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The information in this book is accurate as of July 2012
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Introduction to Hypophosphatasia or HPP
Hypophosphatasia is an inherited metabolic bone disease whose clinical symptoms are highly variable, ranging from a profound lack of mineralization of bone with death occurring prior to delivery up to early loss of teeth in adulthood as the only sign. Still other affected individuals may have the characteristic biochemical abnormality but no outward clinical signs of the disorder while others have multiple fractures with little or no trauma throughout their lives. Hypophosphatasia is due to consistently low levels of an important enzyme in the body, alkaline phosphatase.
Alkaline phosphatase (ALP) is present in nearly all plants and animals. There are at least four different genes known to encode different forms of ALP in humans. Hypophosphatasia is due to a deficiency of the form of ALP that is particularly abundant in the liver, bones, and kidneys. This is often referred to as the tissue non-specific form of ALP, or TNSALP. This form of alkaline phosphatase is important in the mineralization, or hardening, of the bones of the skeleton as well as the teeth. Thus, abnormalities in either the production or function of this enzyme have a direct effect on the formation and strength of these parts of the body. In general, the more severe forms of hypophosphatasia are associated with lower serum TNSALP activity for that individual's age.
The term hypophosphatasia was first coined in 1948 by a Canadian pediatrician, Dr. J.C. Rathbun. He used it to describe a male infant who developed and then died from severe rickets, weight loss, and seizures. Levels of the enzyme alkaline phosphatase were below normal in samples of blood and bone from this child. Rickets is a condition resulting from a deficiency of vitamin D in children, causing inadequate strengthening of developing cartilage and newly formed bone. While this disorder shares many clinical characteristics with hypophosphatasia, the two conditions are separate and distinct. A major difference is that rickets are typically not lethal.
In 1953, the clinical features of hypophosphatasia were expanded to include not only abnormal mineralization of bone but also premature loss of the permanent teeth in adulthood. Since then, hypophosphatasia or HPP for short has been further divided into six different clinical forms. Each form is defined by the severity of the disease and the age at which symptoms first appear
The five most common clinical subtypes are 1 perinatal, 2 infantile, 3 childhood, 4 adult onset and 5 odontohypophosphatasia. The first four forms of which depend on the age of onset. The fifth, odontohypophosphatasia, is characterized by premature loss of primary teeth with no associated skeletal abnormalities. Clinical expression of the disease is highly variable ranging from still-birth without evidence of bone mineralization to pathological fractures only detected in adulthood. The severe perinatal and infantile forms of the disease are transmitted as autosomal recessive traits, whereas the clinically milder forms, including childhood onset, adult onset and odontohypophosphatasia may apparently exhibit both autosomal dominant and recessive transmission.
Recent studies have suggested the existence of a sixth clinical form, termed ‘benign prenatal’ type These reports have described several cases with severe bowing of the long bones in utero in whom there was subsequently a more benign clinical course. In the prenatal benign form, these symptoms are spontaneously improved. This contrasts dramatically with the lethal course often seen with perinatal onset disease. In contrast to the normal autosomal recessive pattern of inheritance associated with early onset disease, there may be autosomal dominant inheritance
Nearly all forms of hypophosphatasia are inherited as an autosomal recessive condition. In order to be affected, an individual must inherit two copies of a hypophosphatasia gene, or one copy from each carrier parent. Carriers have one normal gene and one hypophosphatasia gene and are typically asymptomatic. In some families, hypophosphatasia carriers have been found to have low to low-normal levels of TNSALP in their blood. Research finds more and more that carriers do have symptoms. And: it is quite easy to tell if ALP levels are normal or too low. Everything below 30 is actually too low. Except is in seniors beyond 80 yrs old, because old individuals produce less ALP anyway.
Hypophosphatasia is characterized by defective bone mineralization and deficiency of the tissue non-specific isoform of the enzyme alkaline phosphatase (encoded by the TNAP gene). There are four isoforms of alkaline phosphatase in humans, each encoded by separate genes (tissue non-specific, intestinal, placental and placental-like). TNAP maps to chromosome 1p36.1-34 and consists of 12 exons and 11 introns over 50 kb, although the coding sequence starts at the second exon. In hypophosphatasia, numerous TNAP mutations have been reported, the different consequences of which on biological activity of the enzyme account for the clinical heterogeneity of the condition.
