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The XLH Network GLOSSARY Although I have done my best to ensure that these definitions are accurate, I am only human too, and I am not a medical doctor. These definitions should be confirmed with appropriate care-givers or consultants before embarking on any action as a result of any interpretations of entries in this glossary. While I am grateful to several correspondents who have already pointed out mistakes, which I am delighted to correct, I alone am responsible for errors which may have crept into this glossary. Larry Winger. 1,25 dihydroxycholecalciferol: Often simply abbreviated to 1,25, this is the specific scientific name for the generic Vitamin D analogue calcitriol, which is also referred to by its trade name rocaltrol. 501(c)3: Tax status in the USA for a NonProfit Organisation, this is a necessary requirement for all NPOs to complete. 24,25 dihydroxycholecalciferol: A slightly different Vitamin D analogue, investigated by Professor Carpenter's group at Yale as a possible adjunct therapy in addition to 1,25, this experimental medication, developed with TEVA (a pharmaceutical company) under US Orphan Pharmaceutical legislation, showed some promise in allowing higher levels of rocaltrol to be delivered without affecting PTH and calcium levels. No longer manufactured. Acologix: A biotechnology company in Texas which holds several patents on new biological material that could be relevant to XLH, notably the so-called Phosphatonin and Rickenon, names the company has given to a newly cloned glycoprotein and a processed fragment. It may be important to realise that simply because a company calls its product 'Phosphatonin', the product may not necessarily be the hormone predicted on the basis of PHEX activity. ADHR (Autosomal Dominant Hypophosphatemic Rickets): This syndrome, identified by Professor Michael Econs, exhibits symptoms almost the same as those of X-Linked Hypophosphatemia. Unlike XLH, however, which is linked to the X chromosome and as such can not be passed by fathers to their sons, the ADHR syndrome can be passed from fathers to sons, and is the result of a mutation in the gene coding for FGF23 (fibroblast growth factor number 23), which results in phosphate leakage from the kidneys. Similar frequencies of transmission are observed (50:50 chance of passing the affected gene from an affected parent to children of either gender) as for XLH. Although there are some symptoms that can be recognised as ADHR by the best specialists, the wide variation in symptoms of both syndromes means that the only definitive way of differentiating between these two syndromes (in the absence of large family history which could help in this diagnosis), is by means of genetic tests. alkaline phosphatase: This enzyme plays key roles in the use of phosphorus by the body. The phosphates bonded in an important group of chemicals (AMP, ADP, ATP) are high energy bonds which the body uses to store and release energy to work. A condition in which this enzyme is defective is called hypophosphatasia, and can be mild to fatal, but it also results in rickets symptoms or osteomalacia. In XLH there is often a surplus of alkaline phosphatase, perhaps because the phosphorus or phosphate is not available, having leaked out of the body, or because of the increased activation state of osteoblasts, which are unable to lay down bone properly in the absence of phosphate. allele: We all have 23 pairs of chromosomes, so that's 22 pairs of autosomes and 1 pair of sex chromosomes (2 X's for girls, an X and a Y for boys). Of course, each member of any pair will have a similar gene expressed at the same position. These two copies of the similar gene are called alleles. So for every gene that exists, boys will have the possibility of two alleles on all their autosomes, but only one allele on their Y chromosome, and one allele on their X chromosome, while girls will not have any of the Y chromosome information, but will have two copies of every other gene, including two copies of the genes on their two X chromosomes. allelic exclusion: The process, see also X-inactivation, whereby only one allele (of the two present in a cell), is expressed. The other allele is excluded from expression in that cell. allelic variants: The OMIM database lists allelic variants for genetic conditions, usually at the bottom of its template file for every condition. In the case of XLH, a great variety of allelic variants are listed, but these are also the same as the different mutations in PHEX that are catalogued in Yves Sabbagh's PHEX database. Any different mutation that results in a dysfunctional PHEX molecule is an allelic variant. alpha-calcidol: Also known as 1,alpha, this is another medication that is very similar to 1,25 D3, or calcitriol, and in fact is often used in the same way, in XLH, as calcitriol or rocaltrol. It has been available for longer in a liquid form than rocaltrol. amino acid: The basic building block of proteins, the 20 or so amino acids are coded for by triplet nucleotide codes in DNA. analgesia: A fancy word for pain relief. antibody: A useful tool for biologists, antibodies are specific molecules that because of their specificity can be great tools for identifying things. So a labelled antibody, for example, makes a wonderful probe to light up something like PHEX on the surface of cells, and if the cell is positive for the label, you can say that PHEX is present. ASBMR: The American Society for Bone and Mineral Research holds annual meetings, so in F-HYPDRR we may refer to, for example, ASBMR Montreal (the 2000 meeting), or ASBMR Phoenix (the 2001 meeting). More recent meetings have included the ASBMR San Antonio (2002), the ASBMR Minneapolis (2003) and the ASBMR Seattle (2004). autosome: A general word for any of the 22 chromosomes that are not the sex chromosomes. These chromosomes are numbered in sequence, from largest to smallest, 1-22. base pair: Both sides of the nucleotide backbone of DNA (Every nucleotide has a unique partner with which it pairs up on the other side of the helix, thus Adenine pairs with Thymine, while Cytosine pairs with Guanine). BBB (Big Bear Bio also known as Acologix): A biotechnology company in Texas which holds several patents on new biological material that could be relevant to XLH, notably the so-called Phosphatonin and Rickenon, names the company has