EVIDENCE FOR ANTICIPATION IN AUTOSOMAL-DOMINANT LIMB-GIRDLE MUSCULAR-DYSTROPHY

Anticipation, an increase in severity or decrease in age of onset (AO) inherent in the transmission of the disease gene from affected parent to affected child, has been increasingly described in human disease. To assess anticipation in a large kindred in which autosomal dominant limb-girdle muscular dystrophy (LGMD1A) is segregating, age of disease onset was collected from patient interviews of affected family member s. A total of 25 parent-offspring pairs, in which the parents are thre e (3R), four (4R), or five (5R) generations removed from a common foun ding ancestor, were available for analysis. Life table analyses showed significant decreases in age at first reported symptoms in the offspr ing of the 3R (chi(2)=5.55, p=0.02) and 4R (chi(2)=7.81, p=0.005) pare nts. Pairwise analyses confirmed this decrease with a median decrease of 13 years in transmission to offspring from 3R parents and 18 years in transmission to offspring from 4R parents. The finding of anticipat ion in this pedigree suggests that the mutation in LGMD1A may be the r esult of the expansion of an unstable trinucleotide repeat.