Where is the ALPL gene located?
Cytogenetic Location: 1p36.12
Molecular Location on chromosome 1: base pairs 21,835,857 to 21,904,904
The ALPL gene is located on the short (p) arm of chromosome 1 at position 36.12.
More precisely, the ALPL gene is located from base pair 21,835,857 to base pair 21,904,904 on chromosome 1.
The chances are 25% affected (two mutations) --- 50% carriers (one mutation) --- 25% completely unaffected (no mutation). And we have to keep in mind that also carriers can show symptoms. These risks apply to each pregnancy.
Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles.
The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency.
To understand the various symptoms of HPP, it is important to learn a little more about the biophysical background of this disorder.
Tissue-nonspecific Alkaline Phosphatase (TNAP or TNSALP) is an enzyme. This is important, because the term phosphatase is often mistaken as phosphate; but phosphate is a mineral – while phosphatase is an enzyme.
TNAP is produced in almost all tissues of the body, but mainly in the liver, the kidneys and the bones.
The function of TNAP is simple: it cuts off singular phosphate ions from other, more complex chemicals. And this process, called dephosphorylation, is essential for – at least – dozens metabolic processes throughout the human body. For example the metabolization of vitamin B, the “energy transporter” ATP, and – of course – the formation of bones, cartilage and teeth.
So it’s only comprehensible that TNAP is a very important enzyme – and that an impaired functionality of TNAP can cause many different symptoms.
With regard to Hypophosphatasia TNAP is responsible for the breakdown of three particular substances (often referred to as “substrates of TNAP”) – Pyridoxal-5-Phosphate (PLP), Inorganic Pyrophosphate (PPi), and Phosphoethanolamine (PEA).
Due to various different mutations on the gene that contains the “blueprint” for TNAP, the enzyme can not be produced properly in HPP patients. This means that the enzyme is still produced, but is unable to cut off enough phosphate ions from its substrates. In other words: the enzymatic activity of TNAP is lower than in healthy persons.
As a consequence, the chemicals usually processed by TNAP (PPi, PLP, PEA) accumulate in the body and can be used to diagnose HPP. Blood and/or urine levels of these substrates are often increased in individuals affected by HPP.
The most important substrates of HPP are Pyridoxal-5-Phosphate (PLP) and Inorganic Pyrophosphate (PPi). If not enough PLP can be broken down by TNAP, neurological problems, problems with the central nervous system and the production of certain neurotransmitters (serotonin, dopamine, GABA) can occur. These neurotransmitters usually have a huge impact on the general emotional condition, mood / temper and the individually perceived quality of life; and so an imbalance in these chemicals can lead to an emotional and physical imbalance as well.
Of greater importance for our skeletal system is Inorganic Pyrophosphate (PPi). Pyrophosphate consists of two phosphate ions and is usually split into two separate phosphate ions by TNAP in the surrounding of bone and cells. These single phosphate ions are then available to combine with free calcium ions to wander into the bone cells (osteoblasts) and to form the hard substance of our bones, called hydroxyapatite – also known as calcium-phosphate. What does that mean for HPP patients? As a consequence of its decreased activity, TNAP can not provide enough free phosphate ions, and so the bones are unable to form enough hydroxyapatite to grow strong and rigid.
As a second effect, PPi is also known to inhibit bone mineralization by itself. So, as PPi increases – due to TNAPs inability to break it down – around the bone cells, the formation of bone material becomes even more defective.
Finally, as a third effect, the accumulating pyrophosphate combines with calcium to pyrophosphate-calcium crystals (CPPD crystals). Unlike the normal bone material (hydroxyapatite), CPPD crystals are not recognized/accepted as a natural substance of the body and therefore can induce a response of the auto-immune system. As a consequence an inflammatory response can occur, which is often described as chronic recurrent multifocal (non-bacterial) osteomyelitis (CRMO). The corresponding symptoms are: joint and bone pain, painful hot joints (also referred to as “pseudogout”), swelling of bones (bone edema) and fatigue.
