Pycnodysostosis (cont.)

Pycnodysostosis is a rare disease so that, if there is no family history of the disease, the risk for a child to have pycnodysostosis is very low.

However, with a inbred (consanguineous) union, the risk of pycnodysostosis rises a little. This means that if one parent carries a rare gene like that for pycnodysostosis, the chance that a mate of theirs who is actually related also carries the same rare gene is increased compared to an unrelated mate.

In a family with a child with pycnodysostosis, the risks are much higher. The parents of a child with pycnodysostosis have no signs of the disease themselves but they each carry a single edition of the pycnodysostosis gene and, with a given pregnancy, each has a half chance of transmitting the pycnodysostosis gene (versus the normal paired gene). It is like tossing a coin. The chance for the child to have pycnodysostosis is one-half (from one parent) times one-half (from the other parent). The overall risk of pycnodysostosis in the offspring of parents carrying the gene is, therefore, one-quarter (25%). Just as coins have no memory of a prior toss, the 25% odds of having a pycnodysostosis child apply to every pregnancy conceived together by these parents, irrespective of the status of any of their other children.

In 1995, the gene for pycnodysostosis was first charted by Gelb and associates. It was found to travel preferentially with gene markers known to be in chromosome region 1q21. (This tendency for genes to travel together is termed linkage). Once the location of the pycnodysostosis gene was identified by linkage analysis, genes in that region that seemed logical candidates were seriously scrutinized. Among them was cathepsin K, which is active in bone. Cathepsin K qualified as a "candidate gene."

In 1996, patients with pycnodysostosis were shown by Gelb and coworkers consistently to have mutational changes in the gene for cathepsin K. The defective cathepsin K gene was thus demonstrated to be the gene responsible for pycnodysostosis. Pycnodysostosis is now clearly recognized as being due to cathepsin K deficiency.

What does cathepsin K normally do? Cathepsin K is an enzyme (a catalyst for a reaction of body metabolism) of the type called a cysteine protease. This protease is important in cells of normal bone (osteoclasts) that are responsible for bone reabsorption (or resorption). It is thought that osteoclasts in patients with pycnodysostosis are hampered by a lack of cathepsin K and cannot adequately reabsorb that component of bone called the organic matrix. (This process is essential for normal bone maintenance; a process referred to as remodeling). Because of this inadequate resorption, the bones in pycnodysostosis are abnormally dense and brittle.