Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles.
Friedreich ataxia patients are homozygous for expanded GAA triplet-repeats containing 66 to 1,700 triplets. We report two patients with delayed-onset, hyperreflexia and gradually progressive disease. Both were heterozygous for large expansions and also carried alleles with 44 and 66 triplet-repeats, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with >/=66 triplet-repeats, constituting a plausible mechanism for their mild phenotype. A sibling with a stable GAA-37 allele and a large expansion was clinically normal. Instability of borderline alleles confers a risk for Friedreich ataxia, and the range of pathogenic alleles is broader than previously recognized.
Sharma
Rajesh
R
Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
De Biase
Irene
I
Gómez
Mariluz
M
Delatycki
Martin B
MB
Ashizawa
Tetsuo
T
Bidichandani
Sanjay I
SI
D000483:Alleles; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008875:Middle Aged; D018911:Trinucleotide Repeats / Q000235:genetics*