Familial motor neuron disease: differing penetrance in large pedigrees

It is likely that adult-onset motor neuron disease is inherited more frequently than has previously been believed. We have studied 9 families with familial motor neuron disease and have found apparently wide variation in penetrance. Only one has autosomal dominant inheritance with high penetrance and in this family the average age of onset is similar to that reported in reviews of familial motor neuron disease. The remaining families have a pattern consistent with autosomal dominant inheritance with diminished penetrance. The average ages of onset in these families are comparable with those in sporadic motor neuron disease. Low penetrance appears to be related to higher average age of disease onset because gene carriers have an increased likelihood of dying from other causes before developing motor neuron disease. When penetrance is low the family history may be unknown, causing affected individuals to be mistakenly regarded as having sporadic disease. We conclude that the incidence of familial motor neuron disease is likely to have been underestimated by the exclusion of apparently sporadic cases in which the familial disease has low penetrance. These results and conclusions imply that the lower average age of disease onset reported in familial motor neuron disease may be due to selective recognition of high penetrance families with lower average ages of onset.