HPP is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities.
The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo Saxon origin. The frequency of mild HPP is more challenging to assess because the symptoms may escape notice, or be misdiagnosed. The highest incidence of HPP has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns manifests severe disease.
How Hypophosphatasia is diagnosed
Total serum alkaline phosphatase (ALP) activity: low.
In all types of hypophosphatasia, serum ALP activity is low.
Laboratories use different methods and thus have different reference ranges; it is important to use the gender- and age-specific reference ranges determined by each reference laboratory, preferably the 37®C if CC method.
TNSALP activity requires Zn++ and Mg++, so EDTA tubes should not be used.
Urine concentration of phosphoethanolamine (PEA): elevated
This is the most commonly obtained secondary screen for hypophosphatasia. It may be obtained as part of a urine amino acid chromatogram.
An elevated urine concentration of PEA supports the diagnosis of hypophosphatasia; however, the concentration in urine may be elevated with other metabolic bone disease and may be normal in affected individuals.
Note: Finding an elevated urine concentration of proline adds specificity in interpretation of test results.
Asymptomatic heterozygote’s may have reduced serum ALP activity and increased urine PEA concentration.
Serum concentration of pyridoxal 5'-phosphate (PLP): Elevated
This biologically active metabolite of vitamin B6 may be the most sensitive indicator of hypophosphatasia
Use of vitamin supplements within a week of assaying serum concentration of PLP may lead to false positive results.
Serum concentration of calcium, ionized calcium, and inorganic phosphate: normal or elevated
Normal levels can help distinguish hypophosphatasia from other forms of rickets. Even more so, if calcium is elevated in the individual patient
Hypercalciuria may be present with or without elevated serum concentration of calcium.
Although inorganic phosphate concentration in serum or urine is most typically normal, it may be elevated and thus is probably too variable to be used in diagnosis.
Serum concentration of vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone (nPTH): normal or elevated (Hyperpharathyreoidism)
Inorganic pyrophosphate (PPi): elevated
This is a sensitive marker in affected individuals and heterozygote’s carriers.
The test is only available in specific specialized laboratories.
DNA or Gene mapping
The ALPL gene, encoding for tissue nonspecific alkaline phosphatase, isozyme (TNAP), is the considered the only responsible gene for hypophosphatasia. Though there might be genetic cofactors that influence the natural course of the disease.
Despite patient-to-patient variability and the diversity of radiographic findings, X-ray imaging is commonly used to diagnose HPP, and can reveal characteristic abnormalities especially in the early onset forms
Perinatal/newborns: X-rays readily distinguish perinatal HPP from even the most severe forms of Osteogenesis Imperfecta and forms of congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; especially the metaphyes of the long bones seem to be invisible – or missing – due to areas of non- mineralized bone matrix. The ribs appear to be very thin and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae.
In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed.
Infants: Radiographic features of infantile HPP are striking though generally less severe than those found in perinatal HPP. A very reliable symptom is tongues of radiolucency that protrude from the metaphyses into the shaft of the major long bones. In some newly diagnosed patients, Osteogenesis Imperfecta can be a common misdiagnosis along with ehlers-danlos Syndrome, because of the similar clinical signs and the frequent fracture rate that can occur as the child grows. In these cases the radiolucent tongues can be very helpful sign for HPP.
Serial radiography studies may reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis and gradual generalized demineralization. Often seen is the thickening of the wrist and/or distal part of the forearms.
Adults: In adults, the first symptoms; x-rays images may reveal are metatarsal fractures that occur without any obvious reason. The metatarsals can also show areas of under mineralized bone immediately, next to rather dense areas, which indicate that parts of the cancellous bone have collapsed. Another typical symptom over the course of time bilateral femoral pseudofractures can appear in the lateral subtrochanteric diaphysis. These pseudofractures may remain for years or worsen, but they may not heal until they break completely or the patient receives intramedullary fixation.
Perinatal HPP: Near absent of skeletal mineralization; severe bone abnormalities.