given to a newly cloned glycoprotein and a processed fragment. It may be important to realise that simply because a company calls its product 'Phosphatonin', the product may not necessarily be the hormone predicted on the basis of PHEX activity. Bio-MEP: A biotechnology company in Montreal which holds several patents on new biological material that could be relevant to XLH. MEP stands for Metallo-Endo-Peptidase. bossing: A condition often associated with XLH, where the forehead is quite straight and pronounced, even slightly bulbous, as compared with sloping backwards. bowed or bowing: As in legs, which could be bowed () rather than straight ||. There are other terms for this too, like 'bandy-legged', many of which are used pejoratively rather than descriptively. braces: A general term used to describe any number of bracing devices which may help to straighten lower leg bones, or provide support within which the lower legs can grow straight more easily. C3H: A particular strain of mice, in which the Gy (gyro) mutation has been maintained, of special interest to XLH in that when the Hyp mutation is present, it causes less bone abnormality than when it is in the C57BL/6 strain. C57BL/6: A particular strain of mice in which the Hyp mutation is maintained. The Hyp mutation is the exact mouse equivalent of the mutation which results in XLH in humans. calcitriol: The generic name for rocaltrol, or 1,25 Vitamin D3. calcium: Another important mineral constituent used to build strong bones. It is important to realise that calcitriol is not a calcium substitute, but rather an active Vitamin D. Calcium metabolism is not affected in people with XLH, with the exception of high calcium deposition (in the form of calcium phosphate) in the kidneys, called nephrocalcinosis, which is typically associated with standard treatment for XLH. calcuria: Literally, calcium in the urine, a situation which can contribute to nephrocalcinosis. callus: A term familiar to anyone who has experienced, directly or indirectly, bone healing after a break or osteotomy. A callus is a sheath of osteoid material that is laid down by osteoblasts covering the entire break point, which is observable on X-Rays. With time, the callus will disappear, as the dynamic bone growth process takes place (osteoclasts resorb the callus and the normal bone structure returns) capsule: Typically, and especially for rocaltrol capsules, a gelatin coating of an oil in which the rocaltrol is solubilised. carbohydrate: With reference specifically to our discussions in F-HYPDRR, carbohydrates are important molecules (carbon, hydrogen and oxygen) of sugar-like characteristics that attach to proteins in the golgi apparatus of a cell, whereupon the protein is said to be a glycoprotein. cell-surface associated: This is a particular sort of biological jargon, which means that the entity (usually PHEX, in our discussions in the XLH Network) normally sits on the cell surface. Usually cell-surface associated proteins have a particular region that is able to cross or at least anchor in the bi-layer of the cell membrane, the so-called lipophilic portion, while the other end, which waves around outside of the cell, is, in the case of PHEX, the business end that mediates its endopeptidase function. charity: From St. Paul's Letter to the Corinthians, as per the King James Version: "And now abideth three things, faith, hope and charity, but the greatest of these is charity." Since in some disrepute, certainly in America, since the term is so patronising, and in current parlance the word is better translated as 'love'. In the UK, however, a charity is basically the name for a non-profit organisation, and the trustees of registered charities are bound to abide by the rules of the Charities Commission. cholecalciferol: Vitamin D derived from animal tissue, like cod liver oil (oil from cod liver). chromosome: The structural units in any living cell that carry the DNA or genes. Chromosomes exist in pairs in the body, but as individual elements in the sex cells. CLIMB: Children Living with Inherited MetaBolic conditions, an umbrella charity in the UK which deals with some 700 different metabolic disorders. This organisation used to be known as the RTMDC (Research Trust for Metabolic Disorders in Children). clinical evaluation: As in Dr. Fred Singer's clinical evaluation study of XLH adults in Los Angeles, California, this is, as far as I understand it, a clinical practitioner looking at patients who haven't necessarily been looked at in the context of the XLH syndrome before, as adults. An evaluation, an attempt to describe, if not necessarily to understand, just what is going on in the adult XLH situation. Clinical trials, Phase I: In Phase I of any series of clinical trials of any potential medication (all of which will have had to have been assessed in an animal model), normal volunteers are given the medication, to see what, if any, reactions they might have. This is the first safety test, and all medications have to get through this before they can go on to efficacy trials. Clinical trials, Phase II: I believe that in these trials, the most seriously affected members of any target group of patients are included, in an initial attempt to assess efficacy. This phase is by nature a very small cohort. If a medication works out satisfactorily in Phase II trials, then it goes forward to a much larger cohort of affected people for final testing. Given the small sample size of people with XLH, it is likely that any trial will be held in the same sort of way as Professors Carpenter and Seikaly's two trials (24,25 D3 and thiazide diuretics, respectively), namely: an initial control period without the medication, or with placebo, and then an assessment period with the experimental medication. The two periods might be randomised, as Carpenter's study did. If a large enough population of XLH people could be got together, it might be possible, and it would thereby be quicker, to assess an experimental group as against a control group, with randomised use of placebo in true double-blind fashion. It might be in this context that we as the XLH Network could help best. Clinical trials, Phase III: A large group of patients is tested with the medication, and with this large group definitive estimates of side-effects can be ascertained. congenital: A term that refers to a syndrome or symptom that one is born