Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world

SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Pat ients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients deriv e their disease chromosome from another ancestor. In search of relationship s between patients from different countries, we haplotyped altogether 123 S BMA families from different parts of the world for two intragenic markers a nd 16 microsatellites spanning 25 cM around the AR gene. The fact that diff erent SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases oft en show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms a re and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patient s with defined ages at onset.