Infantile HPP: Deficient skeletal mineralization, bone abnormalities, possible fractures in different phases of healing. Radiolucent tongues in the metaphyses, “copper beaten” patterns or cloudy structures imprinted in the skull bones that indicate increased intracranial pressure due to prematurely fused sutures (caniostenosis)
Childhood HPP: Skeletal deformities and fractures characterize childhood form. Partial thickening of long bones and/or local swelling of bones due to bone edema as result of underlying inflammatory processes (no-bacterial osteomyelitis)
Adult Onset HPP: Bilateral femoral pseudofractures are typically observed. These pseudofractures may remain for years or worsen. An increased incidence of poorly healing stress fractures in lower extremities, especially of the metatarsals is observed.
Odonto HPP: X-rays appear normal except for low bone mineral density in the jaw.
Symptoms, Severities and Clinical Diagnosis;
The severity of Hypophosphatasia is remarkably variable from patient to patient. The most severely affected fail to form a skeleton in the womb and are stillborn. The mildly affected patient may show only low levels of ALP in their blood, yet never suffer bone problems. In the moderate to severely infantile forms to the adult form affected patients may have chronic fatigue, bone pain, Hypotonia (muscle weakness). Rheumatic/inflammatory symptoms but also frequent fractures, and bone deformities that require surgical intervention.
Signs and symptoms
Each individual who has hypophosphatasia has clinical features derived from generalized impairment of skeletal mineralization. Six different clinical forms have been recognized. The prognosis associated with each form is dependent upon the severity of the disease and the age at which the condition is first recognized. Although affected individuals within a family tend to have similar abnormalities, it is possible to see clinical variability even between relatives.
Clinical Features in the different Forms of Hpp
Clinical feature vary widely even within the same form . Individuals may have some or all of the symptoms that are listed with in each form. They may also have a combination of symptoms from different forms or may not have all the clinical features of an individual form.
6 Different Forms of Hypophosphatasia
Perinatal (potentially lethal) hypophosphatasia
This is usually the most severe form of hypophosphatasia. Affected fetuses are often diagnosed during pregnancy with profound under mineralization of their bones. The limbs are typically shortened and bowed. Bone fractures may be present. An excessive amount of amniotic fluid (polyhydramnios) during pregnancy is common. Many affected infants die prior to delivery, or are stillborn. Those who survive delivery are often irritable, have a high-pitched cry, and fail to gain weight. Respiratory failure is a common cause of death. This is usually due to deformities of the chest and associated underdevelopment (hypoplasia) of the lungs. Newborns might also succumb to repeated central nervous seizers, which can be treated with Pyridoxal (a form of B6).
*NOTE: It is important to notice that there is also a benign perinatal form of HPP. In these cases the fetuses show quite severe symptoms in-utero, but these improve during pregnancy and the children are born with rather severe infantile – like clinical features.
Many infants with this form of the disease appear normal at birth and initially begin to develop normally. Patients with infantile form may appear healthy at birth; however, the clinical signs of hypophosphatasia appear during the first 6 months. This form also has respiratory complication due to rachitic deformities of the chest. Despite the presence of the open fontanelle, premature Craniosynostosis is a common finding, which may result in increased intra- cranial pressure. Other clinical symptoms are frequent vomiting, failure to thrive, generalized muscular hypotonia, angulated limbs and a bulging fontanelle. Radiologically, there can be more or less signs of rickets, osteoporosis with delayed bone age, poor ossification of the skull vault, fractures and vertebral collapse. Bony abnormalities of the chest as well as an increased susceptibility to fractures make affected infants more prone to developing pneumonia. About 50% of affected children have been reported to die during infancy, usually from severe respiratory failure and/or central nervous seizures. Those infants who do survive may often suffer from episodes of recurrent vomiting and from abnormal kidney function due to excess loss of calcium and phosphate in the blood stream, because these mineral can’t be used by the bones. In surviving affected children Hypercalcemia may also be present, and the increased excretion of calcium may lead to renal damage. Intramedullary rodding surgery may be needed in order to walk or prevent displaced fractures. Spontaneous overall improvement in health has been reported.