with. The syndrome need not be genetic, or resulting from an affected gene of the individual, but if it is, as in the term 'congenital genetic condition' it could be passed to further generations, even if neither parent had experienced the affected gene (see the definition for spontaneous, for further clarification). CORD: Canadian Organisation for Rare Disorders, affiliated with NORD, this is a non-profit organisation that is not affiliated with government. craniosynostosis: Problems with the development of the skull bones can, rarely, be associated with XLH, and these problems can lead to neurological impairment. cytoplasm: A general term for the inside of a cell, therefore everything contained within the cell's membrane is a constituent of the cytoplasm. All of the cell's organelles, from mitochondria to the Golgi apparatus to the nucleus are found in the cytoplasm. DHT (di-hydro-tachysterol): Another form of Vitamin D, which has been used rather more in the past, for treatment of XLH or Vitamin D Resistant Rickets. Typically 1,25 or 1,alpha are used today, but there are still XLH people being treated with DHT. diuretic: The generic term diuretic describes the activity of any of a number of agents that act to increase the volume of urine by inhibiting the absorption of salts like sodium and potassium, as well as water, by the kidney. DNA: Deoxyribonucleic Acid, the carrier of the genetic code. dominant: A useful term that describes how a gene is expressed in an individual. If a gene is dominant, then it will be expressed, regardless of whether there is another characteristic associated with the homologous gene on the other chromosome. For example, females with XLH have two PHEX genes, or alleles, one on each of their X chromosomes. Yet if they have an affected PHEX gene, its expression (contributing to low phosphate) is always dominant. Why this should be so, however, is a matter of some conjecture. ED-71: First publicly described at ASBMR-Phoenix, in 2001 by representatives of Chugai Pharmaceuticals, this analog of Vitamin D has shown great promise in Hyp mice, eliciting elongated long leg bones as compared with untreated mice. We here at the XLH Network are watching developments with this medication in the pharmaceutical industry with great interest. effervescent: Fizzy, as most often seen in Phosphate Sandoz, which fizzes when it contacts water, quickly solubilising so that phosphate is available for oral ingestion. endocrinology: The study of hormones and their interactions with target cells and organs. Endocrinology is an important discipline in XLH because the hormone that controls phosphate metabolism, the so-called 'phosphatonin' is not definitively established, as yet, though there are several possible candidates, and this is a hot research topic. endopeptidase: Endopeptidases are enzymes that work to cleave proteins from the middle. Certain proteins or hormones need to be cleaved to be active, or to function properly. enkephalin or see [Leu]enkephalin: A substrate we are likely to hear more about in the coming years, this natural peptide neurotransmitter is cleaved by the neutral endopeptidase (NEP), and also, apparently, by PHEX. enthesopathy: Calcification typically of the joints, tendons and ligaments, which can result in constraints on movement. enzyme: Chemically, an agent that catalyses (enhances) a reaction but is not itself used up in the reaction. ergocalciferol: Vitamin D derived from plant sources. EURORDIS: The association of rare disease organisations that lobbies in the European Union on a similar basis to the work of NORD in America, or CORD in Canada. exopeptidase: Exopeptidases are enzymes that chew proteins up from their ends, hence exo. express: A very useful verb in biology, this expression [sic!] conveys the concept that something must show, or express something else. In particular, a cell can express a particular molecule on its membrane, or a transfected cell or bacteria or yeast can express the gene product of a gene that has been inserted into it. FGF23 (fibroblast growth factor number 23): The protein that is mutated in people who have the specific syndrome ADHR, as documented by Professor Econs' group. When this protein is not functional, these people leak phosphate from their kidneys, just as people with XLH do. familial: A general colloquial term meaning something that exists in families, therefore probably genetic in origin. F-HYPDRR: Familial Hypophosphatemia or Vitamin D Resistant Rickets mailing list. Mailing lists are restricted to eight letters, and seem to have to have a hyphen somewhere too, though quite why this should be so is unknown to me. Fleet's Soda: A pharmaceutical preparation of phosphorus suitable for ingestion as phosphate replacement therapy. gene: The basic unit of genetic information encoded by a series of triplet codes in DNA, a gene codes for a particular set of amino acids which are the building blocks of proteins. gene dosage: For genes that are on autosomes, everyone gets an equivalent gene dosage (effectively two of the same gene, one on each of the pairs of chromosome, that are called alleles). But on the sex chromosomes, boys only have one available gene on their one X chromosome, in contrast to girls who have the benefit of two X chromosomes, hence two genes or alleles for each trait. Thus girls should have, in principle, only 50% of the gene dosage as boys, with respect to an affected PHEX gene -- 100% of an affected boy's PHEX gene is affected, while only 50% of an affected girl's PHEX genes are affected. The odd thing about XLH is that the syndrome does not necessarily reflect this difference in gene dosage, since girls can be, and often are, equally as affected in the bone department, as boys. The gene dosage effect is only possibly apparent when it comes to teeth, as boys' teeth seem to give more problems than do girls'. This odd phenomenon is similarly reflected in the hyp mouse model, where homozygous female mice (hyp/hyp) can be shown to be no worse affected than heterozygote (hyp/wild) female mice. GeneDx: A diagnostic company near Washington DC, USA, which specialises in providing genetic tests for rare disorders. genetic counselling: When a genetic trait is identified in an individual, with or without a family history, it can be very useful for the individual (with or without their partner), to have genetic counselling, so that