Disorders Linked to Advancing Paternal Age Begin to Increase Rapidly age 33-35

"It makes sense that the mutations causing these diseases would occur more frequently in older men, and indeed that's what we saw for Apert syndrome," says Ethylin Jabs, M.D., director of the Center for Craniofacial Development and Disorders at Johns Hopkins.

Importantly, disorders linked to advancing paternal age begin to increase rapidly at about the same time as maternal risks increase -- age 33 to 35. Until now, the only evidence for paternal age effects has come from determining how many children with these diseases are born to fathers of various ages.

To obtain the first genetic explanation for these effects, the scientists studied sperm from about 60 men of various ages and looked for two genetic changes responsible for 99 percent of the cases of Apert syndrome. They found that men over 50 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations were not more common in blood samples as men aged.

The scientists say it's likely that the number of cell divisions that go into making a sperm plays a large role in the link between Apert syndrome and paternal age, and represents a fundamental difference between how aging egg and sperm can impact the health of a child.

"In the men we studied, these mutations had not been inherited, but rather collected over time in the reservoir of primitive cells that become sperm," says first author Rivka Glaser, a graduate student in human genetics at the Johns Hopkins School of Medicine.

Cells that mature into eggs are essentially frozen in time from puberty until the time the egg is signaled to develop. Because of the stage at which they are "frozen," the most likely error in an egg is to have an abnormal partitioning of chromosomes, producing an egg with an extra copy or a missing copy, Glaser says. For example, in Down syndrome, an extra copy of chromosome 21 is inherited from the mother.

Sperm, on the other hand, are continually produced throughout a male's lifetime from a reservoir of primitive cells. These primitive cells, like other kinds of so-called stem cells, can either replicate themselves or take a step closer to becoming a sperm, a process called differentiation. All told, these cells divide every 21 days after puberty, and at each cell division the opportunity exists for an error in copying the DNA.

"Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available," says Jabs, also a professor of pediatrics. Their study showed that "high levels" of mutations among men who had no children with Apert syndrome amounted to roughly 3 sperm with the mutation among 100,000 sperm.

If an error is made in any of the steps toward becoming a sperm, the only cells affected are the resulting sperm for that batch. However, if an error appears in a primitive cell as it replicates itself and the mistake isn't fixed, the mutation will continue to be passed on to all of its progeny, including subsequent primitive cells and other batches of semen.

As men age, more of these primitive cells have collected mutations that cause Apert syndrome, leading to more sperm with the mutations in each batch of semen, the scientists suggest. The risk of having a child with Apert is about six times higher for a man age 52 than for someone who's 27.


Authors on the study are Glaser, Jabs, and Rebecca Schulman, of Johns Hopkins School of Medicine, and Karl Broman, of the Johns Hopkins Bloomberg School of Public Health.


Note: This story has been adapted from a news release issued by Johns Hopkins Medical Institutions.