One of the most common clinical features in this form of hypophosphatasia is loss of the primary (deciduous) teeth before the age of five. This premature loss is directly related to abnormal dental cementum. It is this structure that normally establishes the appropriate connection of the teeth to the jaw. In hypophosphatasia, it is frequently completely missing or present but either underdeveloped or abnormally developed. Other typical clinical features for the childhood form are; delayed walking, very significant waddling(“Charlie Chaplin” gait), bone and joint pain, which often occurs together with swelling of the areas (know as non-bacterial osteomyelitis). A history of bone pain, fractures and vertebrate body collapse have frequently been described. The bone pain is often mis-interpreted as growing pains, the inflammatory events are often considered as signs of “normal” juvenile (rheumatologic) osteoarthritis. Especially the swollen boney areas (bone edema) can – in the worst case even be mis-interpreted as bone tumors (Osteosarcoma)
The adult form is probably the most difficult form to diagnose. It usually presents during middle age though, on request many patient describe mild symptoms that show in their childhood and youth, first of all muscles weakness, “bad teeth” or a susceptibility to infection of the ears, nose or the upper respiratory tract. The condition is often completely asymptomatic for a very long time in which it could only be suspected by a low a low alkaline phosphatase activity level found during routine laboratory studies. The first symptom, which can occur between 25 and 50 yrs of age, may be foot pain, which is due to stress fractures of the metatarsals. Thigh pain, due to pseudofractures of the femur, may also be a presenting symptom.
Dental and skeletal abnormalities, however, gradually recur. The age at their onset as well as their severity varies between individuals. Early loss or even extraction of the permanent teeth is common. Other skeletal abnormalities, however, are of greater concern. Osteomalacia is a common complaint. Osteomalacia is the adult form of rickets. It is characterized by increasing softness of the bones. This, in turn, leads to increased flexibility and fragility and can cause’s non-trauma fractures and deformities. Clinically, Osteomalacia in adults with HPP is characterized by chronic pain in the feet due to recurrent, poorly healing stress fractures. Affected adults may also experience discomfort in their thighs and hips from painful thin zones of decalcification (pseudofractures) in the thigh bones. The patients may also suffer from clinical evident inflammatory events – often in several bone & joints at the same time. This is sometimes called bone pain cycles.
The only clinical abnormality associated with this form of hypophosphatasia is dental disease. It may occur in children or adults. Neither rickets nor Osteomalacia seems to occur.
Pseudo-, or false, hypophosphatasia
This is an especially rare clinical form documented in only a few infants. The physical features all resemble those seen in the infantile form of the disease. However, in contrast to all of the other forms of hypophosphatasia, the total alkaline phosphatase activity has been consistently normal or even increased in blood samples from the affected children. It is unclear what the exact biochemical or molecular abnormality is in these children
Due to the large number of genetic mutations on the ALPL gene that have been identified to far (about 300), which can occur in the individual patient in many different variations, it is very difficult to predict what natural course HPP will take in each patient. In fact it has been said that no two patients with HPP are identical – though there are many common features.
The team around the French biologist and geneticist Etienne Mornet has published a list of most mutations that have been found in patients and associated them with the clinical form those patients showed. (http://www.sesep.uvsq.fr/03_hypo_mutations.php)
This list can be used for a first orientation after a genetic test has been performed, but a reliable prognosis for a longer period of time is yet hardly feasible, because there seem to be other factors – besides the actual genetic mutations – that can take influence on the course of the disease. What these factors are and how they impact the patients’ lives remains unclear.
Another phenomenon that makes a prognosis so difficult is the fact that HPP can change its face over a person’s life-time. Indeed can some patients present with rather mild symptoms during their childhood – like achy, swollen joints or weak muscles – only to suddenly develop a severe form of Osteomalacia (soft, brittle bones) in their adult life.
On the other hand, a significant number of infants diagnosed in utero with a severe or lethal form of HPP have spontaneously improved during the last months of pregnancy and survived with a relatively positive prognosis.
So far there is no cure for HPP that could mend the underlying cause for the disease. Such a cure would have to be a genetic therapy that repairs the individual mutations in each patient. At present gene therapies are only available for very few diseases and are often associated with the possibility of severe side-effects.