they can explore the various probabilities and possible outcomes in terms of this trait in their children, or their children's children. Genetic counsellors are trained in human genetics, and they can provide valuable support and guidance as families search for the right way forward for themselves. genome: The entire genetic code for a particular species, as the human genome. gene product: When a gene is transcribed from its residence in DNA in a cell's nucleus, the resulting single-stranded messenger RNA migrates to a ribosome where it is translated into protein by the steady accumulation of amino acids based on the triplet codes which the mRNA carries. The resultant protein is said to be the product of the particular gene. generic: The term especially for a medication which has a chemical structure that is not specifically or proprietarially named by a pharmaceutical company. A generic drug would have less patent restrictions around it than a proprietary drug. Genetic Alliance: American-based international consortium of genetic disorder support networks. Genetic Interest Group: UK-based consortium of UK-based genetic disorder support networks. genetic testing: Diagnosis by using molecular biological (genetic) techniques whereby the presence of a particular mutation can be identified. You have to have a sample of nucleated cells with which to make a genetic test, so the candidate has to provide a sample. This sample could be microscopic, very unintrusive, like a swab of the inside of the cheek. georgia: Always on my mind, georgia.ncl.ac.uk was in at the start of the XLH Network, and the familiar usage of the term in lower case is just a colloquial expression for the web pages served from this domain. glycoprotein: After proteins are built on the ribosome, according to instructions translated from mRNA, they are subsequently further processed by the addition of different kinds of carbohydrates. The resulting molecular complex is called a glycoprotein. golgi: The site in the cytoplasm of the cell where a great deal of post-translational modification occurs, after a protein has been constructed in its linear sequence as a set of amino acid building blocks. Discovered by someone called Golgi, naturally. Gy: Short for gyro, because mice with this mutation exhibit a gyrotary movement, circling and circling because they have an inner ear disturbance. Since identified as a mutation involving at least two genes, involving part of the phex gene and another inner ear gene which in the mouse is right next to the phex gene. haplo-insufficiency: We each have what you might think of as two parallel genes (which are called alleles), on each of every pair of chromosomes. If one of these genes is mutated, perhaps the other gene could still create enough of a gene product to make up for the deficiency. But perhaps not, in which case the situation would be called haplo-insufficiency. The term comes from the way biologists think of the genome: the DNA in our body cells exists in what is called a diploid state (two parallel genes or alleles for every gene in the genome), but in the sex cells (sperm or egg) it exists in a haploid state (only single chromosomes, not chromosome pairs). So each half of a chromosome pair is a 'haplo'. hormone: A protein messenger that interacts with receptors on target cells to mediate some sort of action. [It might be useful to consider the mechanism of insulin hormonal control of blood sugar as an example of a hormone]. It is probable that the proposed phosphate regulating hormone, phosphatonin, works in a double-negative sort of way to stimulate the retrieval of phosphate otherwise excreted by the kidneys. Hyp: The mutation in mice that is the exact equivalent of the PHEX mutation in humans with XLH. hypophosphatasia: A condition in which the levels of alkaline phosphatase in the body are very low. This condition also results in rickets symptoms, but the expression of the syndrome can be mild to very severe. hypophosphatemia: Low phosphate levels in the blood. This condition could be the result of a variety of reasons, but the one that concerns us mostly is when this condition is congenital and X-Linked, and results because of a mutation in the gene that codes for PHEX. Ilizarov: A special device used to hold bones in a sort of external cage with rods stabilising the bones, while the bone knits back together. IPR (Intellectual Property Rights): The general term given to the rights which encompass such things as patents, licenses, distribution contracts, especially in regards to a new invention, medication, approach. knock-knee: The condition whereby legs do not grow straight || but rather the knees are bent together )(. leak: As in phosphate leak from the kidney. In normal kidneys, phosphate passes from the blood out into the urine. But normal kidneys have a means of retrieving that phosphate before the urine goes along out to the bladder, and this retrieval mechanism helps to ensure that phosphate levels in the blood are balanced. In XLH, the kidney is never instructed to retrieve the phosphate, and so it just leaks out into the urine and is lost. It's not that the kidneys are intrinsically defective in XLH, rather it's a case of them just not getting the right signal to retrieve the phosphate. [Leu]enkephalin or see enkephalin: A substrate we are likely to hear more about in the coming years, this natural peptide neurotransmitter is cleaved by the neutral endopeptidase (NEP), and also, apparently, by PHEX. lipid bi-layer: Cell membranes are made up of a double layer of lipids that are oriented with their wavy tails on the inside, and their polar heads on the outside. The region of the tails of the lipids is called hydrophobic, because it doesn't interact well with water molecules. listserv: A generic term for the software that drives email groups on the internet. Messages sent to a central address are distributed to everyone who is part of the list. Commands to the listserv (as for subscription business) can be sent directly to the listserv without bothering the entire list. maelstrom: The name of the computer at St. Johns University which runs the F-HYPDRR mailing list, and several hundred other lists besides. Make-a-Wish Foundation: An organisation in the USA that provides for the special wishes of special children. March of Dimes: A major-league charitable organisation in North America which