Men With MS Twice as Likely to Pass it On to Kids

ROCHESTER, Minn., July 24 -- Although women are more frequently affected with multiple sclerosis, men who have MS are twice as likely to pass it on to their offspring as are women with the disease, according to researchers.

Women are two to three times more likely than men to get MS, suggesting that men have an intrinsic physiologic resistance to it. If this is true, men who buck the odds and develop MS anyway may have a strong genetic predisposition to getting it that they pass on to the next generation, wrote neurologist Orhun H. Kantarci, M.D., of the Mayo Clinic here, and colleagues.

"Due to the apparent excess of intrinsic susceptibility of women to MS, men with MS may require a greater number of risk factors to overcome their resistance to MS relative to women," the authors wrote in the July 24 issue of Neurology.

"If this difference were due to genetic rather than environmental factors, men would need a greater number of or more potent susceptibility genes than women and would be predicted to transmit the disease more often to their children," they added. "This phenomenon is known as the Carter effect and has been explained by a multifactorial threshold model with sex dimorphism for liability."

The authors investigated whether the effect, first described in pyloric stenosis inheritance by British geneticist Cedric O. Carter, Ph.D., in the early 1960s, might also apply to MS, where there is a lopsided gender-based distribution of prevalence.

"The hypothesis of the study is that men are more resistant to MS, so they need stronger or a larger number of genes in order to develop MS, and then pass these genes to their children," Dr. Kantarci said,

The Mayo investigators, along with colleagues at the University of California at San Francisco and at Berkeley, and Kaiser Permanente in Oakland, California, started with a pool of 3,598 people in 206 multiplex pedigrees and narrowed in on 197 families of interest, in which there were 441 children (45 with definite MS) of a father or mother affected with MS.

The researches compared transmission of MS from affected men with transmission from affected women, and found that the fathers with MS transmitted the disease to their children more often. In all, M8 was transmitted to 18 children of men with MS, with 99 children unaffected. In contrast, 27 children of women with the disease had definite MS, and 296 avoided transmission. The odds ratio for MS transmission from fathers vs. mothers was 1.99 (95% confidence interval, 1.05 - 3.77, P=0.032).

"Adjusting for both the sex of the affected child and multiple transmissions from a single affected parent, the sex of the affected parent remained as an independent risk factor for transmission of MS to children, fathers transmitting more often than mothers (P=0.036; OR: 2.21, 95% CI, 1.05-4.63)," the authors wrote.

The investigators noted that because women with MS have fewer children than women who don't have the disease, it is not possible to determine whether the Carter effect is related to over-transmission of genetic susceptibility due to some factor intrinsic among men, or under-transmission among women.

"The magnitude of the Carter effect in our study was similar to that observed in the original description of this phenomenon in pyloric stenosis, which predominates in men and for which there is a 2.2-fold excess of maternal relative to paternal transmission. In our study, as in the results from analysis of pyloric stenosis, the Carter effect was independent of the sex of the child," the noted.

The investigators cautioned that their results should not be factored into genetic counseling of men with MS who are considering fathering children, because the additional risk of transmission is not much greater than the already elevated (~20-fold) risk associated with MS transmission in general.

The findings shouldn't change how men with MS are counseled about the risk to their offspring, wrote the researchers. The risk of having MS if a person has an affected parent is increased by about 20-fold compared to not having an affected parent; the additional risk by virtue of having an affected father is not sufficient to change patient counseling practices, they added.

"The overtransmission by men is primarily of interest to scientists studying the mechanisms of genetic transmission of MS susceptibility, and may indicate that nontraditional, or so-called epigenetic factors, play some role in the transmission of MS," Dr. Kantarci said.