Causes & Risk Factors Of Osteopetrosis
The bones of the average person regenerate at the same rate as the old bone disintegrates. However, there is a condition called osteopetrosis that can cause abnormally dense bones. This occurs when the new bone mass grows faster than the rate the old bone mass disappears. Even though osteopetrosis causes the bones to be denser, the bones will easily break from normal, everyday actions and the disease can cause many other problems in the body. There are three types of osteopetrosis: a severe form that presents itself at or near birth, a less severe form found in children, and the mildest form, which shows up in adolescents or adults. Osteopetrosis is generally caused by a gene breakdown in the body.
Gene Mutations
Osteopetrosis is caused by gene mutations of at least nine genes, which are responsible for the development and functioning of osteoclasts. Osteoclasts are cells that maintain the bone development process of 'out with the old, in with the new.' Gene mutations can either affect the way osteoclasts work or cause osteoclasts to be missing.
The gene mutation that causes the most cases of osteopetrosis is the mutation of the CLCN7 gene. It causes over seventy-five percent of autosomal dominant inheritance cases and almost fifteen percent of autosomal recessive inheritance. In the case of intermediate autosomal inheritance cases, one hundred percent of these cases are caused by the mutation of the CLCN7 gene. Another gene mutation that is a major player in osteopetrosis is the mutation of the TCIRG1 gene, which causes around half of the cases of autosomal recessive osteopetrosis.
Autosomal Dominant Inheritance
This version of osteopetrosis occurs when one of the parents' dominant genes is mutated. This parent is considered a carrier of the mutation. In this scenario, a couple will have a fifty-fifty chance of having a child with osteopetrosis. Autosomal dominant inheritance causes the mildest form of osteopetrosis that occurs in adults. In individuals with this form of the disease, they may not display any symptoms. If they do display symptoms, they include bone fractures, arthritis, scoliosis, or a bone infection called osteomyelitis.
As stated before, the CLCN7 gene causes the vast majority of autosomal dominant inheritance cases. There have been over fifty mutations of this gene that have been discovered to cause osteopetrosis. This gene indirectly regulates the chloride ion levels in osteoclasts. Chloride ion can be thought of like fuel for osteoclasts, and when delivery is impaired, it prevents osteoclasts from breaking down bone at the rate it should.
Autosomal Recessive Inheritance
This version of osteopetrosis occurs when both parents are carriers of the mutation in their recessive genes. This means they have a fifty percent chance of having a child that is a carrier of the mutated gene, and a twenty-five percent chance of having a child who doesn't have the mutated gene at all, and a twenty-five percent chance of having a child with osteopetrosis. Autosomal recessive inheritance causes the most severe form of the disease, which is usually found at birth. This form can cause a huge number of problems in the body, with many of them being life-threatening. For example, the increased bone density can negatively affect bone marrow, preventing it from creating new cells for the immune system. This can lead to abnormal bleeding and anemia due to a shortage of red blood cells.
In a previous section, it was stated the TCIRG1 gene is the leading cause of this type of osteopetrosis. The TCIRG1 gene can be thought of as a sort of instruction manual for making the a3 subunit part of a protein called the vacuolar H+-ATPase (V-ATPase). In the case of osteoclasts, V-ATPases pumps protons into a tightly sealed area between the bone surface and the surface of the osteoclasts. This regulates pH to a precise level that allows osteoplasts to break down old bone mass properly. Osteoplasts are highly sensitive and can be thrown out of whack from even the smallest change in pH, so a mutated TCIRG1 can cause one of the biggest malfunctions of osteoclasts, causing the most severe form of osteopetrosis.
X-Linked Recessive Inheritance
The X-linked recessive inheritance type of osteopetrosis is caused by a mutation of the IKBKG gene, which plays a significant role in controlling the body's immune responses as well as the prevention of apoptosis (self-destruction). This form of the disease usually presents itself at birth.
The X-linked recessive inheritance type of osteopetrosis is also known as OL-EDA-ID. It is caused by a mutation in an X-linked gene, which means the mutated gene is inherited from one or both parents. In men, they only have one X-chromosome, so if the gene is mutated, there is no back up to replace it. This form of the disease is less common in women since they have two X-chromosomes. If one of the genes is mutated, they would still have a good one that isn't mutated, but they would be carriers and can pass the mutated gene on to their children. The chance a baby will inherit the disease largely depends on the gender of the child and which parent, if any, has the mutation.
Affected Populations
Osteopetrosis is a rare condition altogether, but when it does occur it can affect anyone at any age. Autosomal dominant osteopetrosis statistically occurs in one out of twenty thousand individuals. Autosomal recessive osteopetrosis occurs in around one out of 250,000 births. The other types are scarce. In general, affected populations of osteopetrosis is tiny.
Men may have a higher chance of getting the autosomal recessive type and the X-linked recessive type, but overall men and women are equally affected by osteopetrosis. There is no cure for the disease, but if it is caught in early stages, it can sometimes be treated, so a person's quality of life isn't severely affected.