has specialised in orthopedic problems. One of the F-HYPDRR members has been a National Poster child for the March of Dimes. mediate, mediator: An action word that implies something that causes something to be done. A very useful term in biology, which is often concerned with something eliciting a response. membrane: As in biological cells, the semi-permeable barrier that holds the contents of a cell, while keeping the outside out, and yet allowing passage of important ions and biological material through. The cell membrane is also the framework for cell-surface associated reactions mediated by biological entities that sit, or are anchored, or communicate through the membrane. MEPE (matrix extracellular phosphoglycoprotein): A protein identified by Dr. Peter Rowe's research group from analysis of the mRNA of rare bone tumours that produce a phosphaturic factor resulting in rickets symptoms. Meniere's Disease: A term describing a range of symptoms of inner-ear disturbance, consisting of mild vertigo through acute nausea. metabolite: Of particular interest to us in the XLH Network, this term is used to denote the product of biological processes in the body as a result of interactions among the chemicals there. In other words, when a particular chemical is metabolised it is changed, and the changed material is said to be a metabolite. For example, normal dietary Vitamin D from fish oil is called cholecalciferol. When it enters the body, it is changed in the liver by the addition of a new hydroxyl group (OH-) to one end of the molecule. Similarly, later processing adds another hydroxyl group to the other end. Provision of 1,25 dihydroxycholecalciferol (cholecalciferol with hydroxyl groups at the first Carbon and the 25th Carbon in the molecule) directly (as when Rocaltrol capsules are prescribed) therefore means that this metabolite of cholecalciferol is delivered to the body directly. molecular biology: Generally, the term used for the field that considers biology at the level of interacting molecules, but this term has been taken to mean particularly the field that considers the role of genetic information in the construction of proteins. mosaic: In genetic, biological terms, an organism is a mosaic if its gene products are a reflection of both alleles expressed on each of a pair of chromosomes; we are all mosaics, but sometimes the proportion of expression of one or the other alleles can be skewed. mRNA: The means whereby the genetic information carried on DNA is transcribed and ultimately translated into protein. Messenger RNA is single-stranded genetic information transcribed from DNA, and it moves from the nucleus of the cell into the cytoplasm where on ribosomes in the rough endoplasmic reticulum in the cell's cytoplasm, it is decoded with the help of transfer RNA, and the building blocks of proteins, the amino acids, are constructed according to its template. MUMS: An American-based organisation of mothers dealing with various metabolic disorders. murine: The adjective form for the mouse species. Compare: canine for dogs, feline for cats, ursine for bears, bovine for cows, ovine for sheep, caprine for goats, porcine for pigs. mutation: A general term for any discrepancy between normal DNA and that which an individual may possess. Mutations come in a variety of different forms, as in: point mutation; frame-shift mutations; deletion mutations; addition mutations. They can result in completely benign effects on the protein for which the gene is coding, or very disastrous effects, depending on which part of the protein is affected. As a rule of thumb, everyone in the world has about 10 mutations (differences from normal DNA). Some people have mutations that are obvious, while others have them in more benign regions, so they are not seen. nevus: Or giant nevus, a skin birthmark. Some rare cases of giant nevi also seem to secrete a phosphaturic factor which causes rickets symptoms. nephrocalcinosis: When people with XLH are treated, usually with a combination of calcitriol (Rocaltrol), and phosphate, a moderate amount of calcium deposition in their kidneys can be a side-effect of the therapy. In most cases, this calcium deposit does not progress beyond moderate, and the clinical consensus seems to be that this is cause for careful monitoring, but not undue concern, in the long term. nephrology: The science of the kidney and its function. Nephrologists are important in the medical treatment of XLH because the syndrome is the result of phosphorus leaking from the kidney. nephron: The basic blood filtering unit of the kidney, reiterated many thousands of times in the organ. NORD: The National Organization for Rare Disorders, a private organisation in the USA, not to be confused with the Office of Rare Diseases, which is the American government's organisation, affiliated with NIH, I believe. NPO (non-profit organization): The term especially used in North America to describe an organisation that exists not-for-profit but typically for charitable or philanthropic purposes. The equivalent term in the UK is a charity. nucleotide: Term for the basic building blocks of DNA; adenine, thymine, guanine or cytosine are nucleotides. nucleus: Within the cytoplasm of cells (within every cell except the red blood cell, in fact, which is a terminal-stage cell that has shed its nucleus in the process of its formation) sits the nucleus, which holds the genetic information that is processed by the cell to produce appropriate proteins. OHO (Oncogenic Hypophosphatemic Osteosarcoma): The name for very rare benign tumours which are associated with bone, which seem to secrete a factor that makes phosphate leak from the kidneys. This leakage results in rickets symptoms, and so these are often the first sign that such a tumour might exist. The tumour can be very small and hard to find. OMIM: Online Mendelian Inheritance in Man, an online database on the internet which lists all the known genetic disorders and provides useful research synopses for each. ORD: Office of Rare Diseases/Disorders, this is the US government's office, not the non-profit NORD group. Orphan Pharmaceutical Legislation/License: This legislation, used in both the USA and in Europe, is designed to make it attractive for pharmaceutical companies to produce medicines that would probably find only a very small potential market. There are tax write-offs, and other