment.
IInclusion Criteria:

 -  Informed consent will be obtained from the patient or the parents before any study
 related procedures.

 -  Patients of both genders older than 2 month

 -  The patient has a diagnosis of Hypophosphatasia disease or a high-grade suspicion for
 Hypophosphatasia disease

 -  High-grade suspicion present, if one or more inclusion criteria are valid:

 -  Positive family anamnesis for Hypophosphatasia disease

 -  Frequent fractures

 -  Bone pain

 -  Tooth loss

 -  Osteopenia/Osteoporosis

 -  Craniosynostosis

 Exclusion Criteria:

 -  No Informed consent from the patient or the parents before any study related
 procedures.

 -  Patients of both gender younger than 2 month

 -  No diagnosis of Hypophosphatasia disease or no valid criteria for profound suspicion
 of Hypophosphatasia disease