|
We comply
with the HONcode standard for trustworthy health information: verify here. |
|
[The following paragraphs are a personal description of the multifaceted chain of events which result from the mutation in the X chromosome that causes XLH, based on several years of trying to understand the research and its implications.] What happens between the XLH genetic mutation in someone's chromosomes, and the rickets end result? There is a complicated chain of events between the gene and the disorder, and today we understand only part of the sequence between the mutated gene in XLH and low phosphorus in the blood. Everyone with XLH has hypophosphatemia, but some people with XLH may not even know they have it, as they may be symptom-free. These events are biochemical in nature, and so we can't see directly what's happening. Members of the XLH Network have access to more detailed information on the latest science, but these notes provide an overview of the biochemical machinery that is confused as a result of the mutation in the PHEX gene. Only after a careful analysis of many extended families were researchers able to pinpoint the gene, PHEX, that is affected in cases of X-Linked Familial Hypophosphatemia. Identification of this gene has opened many doors to research, but because the protein for which this gene codes seemed to be a processing enzyme, it was not immediately clear just what it actually does, since the biochemical component it processes hadn't yet been discovered. The mutation in PHEX is carried on either sperm or egg DNA, located on the X chromosome. It can be a new mutation that suddenly appears in egg or sperm, or it can be transmitted by a parent who has an affected gene already. In the new baby, every nucleated cell has a copy of the PHEX gene, but it directs the construction of its protein product only in certain specialized cells (bone cells and parathyroid gland). All boys with a mutated PHEX gene are affected, since they only have one X chromosome; it is still a puzzle why girls, who have one normal X chromosome, are often just as badly affected as boys. The reasons why XLH is dominant in girls, when half of their specialized cells should have normal PHEX, are still unknown. In some cases, the abnormal PHEX protein, resulting from the mutated PHEX gene, does not fold correctly, so that it cannot get to the outside of the cell where it would ordinarily carry out its function. In other cases, the functional capacity of the PHEX protein to do its job may be compromised. We know now that the PHEX protein is an important enzyme, called an endopeptidase, that is involved in the regulation or activation of phosphorus processing hormones. It sits conveniently on the surface of specialized bone cells so that when they need phosphorus, it can do its job, calling for more of this important bone mineral. In the absence of a functioning PHEX protein certain phosphorus processing hormones are not activated or regulated correctly, so they don't work appropriately. Normally, when the phosphorus processing hormones work appropriately, phosphorus is retrieved through the kidney cells when needed. Alternatively, other hormone molecules like 1,25 dihydroxy Vitamin D and Parathyroid Hormone (PTH) can call for more phosphorus in the blood. Normally, these hormones are presumed to increase the number of phosphorus transport molecules on the surface of kidney tubule cells, so that they can retrieve more phosphorus before it's lost in the urine. When hormones don't work correctly to increase the phosphorus transport, the phosphorus is not retrieved in the kidney, and so it leaks out of the body in the urine. People with XLH have high levels of phosphorus in their urine. When this happens, only low levels of phosphorus remain in the blood (hypophosphatemia). If the phosphorus-processing hormone works correctly, more alpha hydroxylase (another surface enzyme on kidney cells) appears, thereby processing Vitamin D to its active form, 1,25 dihydroxy Vitamin D. This active hormone may act directly on bone cells to induce bone formation, but it also is presumed to have an effect on phosphorus transport in the kidney cells. So when the alpha hydroxylase is not stimulated to appear by the phosphorus regulating hormones (as in the case of XLH when they have not been activated correctly by the PHEX endopeptidase because of a mutation), the beneficial effect of Vitamin D is not available to act on bones. This seems to be why XLH used to be called Vitamin D Resistant Rickets, and it also explains why people with XLH can often benefit from treatment with the active form of Vitamin D, called calcitriol, which is another name for 1,25 dihydroxyVitamin D. The endopeptidase PHEX may also act on some constituent in the biochemical control of PTH levels. PTH acts normally to regulate levels of calcium and phosphorus in the blood. High PTH levels tell the kidney to lose phosphorus (decreasing the number of phosphorus transport molecules) and retrieve calcium. Low levels tell the kidney to retrieve phosphorus (increasing the number of phosphorus transport molecules) and lose calcium. When this constituent is not processed properly, PTH can be over-expressed, increasing blood calcium levels and pushing phosphorus levels further down. Phosphorus continues to leak out of the kidney and calcium continues to be retrieved from wherever it can be found, generally from the bones. All of these hormones are interconnected in terms of their regulatory balance, and when one is compromised, the whole machinery can get out of kilter. With phosphorus levels low in the body, levels of the enzyme alkaline phosphatase are increased, as the body tries to eke out phosphorus from wherever it can get it. Phosphorus is stored by the body in various complexed organic forms of phosphate, and it's these complexes that alkaline phosphatase breaks down to liberate free phosphorus. If bone cells don't get enough phosphorus, then they can't build the calcium-phosphorus structure that is a crucial component of bone. So why do some people have low phosphate in their blood yet have few bone symptoms? Certain so-called modifier genes are expressed in different individuals. These genes are inherited separately from the inheritance of mutated PHEX and they code for proteins that somehow are very important in bone formation. What these genes might be and how their protein products interact in this complex biochemical machinery is, as yet, unknown, but it's hoped that a more comprehensive understanding of all of the genes in humans, through the Human Genome Project, will help to identify them. If an individual gets a particular modifier gene, or combination of genes, their bone cells may be able to produce bone even when phosphorus levels are low. Some (most) individuals who have not received certain modifier genes can expect to have abnormal bone formation when phosphorus is lacking. Some individuals who have received certain modifier genes, even though they have a mutated PHEX gene, may have normal bones. Much about modifier genes is not yet understood, yet their existence is hypothesized as an explanation as to why two individuals with the exact same genetic mutation can have dramatically different symptoms. Similar results can be seen in different mouse strains which grow better, or worse. Even though they have an identical mutation in the mouse Phex gene Abnormal bone or tooth formation are the first symptoms that most people can actually see, or appreciate, when PHEX is mutated, because their body's levels of phosphorus are too low for proper bone growth. Larry Winger, Ph.D., PGCE 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.
© 2002-2007,
The XLH Network Inc. |