benefits, apparently, to the company for developing these medicines. orthopedics: The study of bones and their proper support for the rest of the body's functions -- rather more of an engineering field than, for example, a metabolic, endocrinological or cell biology area. orthotics: The discipline of applying appropriate support to the skeleton to enable better mobility and posture. osteoblast: Bone is a dynamic tissue, not at all static as we might imagine. It seems that there are two kinds of cells involved in bone dynamics, of which the osteoblast is the orchestator of bone cell function. The osteoblast also lays down osteoid, unmineralised bone, which later calcifies. osteoclast: The other bone cell acts to tear apart (resorb) bone tissue. Bone tissue is in a constant dynamic equilibrium between being laid down by osteoblasts and resorbed by osteoclasts. osteomalacia: This is the name given to defective bone mineralization in adults, while rickets is the term which tends to be used for similar problems in children, whose bones are growing. osteopathy: The study of correcting physical problems by doing various manipulations to the vertebrae. Also referred to in the states and Canada as chiropractic. I think [LW] that it is important to realise that people with XLH are not 'normal' in terms of their bones, and visits to osteopaths or chiropractors should be considered with rather more care than normal people might take. osteotomy: The surgical procedure where part of the leg bone is removed, and a more correct alignment is achieved. The bone heals together in the new position. patent: A particular piece of paper which indicates that a given named individual or company owns the rights associated with the discovery of a new device, product, process or life form. Inventors seek patents to protect their rights over their discoveries. In America, patents are awarded to inventors if they can show or document that they were the first to discover something, while in other countries patents are awarded to the first person to apply, if the discovery has not been in the public domain. peptide: A short section of protein, composed of the amino acid building blocks. Peptides are less likely to act by virtue of their three-dimensional structure than larger proteins which take on characteristic folding patterns -- rather their primary structure, their amino acid sequence, is crucially important in their activity. PEX: The original name for the affected gene in XLH, as reported by the HYP Consortium in the scientific journal Nature, in 1996. Since changed to PHEX because another gene had already been called PEX, so it was deemed convenient to add an 'H'. PHEX (Phosphate regulating gene with Homologies to Endopeptidases on the X chromosome): This enzyme that sits on the surface of osteoblasts must have a function, because when it is inactive (as when it is mutated in XLH), phosphate leaks from the kidney. It's believed that this endopeptidase must function to cleave a particular hormone (like PTHrP, for example) which might then tell the kidney to retrieve the phosphate. phosphate: Phosphorus doesn't exist in the body just as the element. Rather, it combines with oxygen to form the phosphate ion. In XLH, it is the inorganic phosphate that is typically measured in the serum, rather than the so-called organic phosphate, which is the phosphate that goes into the high energy bond molecules like ATP. phosphatonin: The holy grail of phosphate homeostasis research, this proposed hormone is one of those materials that must exist because the effects of its absence, or rather its inappropriately processed presence, are self-evident. The question is, which of various candidates, could it be? It is believed that the phosphatonin hormone must be processed by the PHEX gene product, to keep phosphate from leaking out of the kidneys, and this lack of processing by the PHEX gene product in people with XLH means that the phosphatonin does not work properly, thereby allowing phosphate to leak without control from the kidneys. Phosphatonin: The generic term phosphatonin should be distinguished from the possibly proprietary name Phosphatonin which may be registered by the Big Bear Bio company to describe a new product which they state is phosphatonin. If this Phosphatonin is indeed phosphatonin, or the phosphatonin that is crucial in XLH, then it should be processed by PHEX, which should in principle make an appropriate fragment that reduces phosphate leakage from the kidneys. phosphaturic: Something that makes phosphate leak into the urine. phosphorus: An essential element used by the body in a variety of ways, from bone building to high energy bonds that allow the body and its cells to do work, to helping form the structure of DNA, to being incorporated in a osteoid mix of material that is crucial in mineralised bone formation. polypeptide: See peptide. Polypeptide refers to a chain of amino acids joined with standard peptide linkage, and this term is often used interchangeably with peptide. prenatal: Before birth. proprietary: The term given to a medication indicating that particular rights to it are owned by a particular company or individual. protease: A general term for enzymes that cut, cleave, digest or otherwise chew up proteins. protein: Composed of amino acid building blocks, each of which is coded for by a characteristic triplet code translated from messenger RNA which itself has been transcribed from DNA, proteins are constructed on ribosomes in the rough endoplasmic reticulum of the cell. When a sequence has been constructed, it can and almost always is, subject to post-translational modification, in which bits of it may be chopped off (by endopeptidases) or chewed off (by exopeptidases), or sugar components added, or different folding patterns adduced, or conjoined with different proteins to form an entire active entity. proteome: The field of materials that constitutes what happens to proteins after they are subjected to post-translational modification. Only some 30,000-40,000 proteins are coded for by different genes, but each of these is subject to a host of post-translational modifications, which make up the proteome. It's likely, for example, that the human proteome is much more complicated than the bacterial proteome, because there are so many modifications to proteins in higher organisms. proteosome: I believe that this is another