MS May Be Family Matter with Differing Clinical Course

CAMBRIDGE, England, Jan. 29 -- If multiple sclerosis strikes two or members of a family, the age of onset is likely to be similar, although disease severity may differ, an international research team has found.

In a study of more than 1,000 families in which at least two first-degree relatives developed MS, investigators found that there was concordance for age at disease onset between siblings and parent-child pairs, but varying degrees of clinical course.

"Familial factors do not significantly affect eventual disease severity," they wrote in the Jan. 29 issue of Neurology. "However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing-remitting disease."

"We've known for some time that family influence plays a role in whether you are susceptible to MS, but it has not been clear whether your family influence affects the course of the disease," said Alastair Compston, Ph.D., of the University of Cambridge, and colleagues.

The familial influence is most likely to be genetic, the authors speculated, but they also noted that environmental factors could affect the phenotypic expression. Evidence for this comes from their finding that among affected siblings but not parent-child pairs, the year of onset was similar, suggesting that some factors in the shared environment could have contributed to MS.

"Siblings may have less genetic sharing than must occur between parents and their children, but they are more likely to share environmental exposure during development," the investigators wrote.

The authors looked at data on 1,083 families with two or more first-degree relatives with MS. Specifically, they focused on concordance for the age of onset, clinical course, and disease severity, and looked for transmission patterns of clinical features among affected parent-child pairs.

They found that for all families there was concordance for age at onset (correlation coefficient 0.14; P < 0.001). In addition, when they considered affected siblings and parent-child pairs separately, they again found concordance for age at onset (correlation coefficient 0.15; P <0.001 for siblings, and 0.12; P =0.03 for parent-child pairs).

But when they looked at year of onset, however, they found concordance among affected siblings (correlation coefficient 0.18; P <0.001) but not among affect parent-child pairs (correlation coefficient 0.08; P=0.15).

When they turned their attention to the clinical course of MS, they found it to be similar among siblings (kappa 0.12; P <0.001) but not between affected parents and their children (kappa -0.04; P=0.09).

"This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease," the investigators wrote.

When they considered disease severity, they found no concordance within any of the combinations examined, either among all families analyzed together (correlation coefficient, 0.02, P =0.53), affected siblings (correlation coefficient 0.02, P=0.61) or affected parent-child pairs (correlation coefficient 0.02, P =0.69).

There were no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs, the authors did not find evidence for anticipation or effects of genetic loading.

Their findings suggest that genetic counseling of patients and studies of families with MS should be centered on features such as the clinical course of the disease rather than disease severity.

"These data have significant implications for the counseling of patients with affected family members," they wrote. "They indicate that the analysis of genetic studies should be stratified (according to clinical course rather than severity) in order to separate effects that increase susceptibility to MS from those that determine the pattern of tissue injury and its clinical expression as disease progression. The independent effect on disease progression further supports the concept that the natural history of MS depends on a complex interplay of inflammatory activity in the CNS and axon degeneration. factors (which are effective in childhood/ teenage years) in determining course concordance."