This means that HPP is treated primarily with a basic management that consists of four components:
managing occurring fractures and bone deformities (including craniostenosis),
active physical therapy to promote mobility,
a reduction of phosphate and calcium intake (if laboratory levels the necessity), and
the administration of non-steroidal anti-inflammatory drugs (NSAIDs).
Management and Care
Disease management is mainly directed toward the prevention or correction of disease-related complications. Expert dental care is highly recommended for those individuals with dental abnormalities. Physical therapy and orthopaedic management are important in the care and treatment of bone complications such as fractures. Young children with the infantile form should also be monitored carefully for increasing pressure within the head from a premature fusion of the bones of the skull.
Traditional treatments for rickets or Osteomalacia, such as vitamin D or other mineral supplements, should be avoided in general, as these bone symptoms represent only one component of an inherited, complex medical problem. Although a significant number of HPP patients does indeed present with low levels of active vitamin D3. If a supplementation is considered, it must be administered under close monitoring, because Vitamin D can increase serum calcium levels – and thus the risk of a nephrocalcinosis.
Prolonged immobility can further weaken bones and lead to muscle loss, weakness and more fractures. Orthopaedic tend to prefer to treat fractures with short term immobility in a light weight cast, splint or brace to allow some movement as soon as possible. It has been found that long bone fractures and incomplete fractures (so-called “pseudofractures”) should be stabilized with intramedullary nail fixation (“rodding”). If bone grafts or plates are needed the preferred attachment is by strapping them onto the bone instead of using screws.
Patients with HPP benefit most from a multi-disciplinary management that includes a number of different medical specialists, such as endocrinologists, neurologists, orthopaedic surgeons, rheumatologists, pain management experts, dentist, nephrologists, geneticists, physical therapist and perhaps occupational therapists.
Therefore families affected by HPP should try to find a medical centre where theses resources are available and resident experts already have experience with the disease – or are willing to cooperate with other centres, where the required expertise is available
Physical Therapy and Exercise.
Physical therapy should begin as soon as it is evident that an infant has muscle weakness or motor skill delay when compared with same age peers. The long-term goal for children with HPP is independence in life functions (e.g. self-care, locomotion, recreation, social interaction and education), with adaptive devices as needed. Occupational therapy can help with fine motor skills so they can meet their milestones. Adults with HPP also benefit from safe, regular exercise to maintain bone and muscle mass. Swimming and water therapy are particularly well suited for people with soft bones of all ages, as they allow independent movement with little fracture risk.
All kinds of physical therapy should be applied in the knowledge that two of the major clinical features of HPP might not be significantly improved – the low muscle tone and the fragility of the bones. In other words: more exercise will not always bring a continuous improvement; the main focus should be laid on the safety of the physical therapy.
People with HPP benefit from a healthy lifestyle that includes safe exercise and a diet low in foods that cause bone lose. People with HPP should avoid smoking, excessive alcohol, high caffeine consumption and steroid medications which will reduce bone density. Adequate intake of nutrients should be maintained while limiting intake of Calcium and Vitamin B6 and Vitamin D. These vitamins are usually normal or high in most patients so before taking any supplement it is important to have talk to your doctor and have them check with a blood test. Maintaining a healthy weight reduces stress on fragile bones.
Of course activities that are linked with significant physical stress – especially on the bones – should be avoided. This includes contact sports like martial arts, football, basketball etc., but also (if a patient is very fragile) roller coaster rides, skating and similar leisure activities.
Enzyme Replacement Therapy (ERT)
Enzyme replacement therapy is the latest therapeutic approach to treat HPP. The intended effect of such a therapy is to replace the missing enzyme and to bring it to those areas where it is required the most – the bones. Presently under investigation is an experimental drug that has to be designed especially for this purpose. It is a recombinant protein that is potentially able to fulfil the tasks of natural TNAP.
So far clinical trials (Phase I and II) have brought forth promising results, especially in infants with HPP, by improving bone development, respiratory function and muscle strength.
Things that should be followed in all Hypophosphatasia patients.
Hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. However, this should be done carefully so as not to increase the skeletal demineralization that results from the disease itself. Subcutaneous injections of salmon calcitonin also may help reduce hypercalcemia in HPP patients. Vitamin D sterols and mineral supplements traditionally used for rickets or osteomalacia should not be used unless there is a deficiency, as blood levels of calcium ions (Ca2+), inorganic phosphate (Pi) and vitamin D metabolites are often not reduced. In a number of cases Vitamin D can be decreased; in these cases supplementation must be monitored very closely to avoid hypercalcemia. The major risk of hypercalcemia in HPP patients is a calcification of kidney tissue, known as nephrocalcinosis.
Hyperphosphatemia is also often found in patients affected by HPP. Both calcium and phosphate levels can be increased due to the body’s inability to process these minerals to bone material (hydroxyapatite). Most natural foods that contain high amounts of calcium also contain lots of phosphate, so limiting their intake will in most cases help to reduce both serum levels.
Premature Craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infant.
Bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. Fractures and corrective osteotomies (bone cutting and re-arrangement) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. A load-sharing intramedullary nail or rod has been shown to be the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult HPP patients.
Dental problems: Children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. Dentures may ultimately be needed. Dentists should carefully monitor patients’ dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease.
Physical Impairments and Pain:
Rickets and bone weakness associated with HPP can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. Nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance. Moreover NSAIDs can help avoid further bone damage caused by chronic inflammatory processes that are rather common in HPP patients. Pain is often caused by incomplete fractures (pseudofractures) that develop slowly and often remain invisible in regular x-ray imaging. In these cases MRI (magnetic resonance imaging) can reveal the development of this kind of stress fractures.
Due to (potentially) chronically high levels of minerals like phosphate and calcium in the patients’ blood serum and urine, renal functions should regularly be followed. Besides electrolyte concentrations, parameters like creatinine, glomerular filtration rate (GFR), urea, uric acid etc.
HPP-Choose Hope, Inc: US Foundation
Hypophosphatasie Deutschland e.V. (Germany)
Hypophosphatasie Europe (EU)
National Institute of Health
SESEP Laboratory and the Human Molecular Genetics laboratory of the University of Versailles-Saint Quentin
Soft Bones: The US Hypophosphatasia Foundation
Alkaline phosphatase, liver/bone/kidney (tissue non-specific)
A membrane-bound glycosylated enzyme, the function of which remains unknown, but which has been linked directly to hypophosphatasia.
One of two or more alternate forms of a gene that resides on a specific site (also known as a locus) on a chromosome.
The specialized bone structure that contains the alveoli, or sockets, of the teeth.
Also known as immunoglobulins, these molecules are found in blood or other bodily fluids and are used by the immune system to identify and neutralize foreign substances, such as bacteria and viruses.
Cells or tissues that are reimplanted in the same individual from which they came.
A mode of genetic inheritance in which the presence of only one copy of a gene that resides on an autosomal (non-sex determining) chromosome will result in phenotypic expression of that gene.
A mode of genetic inheritance in which the phenotypic expression of a gene of interest requires its presence on both paired autosomal (non-sex determining) chromosomes.
The degree to which a drug becomes available to the target tissue after administration.
A hormone, enzyme, antibody, or other biochemical substance that is detected in bodily fluids or tissues that may serve as a sign of disease or abnormality.
A class of drugs used to treat osteoporosis and similar diseases that prevent the loss of bone mass by inhibiting the digestion of bones by osteoclasts.
Bone marrow cell transplantation
The extraction of bone marrow containing normal stem cells from a healthy donor and the subsequent transfer to a recipient whose body cannot manufacture adequate quantities of normal blood cells.
The process by which the body uses minerals to build bone structure.
A component of mineralized tissues such as bone, dentine, cementum, and calcified cartilage.
A hormone produced by the parafollicular cells of the thyroid that acts to reduce blood calcium (Ca2+).
Calcium pyrophosphate dihydrate disease (CPPD)
A rheumatologic disorder caused by precipitation of calcium pyrophosphate dihydrate crystals in the connective tissues.
The cells that form cartilage.