name for a ribosome, a place where protein is manufactured by the cell in its cytoplasm. PGD (Pre-implantation Genetic Diagnosis): When an embryo at the 8 cell stage is tested, by genetic testing, to see if a particular mutation is or is not present, that embryo may or may not be used for implantation in the uterus for further normal development. PTH (ParaThyroid Hormone): This hormone, released from the parathyroid glands that sit just beside the thyroid gland in the neck, is the body's calcium regulator. If calcium levels are low, PTH levels respond by increasing It also acts directly on osteoblasts which then produce factors that enhance osteoclast (resorption) activity. PTHrP (ParaThyroid Hormone related Peptide): Originally described as a factor from tumours which exerts PTH like activity, this peptide has recently been shown to be a substrate for the activity of PHEX, the endopeptidase affected in XLH. rachitic: The adjective form of the noun rickets. recessive: A useful term that describes how a gene is expressed in an individual. If a gene is recessive, then it will not be expressed, in favour of the complementary characteristic associated with the homologous gene on the other chromosome, which would be expressed in a dominant manner. If the homologous genes (called alleles) on both of the pair of chromosomes are recessive, however, then the recessive trait will be expressed. research study: Typically in these studies, samples of body tissue are donated by candidates, such that enough tissue for doing a particular project, in vitro, is available. This study could involve, for example, blood samples, urine samples, saliva samples, sweat samples, or it could get relatively invasive, if bone marrow aspirates were required. Of course, if someone is already having an osteotomy, that is a brilliant opportunity for acquiring a sample for research purposes that would not involve any further invasiveness than is already being done for therapeutic reasons. ribosome: The site, in the endoplasmic reticulum, where proteins are produced by translation from messenger RNA. It's because of the presence of ribosomes that the endoplasmic reticulum is called 'rough'. Rickenon: The name given by Big Bear Bio, a biotechnology pharmaceutical company, to the processed fragment of a new protein hormone they have called Phosphatonin. BBB state that Rickenon is the active form of the hormone, and that it has exhibited a significant capacity to decrease phosphate excretion into the urine of normal rats, but further data for this capacity are not available on the company's website. rickets: A disorder of childhood characterised by defective bone and mineralisation, where characteristic lower limb bowing or bending occurs. Other outward signs of rickets can be the so-called rachitic rosary on the ribs, and thickened wrists, as well as bossing of the forehead. RNA: The single-stranded carrier of the genetic code between the nucleus where the double-stranded DNA exists, to facilitate the construction of protein in the cytoplasm of the cell. RNA is the template of the code on which in the ribosome the protein is constructed. There are basically two kinds of RNA that are important in the translation of genetic information from DNA: messenger RNA (mRNA) and transfer RNA (tRNA). Messenger RNA is the single-stranded template that is a copy of one or the other side of the DNA double helix, and as such it is the message that moves from the nucleus of a cell to the cytoplasm. There, on ribosomes, individual transfer RNA (specific for each amino acid) binds to amino acids in the cytoplasm and inserts them into position along the mRNA template. rocaltrol: The trade name (manufactured by Roche) of calcitriol, or 1,25 dihydroxycholecalcidol. Traditionally available as an 0.25 microgram or 0.5 microgram capsule, recently rocaltrol has been released in a soluble form which can be much easier to administer to babies and toddlers. rough endoplasmic reticulum: The site in the cytoplasm where proteins are manufactured, ie where proteins are constructed based on their amino acid building blocks. rosary: Traditionally, the set of beads which are a useful prayer aid, but in the case of rickets, apparently a characteristic bead formation on the ribs of affected individuals, in which case it is referred to as a rachitic rosary. sex chromosome: There are two sex chromosomes, in addition to the 22 other pairs of autosomes. These sex chromosomes are known as the X and the Y chromosomes, probably because they look like an X and an upside-down Y (when the chromosomes are individually cut out of a photograph and pasted into a standardised pattern known as a karyotype.). Everybody has at least one X chromosome, but to complete their pair of sex chromosomes, boys have a Y chromosome and girls have an X chromosome in addition, which they receive from their father. Shriner's: A benevolent organisation founded in the USA but now covering North America, which is famous for its conferences, and the odd uniforms (incorporating fezzes) which the members wear. The Shriner's main philanthropic mission is to help children with orthopedic problems (bones) and burns. They have set up several hospitals and centres throughout NA for the purpose of philanthropic care of these children, and many people with XLH have been the beneficiaries of the Shriner's philanthropic work, which in addition helps to fund research into bone disorders. soluble: Dissolved or capable of being dissolved in a solvent, like an aqueous solution of physiological saline or water, or an organic solvent like ethanol. Cell-surface components are often difficult to solubilise in aqueous solutions without the addition of detergents, because they have a lipophilic portion that hates water. sPHEX: soluble or secreted PHEX: Because cell-surface components are difficult to keep in solution in solvents like physiological saline, the demonstration by Boileau et al in 2001 of soluble PHEX which acts on a substrate (PTHrP) is a singularly dramatic discovery, and poses new challenges for further research and therapeutic intervention. spontaneous: Occurring out of nothing. We like to refer to people without a family history of XLH, but who nevertheless are diagnosed as having a congenital disorder of their PHEX, as spontaneous, because they are themselves entirely affected. You could have spontaneous XLH because a mutation