The XLH Network GLOSSARY
Larry Winger, Ph.D., PGCE
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.
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
501(c)3: Tax status in the USA for a NonProfit
Organisation, this is a necessary requirement for all NPOs to
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Ilizarov: A special device used to hold bones in a sort of
external cage with rods stabilising the bones, while the bone knits
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,
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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 Mar 27, 2011
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 spontaneous
dental abscesses, and low blood phosphorus levels.
The XLH Network Inc.
The authors of this web site are not medical professionals, and this
information does not substitute for medical care. Information on
these pages is based on biomedical research, published in
peer-reviewed journals, and international research conferences.
Additionally, in some cases anecdotal information is provided by
subscribers of the F-HYPDRR group, a mailing list for The XLH Network
Inc. A complete web-site
is available. Please read our full