The organized structure of DNA and proteins found in the cell nucleus. Chromosomes come in pairs, and a normal human cell contains 46 chromosomes.
A research study that uses consenting human subjects to test the safety and efficacy of new therapeutic interventions and diagnostic tests.
A genetic term for having two heterogeneous recessive alleles at a particular locus that can result in disease. Because the mutations involved are less deleterious than that in a homozygous individual, compound heterozygotes frequently become ill later in life and display less severe symptoms.
An improper development of bones with marked shortness of limbs that occurs early in fetal development.
A type of fibrous joint that resides between bones in the skull.
A condition in which some or all of the cranial sutures in a child close too early, which affects brain and skull growth.
The first set of teeth to develop in humans, which are lost and replaced by permanent teeth. Also known as “baby teeth.”
The natural teeth in position in the dental arches.
The removal of a phosphate group to a protein or other organic molecule.
The main section (shaft) of a long bone.
An enzyme that works outside of the cell that secretes it.
A subcutaneous enzyme replacement therapy with affinity for bone that is currently in clinical trials.
A molecule that catalyzes or triggers biochemical reactions.
Enzyme replacement therapy
A medical treatment that replaces an enzyme in patients who either lack or have a deficient form of the particular enzyme.
A chronic neurological disorder characterized by recurrent episodes of unprovoked seizures.
Outside of the cell.
The biological unit of heredity that is made up of a DNA sequence, occupies a precise location (locus) on a chromosome, and contains instructions for the production of a particular protein.
An individual who inherits an allele without exhibiting its effects, which is usually recessive.
A health care professional who assists individuals or families who may be at risk for a variety of inherited conditions.
A variation in composition, quality, or structure.
The presence of identical alleles of a gene on both homologous chromosomes.
An elevation of calcium in the blood.
Relating to joints that stretch farther than normal. Also known as “double-jointed.”
Relating to a deficiency of minerals.
A rare, inherited, and sometimes fatal metabolic bone disease characterized by poor bone mineralization and profound skeletal defects.
Incomplete development or under development of an organ or tissue. enamel hypoplasia incomplete or defective development of the enamel of the teeth
A condition in which there is diminution or loss of muscular tonicity, resulting in stretching of the muscles beyond their normal limits.
Occuring in the uterus or fetus before birth.
Regulates certain intracellular functions and extracellular crystal formation.
Genetic mutation that results in a protein with little or no function.
A bone that forms directly within membranous connective tissue without previous cartilage formation. Examples include the clavicle and bones of the skull.
The intermediates and products of metabolism.
The wider portion of a long bone adjacent to the epiphyseal plate. This part of the bone grows during childhood
The five long bones of the foot.
A mutation in which a single base change results in the insertion of a different amino acid, giving rise to an altered protein.
A form of gait abnormality. Also known as “waddling gait.”
The process of bone formation.
Cells responsible for bone formation.
A genetic bone disorder typically caused by a deficiency of Type-I collagen that results in fragile bones. Also known as brittle bone disease.
The adult form of rickets, which is a softening of the bones caused by defective bone mineralization.
(osteo- derived from the Greek word osteon, meaning bone, myelo- meaning marrow, and -itis meaning inflammation) simply means an infection or edema of the bone or bone marrow
A glycoprotein that is abundant in bone mineral matrix and has been implicated as an important factor in bone remodeling.
The most common type of malignant bone cancer.
A surgical procedure where a bone is shortened, lengthened, or re-aligned.
A chronic disorder resulting in enlarged and deformed bones.
Parathyroid hormone (PTH) 1-34
A hormone secreted by the parathyroid glands that acts to increase the concentration of calcium in the blood.
The proportion of individuals with a genetic mutation who exhibit clinical symptoms.
A gum disease that destroys the structures supporting the teeth, including bone.
The study of the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body.
The observable characteristics of an organism, as determined by genetic and environmental influences.
The fluid portion of blood, in which blood cells are suspended.
Research done prior to a clinical study.
Clinically evident acute inflammation of synovial joints that resembles gouty arthritis.
The active form of vitamin B6.
Refer to Osteomalacia
A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency.
A genetically engineered mouse that has one or more genes turned off.