could have arisen on one of the X chromosomes that you received from either of your parents' sex cells (egg or sperm), without them being affected in any way. sporadic: The more clinical way of referring to spontaneous cases of XLH. We tend not to use this among ourselves because there is nothing sporadic about the disease in any individual, and so this can cause some confusion. stapling: A relatively new surgical intervention technique which seems much easier than a full osteotomy, this approach was introduced several years ago to the F-HYPDRR membership. Apparently a metal staple inserted into one side of the leg bone, at the growing point, causes growth of the bone at that side to stop, and thereby the growth of the bone occurs only on the other side. In this way, apparently, the inside of a bowed bone would continue to grow, but the outside bowed side would not, and the bone should straighten up. When both sides are even again, the staple can be removed to allow further growth of the whole bone. stenosis: Although I have never been entirely sure of the definition, I believe this to be a sort of bony projection particularly into the spinal cord from the vertebrae, which can cause problems as it accretes. substrate: The substance upon which an enzyme acts is said to be its substrate. In the case of XLH, the search has been ongoing for several years to determine what is the substrate upon which the endopeptidase PHEX (the protein that is affected by the mutated gene in XLH) acts. There are several candidates now for this substrate. tablet: Pharmaceutically speaking, a tablet is a solid pill which is swallowed. Taylor Frame: A modification of the Ilizarov apparatus, in which rods inserted into leg bones are tightened by fractions of turns on a daily basis, to achieve straightening or even lengthening of the leg over the course of several months. transfection: The process whereby a new piece of DNA is inserted into a cell, which then incorporates it into its own DNA, so that when the cell divides, it replicates both its own and the new DNA so that all subsequent cells will have the new DNA as well. transgenic: Typically, an animal that has been transfected in some way at the level of the genome, so that it will pass along the new DNA to some of its offspring. tRNA: Transfer RNAs are the independent expeditors of each particular triplet codon encoded originally in DNA, but then transcribed onto single-stranded mRNA. Individual transfer RNAmolecules specific for each triplet codon have at their other end a particular specificity for a unique amino acid, and so by binding to that amino acid, and then fitting onto the mRNA template that matches their codon end, they can lay down the correct amino acid sequence on the ribosome, the protein factory of the cell. ultrasound: The non-invasive process of using sound waves to image structures, particularly in XLH with reference to looking at kidneys to determine whether there is increased deposition of calcium phosphate there, which is called nephrocalcinosis. Vitamin D: Not a 'proper' vitamin, Vitamin D is a hormone whose role in bone development was finally conclusively pinned down in Newcastle upon Tyne by Sir James Spence. Vitamin D is constructed by the body when the ultraviolet rays of the sun impact on cholesterol. Alternatively, Vitamin D can be ingested by eating the oil of fatty fishes, as for example from cods' livers. windswept: The characteristic appearance in rickets where one leg bows and the other goes knock-kneed, like a 'K' perhaps, or like nestled brackets ((. Neither totally knock-kneed nor bowed, but rather a combination of both. X-inactivation: On the X chromosome, in any given cell, the phenomenon of selective X-inactivation occurs. Each cell expresses the gene products of only one of the X chromosomes that it carries. Girls are therefore something of an X-mosaic, since roughly half of their cells will express the gene products of one of their X chromosomes, and roughly half of the others will express the gene products of the other X chromosome. XLH (X-Linked Hypophosphatemia): The syndrome that connects the XLH Network, XLH is not necessarily a bone disease, but is more precisely thought of as an X-Linked dominant phosphate wasting disorder, in that the primary symptom of this condition is low phosphate levels in the blood, accompanied by high phosphorus levels in the urine. Bone problems tend to occur to 95% of those who have the affected gene, while some 5% do not seem to have any bone troubles at all. Fathers with the condition by definition will have affected daughters, but could not have affected sons, while mothers with the condition have a 50:50 chance of passing it on to either their daughters or their sons. XLH Flyer: The XLH Network has created a brochure describing itself, and trying to answer some useful questions about the syndrome. It is available either as a hard copy from any of the coordinators, in the standard paper of your country, or as a .pdf electronic version which in theory should be printable by anyone. xlhnetwork: Currently xlhnetwork.org is the emerging web presence of the XLH Network organisation. Earlier manifestations of much of the content presented here were served from a desktop computer in Newcastle upon Tyne (as georgia.ncl.ac.uk or xlhnetwork.ncl.ac.uk) and these pages are archived for posterity in the private members space at xlhnetwork.org. X-rays: The process, invented by Roentgen, whereby an energy source produces X-rays to make an image. Because X-rays are such a powerful wave energy, they can travel right through material. If something is placed between the X-ray source and a photographic film, the X-rays will be slowed in proportion to the density of the material, and so a differential picture, particularly of bone, can be seen when the film is developed. We refer nowadays to the picture as the X-ray, when we might more appropriately call it an X-ray image. Last modified Aug 8, 2007 XLH is also known as X-Linked Hypophosphatemia (sometimes also spelled as hypophosphataemia), X-Linked Hypophosphatemic Rickets, Familial Hypophosphatemia, Vitamin D-Resistant Rickets (VDRR) Rickets and even Genetic Rickets. Its notable characteristics are bowed legs, short stature, poor teeth formation causing spotaneous dental abscesses, and low blood phosphorus levels.
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